A new paper appearing in the journal Cancer reports that men treated for testicular cancer at a public safety net hospital (Parkland Memorial Hospital) and at an academic tertiary care center (UT Southwestern Medical Center) had the same outcomes.

Aditya Bagrodia, M.D.

“It was really encouraging to verify that these men are being treated based on their disease characteristics, not on who they are or what hospital they’re being treated at,” says study leader Aditya Bagrodia, M.D., an assistant professor of urology at UT Southwestern. “It doesn’t – and shouldn’t – matter if you’re Black, white, or Hispanic, rich or poor, insured or uninsured.”

Sociodemographic factors that include race, income, health insurance status, immigration status, and education have all been shown to play a role in the detection, treatment, and survivorship of many types of cancer. Testicular cancer, which affects an estimated 9,000 men a year in the United States, is typically diagnosed when patients are in their 30s. 

“These young men often get embarrassed about their symptoms, and then they delay coming in to be seen for other reasons – they can’t miss work, they don’t have insurance, they’re worried about being deported,” says Bagrodia, a member of UTSW’s Harold C. Simmons Comprehensive Cancer Center. Moreover, he says, men from lower socioeconomic groups tend to be treated at smaller safety net hospitals, where doctors might not see many cases of testicular cancer or be as familiar with current treatment guidelines as are physicians at large academic hospitals.

Bagrodia and his colleagues who treat testicular cancer at UT Southwestern also treat patients with testicular cancer at Parkland Memorial Hospital, the public hospital in Dallas County. During multidisciplinary team meetings, the group of doctors – including urologists, oncologists, radiologists, radiation oncologists, and pathologists – review patient cases from both locations simultaneously. The same clinicians rotate between hospitals to provide in-person care and surgeries.

The new study followed 201 patients diagnosed with testicular cancer between 2006 and 2018; 106 were treated at Parkland and 95 at UT Southwestern. On average, the Parkland patients were younger (29 versus 33), more likely to be Hispanic (79 percent versus 11 percent), less likely to be insured (20 percent versus 88 percent), more likely to first be seen in the emergency department rather than by a primary care physician (76 percent versus 8 percent), and had been experiencing symptoms more than twice as long before seeking care (65 days versus 31 days).

Despite these differences, the study showed that the groups were treated similarly. Men at Parkland received an orchiectomy – surgical removal of the testicle that’s the first-line treatment for testicular cancer – within an average of one day after diagnosis. This average was four days for UTSW patients. To overcome some of the socioeconomic barriers at Parkland, the team rapidly mobilizes relevant physicians and social workers to make sure the comprehensive needs of the patients are met. And after the initial orchiectomy, patients at Parkland and UTSW were equally likely to receive other chemotherapy and surgery treatments, depending on the stage of their tumor.

“If you have metastatic testicular cancer that isn’t fully treated by chemotherapy, the standard of care is to perform a very complex surgery,” says Bagrodia. “A lot of smaller hospitals – whether community or safety net – don’t do that because they don’t have experience with the surgery. So we were happy to show that our patients get that surgery at equal rates between hospitals.”

There was no statistical difference between the recurrence rate of cancer in patients initially diagnosed with early stage disease: 4.7 percent of patients at Parkland and 6.3 percent of patients at UTSW experienced recurrence. Four patients at Parkland (4 percent) died during the time period, while none at UTSW died, but the difference was not statistically attributable to the hospital, instead linked to the stage of cancer when patients were diagnosed.

Some factors still differed between the patient groups. Rates of sperm banking and testicular prosthesis (both expensive options for men going through testicular cancer treatment) were lower at Parkland. Compliance rates among men – how likely they were to make follow-up appointments – also were lower in the Parkland group.

Bagrodia says the new data underscore how much of a difference it can make to have experienced clinicians – who see a high volume of rare cases – working at safety net hospitals and with community hospitals that would typically have less experience with these conditions. Many major academic medical centers already have affiliated safety net hospitals, he points out, but there are ways to expand this idea even further.

“Whether it’s for cancer, refractory diabetes, or heart failure, I think having mechanisms to make sure you have the right expertise, and committed clinicians, makes a big difference to patients,” says Bagrodia, who is also a Dedman Family Scholar in Clinical Care.

Other UTSW researchers who contributed to this study were Nathan Chertack, Rashed Ghandour, Nirmish Singla, Yuval Freifeld, Ryan Hutchinson, Kevin Courtney, Alex Bowman, Waddah Arafat, Xiaosong Meng, Joseph Moore, Ahmet Aydin, Arthur Sagalowsky, Vitaly Margulis, Yair Lotan, and Solomon Woldu.

Courtney reports personal fees from Exelixis and Janssen and grants from Astellas outside the submitted work. Bowman reports personal fees from Foundation Medicine Inc, and Dendreon Pharmaceuticals LLC outside the submitted work.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – July 6, 2020 – UT Southwestern researchers have identified vast webs of small snippets of the genome that interact with each other and with genes to promote prostate cancer. Their findings, published June 22 in the Journal of Clinical Investigation, could lead to new ways to treat the most common type of malignancy in American men other than skin cancer.

Ram S. Mani, Ph.D.

Research over the past few decades has shown that genetic mutations trigger and encourage the growth and spread of many cancer types. However, prostate cancers typically have relatively few of these mutations, explains study leader Ram S. Mani, Ph.D., an assistant professor in the departments of pathology and urology at UTSW.

Instead, how prostate cancers regulate gene expression – which genes are turned off and on, and to what extent – tends to go awry. What causes this aberrant gene regulation has been a mystery. Although previous research had identified pieces of DNA throughout the genome that appeared to be connected to prostate cancer, many of these pieces weren’t genes, so their role was unclear.

To help answer these questions, Mani and his colleagues focused on genetic enhancers, short pieces of DNA that help encourage genes to make proteins. However, explains Mani, it’s not as simple as a one-to-one ratio of enhancer per gene target. One enhancer may target several genes, or multiple enhancers might target a single gene. Additionally, each enhancer could be up to a million base pairs away from its gene target on the same chromosome – a significant distance that makes it difficult to link enhancers with their genes.

To pair enhancers to their gene targets in prostate cancer, Mani and his team used a technique called ChIA-PET, short for chromatin interaction analysis by paired-end tag sequencing. This technique maps associations of particular proteins with DNA throughout the genome.

The researchers used ChIA-PET to find DNA targeted by a protein called RNA polymerase II, looking for differences between benign prostate cells and prostate cancer cells. RNA polymerase II not only binds to genes to start transcription – the process in which cells use the instructions in DNA to make RNA – but also enhancers for these genes. “When this technique identifies a gene, it also identifies all the enhancers that target that gene at the same time,” says Mani, a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.

Using sophisticated analytical techniques, the scientists sorted out each of these complicated interactions unique to prostate cancer cells, finding vast hubs of enhancers that interact not just with genes but also with each other. They found that many enhancers interacted with tens of other enhancers or genes. These interactions explain the abnormal expression of several key prostate cancer genes, such as the androgen receptor gene that’s over-expressed in many subtypes of prostate cancer and the oncogene MYC, which plays a role in many cancer types. Further investigation identified some “grammar rules” for enhancers in prostate cancer, grouping genes and enhancers into clusters that strictly interact with each other.

Mani notes that finding these hubs of enhancers and their genes also helps explain the long-standing mystery of the short pieces of DNA connected to prostate cancer that are scattered throughout the genome. This new research suggests that many of these pieces are enhancers.

Manipulating the interaction between these enhancers and their gene targets could eventually be used as a strategy to slow or stop prostate cancer spread or potentially prevent it from developing at all, he adds. “These findings open up a whole new field focused on enhancers,” he says, “that could lead to novel prostate cancer treatments.”

Susmita G. Ramanand and Jiapei Yuan from UTSW, and Yong Chen from UT Dallas are co-first authors in the study. Mani and Michael Zhang (UT Dallas) are the corresponding authors. Other UTSW researchers who contributed to this study include GuemHee Baek, Mohammed Kanchwala, Yunpeng Gao, Adam Aslam, Nida Safdar, Xiaowei Zhan, Ganesh V. Raj, and Chao Xing.

This study was funded by the NIH Pathway to Independence (PI) Award (R00CA160640), the NIH/NCI R01 grant (R01CA245294), the CPRIT Individual

Investigator Research Award (RP190454), the U.S. Department of Defense Prostate

Cancer Research Program (PCRP) – Impact Award (W81XWH-17-1-0675), Kidney

Cancer Specialized Programs of Research Excellence (SPORE) Career Enhancement Program (CEP) award (P50CA196516), and UT Southwestern startup funds.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Sean Morrison, Ph.D., Kim Orth, Ph.D., Michael Rosen, Ph.D., and Sandra Schmid, Ph.D., were selected by their peers in recognition of distinguished and continuing achievements in original research. With their elections, UT Southwestern has 25 members of the National Academy of Sciences among its faculty, more than any other institution in Texas.

“Election to the prestigious National Academy of Sciences recognizes the pioneering contributions these scientists have made to advance our understanding of basic cellular function and molecular processes with application to addressing a broad spectrum of unmet medical needs including cancer and treatments for bacterial infections,” said Daniel K. Podolsky, M.D., President of UT Southwestern Medical Center. “Their election enriches the National Academy of Sciences’ efforts to provide data and advice on the nation’s most critical issues in science, health, and medicine.”

The UT Southwestern scientists, including three Howard Hughes Medical Institute Investigators, are among 120 U.S. and 26 nonvoting foreign members elected this year. New members will be formally inducted at next year’s event.

“This important recognition by their peers reflects the breadth and quality of research underway at UT Southwestern, and serves as inspiration for new generations of trainees and scientists to carry on the tradition of discovery that is the hallmark of distinguished academic medical centers,” said W. P. Andrew Lee, M.D., Executive Vice President for Academic Affairs, Provost and Dean of UT Southwestern Medical School.

The UT Southwestern scientists elected this year are:

Sean Morrison, Ph.D.

Sean Morrison, Director of the Children’s Medical Center Research Institute (CRI) at UT Southwestern and Professor of Pediatrics

Morrison, who joined UT Southwestern in 2011 to direct the Children’s Medical Center Research Institute at UT Southwestern, has contributed trailblazing discoveries in the fields of stem cell biology and cancer. The Morrison laboratory studies the mechanisms that maintain stem cell function in adult tissues and the ways in which cancer cells hijack these mechanisms to enable the formation of tumors. His achievements include pioneering new methods to purify stem cells from multiple tissues and discovering molecular mechanisms that allow stem cells to persist throughout life and regenerate tissues after injury.

A Howard Hughes Medical Institute (HHMI) Investigator, he was elected to the National Academy of Medicine (NAM) in 2018. He majored in biology and chemistry at Dalhousie University in Canada, received his doctorate in immunology from Stanford University, and completed a postdoctoral fellowship in neurobiology at Caltech. Before coming to UT Southwestern, he was a professor at the University of Michigan, where he directed its Center for Stem Cell Biology. He is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and member of the Harold C. Simmons Comprehensive Cancer Center.

Kim Orth, Ph.D.

Kim Orth, Professor of Molecular Biology and Biochemistry

Orth’s discoveries have advanced the understanding of the basic biochemical mechanisms underlying many bacterial infections by identifying new ways that invading bacteria hijack and deregulate a cell’s signaling systems. The Orth lab studies how pathogens manipulate host cells for their own benefit, providing insights into bacteria that cause foodborne illnesses.

Also an HHMI Investigator, Orth earned her undergraduate degree at Texas A&M University. She received her Ph.D. in biochemistry and molecular biology from UT Southwestern, and joined the University’s faculty as an endowed scholar in 2001. She has received many honors, including a Burroughs Wellcome Investigator in Pathogenesis of Infectious Disease in 2006, the Norman Hackerman Award in Chemical Research from The Welch Foundation in 2010, the Edith and Peter O’Donnell Award in 2011 from The Academy of Medicine, Engineering and Science of Texas, the American Society for Biochemistry and Molecular Biology (ASBMB) Young Investigator Award in 2012 and the ASBMB Merck Award in 2018.

Mike Rosen, Ph.D.

Mike Rosen, Chair of Biophysics and Professor in the Cecil H. and Ida Green Comprehensive Center for Molecular, Computational, and Systems Biology

Rosen investigates how cells compartmentalize processes without the use of membranes. These phase-separated structures are involved in many cellular mechanisms in health and disease, and represent a fundamental process by which proteins function within the cell. His lab uses biophysical techniques to understand the formation, regulation, and functions of biomolecular condensates – cellular compartments that arise much like the way oil and water droplets separate in a flask.

Rosen, who joined UTSW in 2001, received undergraduate degrees in chemistry and chemical engineering from the University of Michigan, then spent a year as a Winston Churchill Foundation Scholar at the University of Cambridge before earning his Ph.D. from Harvard University in 1993. In addition to being an HHMI Investigator, his many honors include receiving an Edith and Peter O’Donnell Award from The Academy of Medicine, Engineering and Science of Texas in 2006, becoming the University’s first Allen Distinguished Investigator in 2018, and winning the 2020 Wiley Prize in Biomedical Sciences.

Sandra Schmid, Ph.D.

Sandra Schmid, Professor and Chair of Cell Biology

Schmid is internationally recognized for her research on endocytosis – how cells take in nutrients and other molecules. She studies the molecular mechanisms and regulation underlying clathrin-mediated endocytosis, the major pathway for uptake into the cell. A pioneer in defining the GTPase dynamin as a catalyst of membrane fission, Dr. Schmid recently discovered isoform-specific functions of dynamin that are activated in cancer cells.

Schmid, who joined UT Southwestern in 2012, majored in cell biology at the University of British Columbia and received her doctorate in biochemistry from Stanford University. After a postdoctoral fellowship at Yale University, she moved to The Scripps Research Institute, serving as Chair of the Department of Cell Biology before joining UT Southwestern in 2012. She is a former President of the American Society for Cell Biology and was elected to the American Academy of Arts and Sciences in 2015. Her numerous honors include the American Society of Biochemistry and Molecular Biology’s William C. Rose Award and the Biophysical Society’s Sir Bernard Katz Award. In May, she will join the Chan-Zuckerberg Biohub in San Francisco as its inaugural Chief Scientific Officer.

Other UT Southwestern faculty who are members of the NAS and the years they were elected are: Michael Brown, M.D., 1980; Joseph Goldstein, M.D., 1980; Jean Wilson, M.D., 1983; Jonathan Uhr, M.D., 1984; Roger Unger, M.D., 1986; Steven McKnight, Ph.D., 1992; Ellen Vitetta, Ph.D., 1994; Johann Deisenhofer, Ph.D., 1997; Eric Olson, Ph.D., 2000; Joseph Takahashi, Ph.D., 2003; Masashi Yanagisawa, M.D., Ph.D., 2003; Melanie Cobb, Ph.D., 2006; David Russell, Ph.D., 2006; Helen Hobbs, M.D., 2007; Bruce Beutler, M.D., 2008; David Mangelsdorf, Ph.D., 2008; Luis Parada, Ph.D., 2011; Beth Levine, M.D., 2013; Zhijian “James” Chen, Ph.D., 2014; Lora Hooper, Ph.D., and Steven Kliewer, Ph.D., both in 2015.

Lee holds the Atticus James Gill, M.D. Chair in Medical Science.

Morrison holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children's Research Institute (CRI) at UT Southwestern and the Mary McDermott Cook Chair in Pediatric Genetics.

Orth holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research.

Podolsky holds the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration, and the Doris and Bryan Wildenthal Distinguished Chair in Medical Science.

Rosen holds the Mar Nell and F. Andrew Bell Distinguished Chair in Biochemistry.

Schmid holds the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology.

About CRI

Children’s Medical Center Research Institute at UT Southwestern is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas, the flagship hospital of Children’s Health. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology, and metabolism. For more information, visit: cri.utsw.edu. To support CRI, visit: cri.utsw.edu/support/.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Dr. Wen Jiang

The immune system has two branches: innate immunity, an evolutionarily older system that continually scans the body and removes foreign invaders such as bacteria or viruses often by “eating” them in a process called phagocytosis; and adaptive immunity, which provides a more targeted and stronger response based on memory acquired from previous exposure to a pathogen. These branches overlap somewhat: For example, the innate immune system trains the adaptive one on where to focus its efforts using the potential pathogens it encounters.

In recent years, researchers have had considerable success in harnessing the immune system to fight some cancers, developing several drugs that have vastly extended survival. However, explains study leader Wen Jiang, M.D., Ph.D., assistant professor of radiation oncology at UT Southwestern Medical Center, these efforts have mostly focused on adaptive immunity.

Some pharmaceuticals in development aim to boost the innate immune system’s action against cancer by blocking CD47, a protein that many cancer cells display on their surfaces that functions as a “don’t eat me” signal. Glioblastoma (GBM) – the most common primary central nervous system malignancy in adults and a cancer that Jiang frequently treats in clinic – often displays substantially elevated amounts of CD47 on its tumor cell surfaces, with higher amounts generally suggesting worse outcomes for patients. But these drugs have had mixed results in clinical trials, Jiang says; although they’ve shown promise for blood cancers, such as leukemias, their performance for solid tumors has been disappointing.

Seeking to boost survival for GBM patients, Jiang and his colleagues searched for ways to encourage innate immune cells to eat GBM cells, which not only destroys these cells directly but also helps train the adaptive immune system to continue the attack.

The researchers first tested how well CD47 monoclonal antibodies – proteins that stick to and mask CD47 – work on GBM cells grown with innate immune cells called phagocytes in petri dishes. Although this agent did boost the phagocytes’ consumption of the cancer cells, “the activity wasn’t too striking,” Jiang says. “It was nothing to brag about.”

Next, he and his colleagues tested increasing the cancer cells’ “eat me” signal by administering a drug called temozolomide (TMZ), a decade-old pharmaceutical that’s a mainstay for most GBM treatment protocols. The drug activates stress responses in cancer cells that make the immune system more likely to eliminate them. Although this drug also increased phagocyte consumption of the cancer cells, these results were also lackluster, says Jiang, also a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.

Jiang and his colleagues then reasoned that because these two pharmaceuticals operate using completely different mechanisms, they might get more of a response combined. Sure enough, when they administered both agents together, they appeared to work in synergy, prompting phagocytes to eat many more GBM cells than either drug alone. Further experiments showed that once phagocytes had eaten their cancerous prey, they used components from these tumor cells to prime the immune system’s T cells – the primary adaptive immune cells that fight cancers – to kill more GBM cells.

When the researchers tested this combination therapy in a mouse model of GBM, it successfully shrank tumors and extended life. However, in time, the tumor cells developed a different way to evade the immune system by boosting their production of a protein called PD-L1, which shields them from T cell attack. Thwarting this move, the researchers added an antibody against this protein called anti-PD-1. Together, this three-part regimen – anti-CD47 antibodies, TMZ, and anti-PD-1 antibodies – dramatically extended survival. About 55 percent of these animals did not die over the course of the study, a scenario akin to long-term remission in patients, Jiang says. He and his colleagues hope to test this approach in humans soon in a clinical trial, he adds.

“If a new therapy extends survival by even one to two months, it’s considered a blockbuster drug,” Jiang says. “Here, we’re talking potentially about a significant proportion of patients who could be cured. Bridging the innate and adaptive immune systems could prove to be a major advance for GBM.”

Other UTSW researchers who contributed to this study include Yifan Wang, Zhaogang Yang, Mingming Yang, and Weiye Deng.

This research was supported by grants from the National Institute of Neurological Disorders and Stroke Grant R01 NS104315, the Cancer Prevention and Research Institute of Texas RR180017, the American Brain Tumor Association DG1900021, the National Cancer Institute K08 CA241070, and the Preston A. Wells, Jr. Endowment at the University of Florida.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – April 20, 2020 – Immunotherapy drugs that target a protein called programmed death ligand 1 (PD-L1) on the surface of cancer cells have quickly become a mainstay to treat many forms of cancer, often with dramatic results. But exactly how cancer cells turn on this protein was not completely understood. New research by UT Southwestern Medical Center scientists, published online today in Nature Cancer, lays out key pieces of this mechanism. The findings could offer new targets that may further improve how well current cancer immunotherapies work.

Kathryn A. O'Donnell, Ph.D.

Nearly a decade ago, the Food and Drug Administration approved the first drug in a new class of pharmaceuticals called checkpoint inhibitors. These drugs reverse a cloaking mechanism that many types of cancer cells use to avoid being discovered by the immune system, allowing cancer-fighting immune cells called T cells to attack tumors. Blocking the interaction between one of these cloaking proteins, PD-L1, and its receptor on T cell surfaces forms the basis of several pharmaceuticals currently on the market, including nivolumab, pembrolizumab, and atezolizumab.

Although these drugs have made headway in several types of cancer, notably non-small cell lung cancer (NSCLC) – the leading cause of cancer-associated deaths worldwide – how cancer cells overexpress PD-L1 to shield themselves from immune system attack has been a mystery.

To help answer that question, Kathryn A. O’Donnell, Ph.D., an associate professor of molecular biology at UT Southwestern, and her colleagues started by looking broadly at which genes might serve as regulators for manufacturing PD-L1 in NSCLC. Using CRISPR, which acts as molecular scissors to remove specific genes, the researchers individually removed 19,000 genes in a human NSCLC cell line. Then, they used a fluorescent PD-L1 antibody to see which cells had more or less PD-L1. This allowed them to identify genes that normally encourage PD-L1 production, or positive regulators, and those that stymie PD-L1 production, or negative regulators. 

Surprisingly, they found that a potent inhibitor for the manufacture of PD-L1 is a gene called UROD, which plays a key role in producing heme. This iron-containing chemical is pivotal for carrying oxygen in red blood cells, but is also broadly necessary in other cells for maintaining normal balance, or homeostasis. To confirm these findings, the researchers used other methods to remove heme in NSCLC cells, which also triggered the lung cancer cells to make more PD-L1 protein. When tumors in which UROD was depleted were implanted into healthy mice, they grew significantly faster than those in mice lacking working immune systems. These findings suggest that by activating PD-L1 production, this gene accelerates cancer by suppressing anti-tumor immunity, O’Donnell says.

Further experiments showed that hampering heme production turned on a pathway called the integrated stress response (ISR) that cells broadly use to deal with diverse stress conditions such as low oxygen, toxins, or nutrient starvation. Under these conditions, NSCLC cells used a specialized mechanism, relying on a protein known as eIF5B, to increase PD-L1 production. Just stimulating cells with this single protein could turn up PD-L1 production, the researchers found, even without tampering with heme synthesis.

By examining a database of genes that are over- or underproduced in various cancers, O’Donnell and her team found that the gene encoding eIF5B is frequently overproduced in lung cancers, and that this overproduction in lung cancer patients was a marker for poor prognosis. “Developing new drugs that specifically target this protein, or other proteins involved in making PD-L1, could help improve the success of immunotherapy drugs currently in use,” says O’Donnell, also a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.

“Investigating the relationship between stress responses and immune evasion in cancer will be an important priority for future work,” says Shruthy Suresh, Ph.D., a former graduate student researcher and first author of this study.

Other UTSW researchers who contributed to this study include Vanessa Schmid, Sojeong Jun, Michael Peyton, Adwait Amod Sathe, Chao Xing, John D. Minna, Joshua T. Mendell, Yang-Xin Fu, Yang Xie, Guanghua Xiao, Shruthy Suresh, BeiBei Chen, Jingfei Zhu, Changzheng Lu, Xiaowei Zhan, Chelsea M. Karacz, Lin Zhong, Zhuoyu Wen, Ryan Golden, and Bret Evers, plus graduate students Bethany Smith and Nicole Novaresi. Mendell and Golden collaborated with the team on the CRISPR screen.

This research was supported by funding from NCI (R01 CA207763 and P50CA70907, R35CA19731104), Sidney Kimmel Foundation (SKF-15-067), Cancer Prevention and Research Institute of Texas (CPRIT) (R1101 and RP150676), Welch Foundation (I-1881-20180324 and I-1961-20180324), LUNGevity Foundation (2015-03), UTSW Friends of the Comprehensive Cancer Center, and the Howard Hughes Medical Institute.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Dr. Amyn Habib

The findings, published in the journal Nature Cancer, focused on epidermal growth factor receptor, EGFR, a protein that has a prominent role in the growth and survival of cancer cells, and resistance that builds up against inhibitors used to battle it. The researchers found that adding an interferon blocker, normally used to treat lupus, effectively wiped out this resistance in mice.

Clinical trials will be needed to confirm the effects in humans. But the drug combination could represent a significant step in the fight against lung cancer, which is the deadliest form of cancer in Texas and the nation.

“This could be very important because it could expand the reach of the drug from about 15 percent to the majority of patients with lung cancer. That’s millions of people worldwide,” says Amyn Habib, M.D., associate professor of Neurology and Neurotherapeutics at UT Southwestern Medical Center, a member of the Harold C. Simmons Comprehensive Cancer Center, and a staff physician at the Dallas Veterans Affairs Medical Center.

About 15 percent of lung cancer patients have a mutation in EGFR that makes it more active. EGFR inhibitors work well initially, but are eventually thwarted by signaling pathways developed by cancer cells to resist the drug. Crippling one or two of the pathways robs the cancer cells, at least for a while, of their ability to resist the EGFR inhibitors.

Habib’s lab discovered that the signaling pathways release proteins called interferons that resist the EGFR inhibitor. It was an unexpected finding because oncologists normally see interferons as allies in fighting cancer. In this case, they are foes, and the research team looked for something to block them.

Their broad search included drugs outside of cancer treatment and found an interferon blocker used in lupus patients called anifrolumab. The researchers used anifrolumab to block interferons in mice, crippling the signaling pathway and wiping out the resistance to the EGFR blocker.

They also found that patients who did not have mutated EGFR also increased their interferon levels in response to EGFR inhibitors. This has kept those patients from responding to the EGFR inhibitor drugs. That means that if the lupus drug could block the interferons, it would also open those patients up to the benefits of the EGFR blocking drugs.

“Research that leads to drug combinations like this are hugely valuable in the fight against cancer because new drug development is expensive and slow. This speeds up new possibilities for treatment,” says Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center.

Habib’s lab made the discovery by focusing on about 3,000 genes in the lung cancer cell and charting that were turned on or off. The data clearly led the researchers to increased activity with interferons.

“That’s what gave us proof that the interferon mechanism was in play,” Habib says.

This was previously unknown to medical science, and it is significant because EGFR signaling plays a role in other cancers including breast cancer and glioblastoma. Habib says his next step is to pursue clinical trials in lung cancer patients.

Other authors of the study from UT Southwestern are Ke Gong, Gao Guo, Nishah Panchani, Matthew Bender, David E. Gerber, John D. Minna, Farjana Fattah, Boning Gao, Michael Peyton, Kemp Kernstine, Cheng-Ming Chiang, Adwait Amod Sathe, Chao Xing, and Esra A. Akbay. Authors from other institutions are Kathryn H. Dao of Baylor Research Institute in Dallas, Dawen Zhao of Wake Forest School of Medicine in Winston-Salem, North Carolina, and Sandeep Burma and Bipasha Mukherjee, both at the University of Texas Health Science Center at San Antonio.

The authors declared no conflicts of interests. This research was supported in part by the Office of Medical Research, the Department of Veterans Affairs, a Lung Cancer Specialized Programs of Research Excellence Career Enhancement Program Award, and the Dallas VA Research Corporation. The work was also supported by the National Cancer Institute (NCI) Lung Cancer Specialized Programs of Research Excellence, the Cancer Prevention and Research Institute of Texas, an NCI Midcareer Investigator Award in Patient Oriented Research, and grants from the National Institutes of Health, NASA, The Welch Foundation, a Career Enhancement Award through the National Institutes of Health, and the Harold C. Simmons Comprehensive Cancer Center’s Biomarker Research Core, which is supported by an NCI Cancer Center Support Grant. An NIH shared instrumentation grant funded the MRI equipment.

Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Dr. Daniel Siegwart

For the past several years, researchers have studied the gene editing tool CRISPR, a system derived from the immune systems of bacteria that can be harnessed to remove genes and insert new ones. Researchers have used this tool not only for fundamental genetics study, but also as a potential way to treat genetic diseases in humans by removing faulty genes and replacing them with healthy ones.

But despite its promise, CRISPR has a major drawback: The system is composed of large molecules that can be difficult to get into cells. Thus far, researchers have mainly encapsulated these molecules in lipid nanoparticles as delivery vehicles. These nanoparticles are typically formulated with four components that work together to entrap their cargo and release it in the cell’s interior.

However, when these nanoparticles are delivered intravenously, they nearly universally end up in the liver due to their chemical similarity to the proteins that carry cholesterol to and from this organ, explains Daniel Siegwart, Ph.D., associate professor in the Department of Biochemistry and a member of the Harold C. Simmons Comprehensive Cancer Center at UTSW.

“This is great news for diseases that affect the liver,” he says. “But if we want to treat diseases in other organs, we need to be creative about getting our gene editing machinery there.”

Siegwart and his colleagues speculated that changing the charge and other physical properties of the lipid capsules might affect where they target. To test this idea, they added a fifth lipid to a four-component lipid nanoparticle developed at UTSW. For some of these new nanoparticles, the fifth lipid carried a positive charge; others carried a negative charge; and a third batch carried an “ionizable” charge that changes its value based on pH. They named this system SORT, short for Selective Organ Targeting.

Qiang Cheng, Ph.D.

Experiments in mouse models showed that as the percentage of this fifth “tuning” component rose in the nanoparticles, they were more likely to target the lungs if the lipid was positive, the spleen if it was negative, or more heavily target the liver if it was ionizable. Further study showed that this system could selectively remove a gene that prevented cell fluorescence in mice genetically altered to carry this trait, allowing specific organs to glow under a special light.

When the researchers altered the nanoparticles to carry nucleic acids that caused cells to manufacture specific proteins – including those important for immune function, blood production, and aging –the lungs, spleen, and liver selectively produced these proteins based on the nanoparticle properties.

To show that this system could impact clinically relevant genes, the researchers used the nanoparticles carrying the ionizable charge to shut down the production of a protein known as PCSK9 involved in cardiovascular disease in the liver. Tests showed that enhanced targeting in the liver eradicated nearly 100% of this protein.

Additional experiments showed that this strategy of adding a charged fifth component could be used with a variety of four-component lipid nanoparticle formulations – not just the one developed at UTSW – and that the exact molecule for the fifth component could be altered as long as it shared common values. Siegwart anticipates that this flexibility will enable SORT to be used by different scientists for a variety of purposes.

Tuo Wei, Ph.D.

This strategy is so versatile and promising, Siegwart says, that he and his colleagues created a spinoff company called ReCode Therapeutics to develop this technology into new treatments for genetic diseases and those spurred by mutations. They are already testing this strategy in animal models of cystic fibrosis, primary ciliary dyskinesia, and cancer and searching for ways to target even more organs and tissue types.

“We anticipate that SORT could offer a long-standing or maybe even permanent strategy to treat a variety of conditions,” he says.

Other UTSW researchers who contributed to this study include Qiang Cheng, Tuo Wei, Lukas Farbiak, Lindsay Johnson, and Sean Dilliard.

This research was supported by the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering (grant no. R01 EB025192-01A1), the Cystic Fibrosis Foundation (grant no. SIEGWA18XX0), the American Cancer Society (grant no. RSG-17-012-01), and The Welch Foundation (grant no. I-1855).

Siegwart, Cheng, and Wei and the Regents of the University of Texas System have filed patent applications on SORT and related technologies. Siegwart is a co-founder of and a consultant for ReCode Therapeutics, which has licensed intellectual property from UT Southwestern.​ UT Southwestern also has a minority financial interest in ReCode.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

The March 21 decision by NCCN to include the Simmons Cancer Center among its members recognizes Simmons Cancer Center’s elite status and will deepen its collaboration with national peers at the highest levels.

“Our entrance into this prestigious group does not just recognize the stature of the Simmons Cancer Center, but opens new doors to our strategic vision for cancer research and patient care,” says Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center. “Collaboration is the hallmark of medical advances, and our inclusion into NCCN will amplify our work with the nation’s most advanced institutions.” 

Cancer centers at Harvard, Yale, Stanford, and the Mayo Clinic are among the members of NCCN, a Pennsylvania-based not-for-profit organization.

Dr. Carlos Arteaga

“We are very excited to incorporate the significant medical and scientific expertise from the Simmons Cancer Center into our network of top academic cancer centers,” says Robert W. Carlson, M.D., Chief Executive Officer of NCCN. “The Simmons Cancer Center has a proven track record when it comes to improving outcomes and quality of life for people with cancer. Their facility includes top-notch programs throughout the spectrum of cancer management, including pediatric oncology, genetics, immunotherapy, telemedicine, and other increasingly important areas of interest for NCCN and the greater cancer care community.”

John Sweetenham, M.D., the Simmons Cancer Center’s Associate Director for Clinical Affairs, says the Center’s inclusion in NCCN will allow it to be part of larger national discussions on the cost of care and further integrate best practices from peer institutions. It will also open new avenues of research funding for young investigators and clinical trials, and it will give the Simmons Cancer Center a more prominent role in establishing national and international guidelines for cancer care.

Entrance into NCCN is the latest in a series of milestones that the Simmons Cancer Center has achieved in the last year. In June, the Simmons Cancer Center broke ground on a nine-story tower that will add 300,000 square feet for outpatient care and clinical trials. Construction started on a second three-story radiation oncology building in September. 

Dr. John Sweetenham

In February, the Simmons Cancer Center was awarded more than $8.5 million in grants from the Cancer Prevention and Research Institute of Texas (CPRIT). In all, the Simmons Cancer Center has received more than $500 million in CPRIT research funding since CPRIT was established in 2007.

Other Simmons Cancer Center research funding involves two Specialized Program of Research Excellence (SPORE) awards from the National Cancer Institute. One is in lung cancer – one of the largest thoracic oncology efforts in the U.S. – and the other is in kidney cancer, one of just two in the nation in that field. Total research funding for the Simmons Cancer Center for 2019 totaled more than $90 million, up 40 percent from five years ago.

As one of 32 cancer centers named as a National Clinical Trials Network Lead Academic Participating Site, the Simmons Cancer Center offers patients greater access to new and investigational treatments. The Simmons Cancer Center oversees approximately 3 million outpatient cases a year and has nearly 200 faculty members, including 2011 Nobel Laureate Bruce Beutler, M.D. Simmons Cancer Center members have published in many prestigious medical journals including the New England Journal of Medicine, Nature, Science, JAMA, Journal of Clinical Oncology, and Cell.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

If not teamed with psychological, social, and emotional support, the news can negatively impact young patients’ emerging developmental needs and perspectives, based on results of a new study outlining the value of cancer psychosocial support programs.

Dr. Sarah Pennant

“Adolescence is already a difficult developmental period, as teens and emerging adults are striving for independence and autonomy, are separating from parents, and are initiating romantic and peer relationships. Cancer diagnosis and treatment really disrupts this critical period in their lives,” says first author Sarah Pennant, Ph.D., a clinical child psychology fellow specializing in pediatric health at Children’s Health/Children’s Medical Center Dallas and former doctoral student at UT Southwestern Medical Center.

“Adolescents and young adults may have to rely on their parents and families more than they had prior to diagnosis. Frequently, these patients have decreased social interaction due to a number of limitations, such as being at the hospital for treatment, being removed from mainstream school or college, and restrictions on being in crowded areas due to being immunocompromised. Yet, we know these peer relationships are crucial during this time,” Pennant adds.

The authors are part of the Adolescent/Young Adult Oncology Program at Children’s Health and members of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and Moncrief Cancer Institute. They looked into how adolescents and young adults (AYAs) ages 15-26 individually cope during cancer treatment and what social supports helped them. The researchers surveyed 10 cancer patients undergoing treatment and 10 parents. Participants scored within the normal to high range on measures of hope, depression/anxiety/stress, quality of life, and social support.

Researchers used oral interviews to explore specific actions helpful to AYA patients, what behaviors they would like from their social supports, and what advice they would give others in their situation – all aimed at helping develop future interventions and to provide guidance for family, friends, cancer peers, and medical teams.

The findings, which appeared in the cover story of the Swiss open-access journal Children, include:

• Friends: These patients struggle with feeling as though their lives are at a standstill due to cancer treatment, particularly when comparing their lives to those of their friends and peers, and believe their peers sometimes treat them differently after their cancer diagnosis, leading them to feel as though cancer consumed their identity or that others pitied them. Maintaining connections and communication with friends throughout treatment is a way of continuing to develop deep friendships and experience social milestones.
• Parents/family: Some AYAs experience discomfort in seeing their parents become tearful or worried during their treatment, preventing them from sharing their own emotional experience in order to protect their family. But they also expressed the importance of parents and family providing physical and emotional support, advocating for the AYA patient’s needs, providing additional information related to treatment, maintaining the AYA’s autonomy, modeling a positive attitude, and assisting in everyday tasks.
• Others: Others who provided support included similarly aged individuals with cancer, medical staff, significant others, classmates or work colleagues, community members, cancer-specific organizations, and professional or collegiate athletes.
• Online resources: When searching for information online, some teens and young adults felt discouraged by articles and statistics that may or may not apply to their cancer situation. Medical staff were helpful by directing them to trustworthy websites and articles and providing accurate, tailored information about their disease course.

“In our Adolescent/Young Adult Oncology Program, we have a core set of providers who pay particular attention to the developmental needs of our patients, help patients find solutions to their unique needs, and also train the other departmental providers in this age group’s needs,” says Julie Germann, Ph.D., associate professor of Psychiatry at UTSW and program lead of the AYA Oncology Program at Children’s Health.

AYA cancer patients are a psychosocially at-risk group, as they are less studied than pediatric and geriatric cancer cohorts. As a result, the authors say, these AYA patients can experience disparities in access to developmentally informed treatment. Before intervention studies were put in place, it was important to gather the experience from AYAs themselves to see how they were coping.

“Programs and hospitals across the nation are beginning to focus on this unique age group, trying to be more innovative and creative with their approaches,” says Pennant. “Our research has found certain categories and themes that seem relevant to AYAs going through cancer treatment, but the goal would be to meet each individual’s needs based on what they find the most challenging and the most relevant in their lives at the time.

“As a result of these findings, we are currently in the process of examining ways to normalize and validate the AYA experience through educational handouts and an interactive personal coping plan to use with patients. Awareness continues to grow within the AYA oncology world, and we hope to continue to highlight this at-risk population with developmentally tailored care.”

The National Cancer Institute reports that about 70,000 people between 15 and 39 years of age are diagnosed with cancer each year in the U.S., six times the number of cancers diagnosed in children up to age 14. AYAs are most likely to be diagnosed with cancers such as Hodgkin lymphoma, testicular cancer, and sarcomas. Incidences of specific cancer types, however, vary according to age – with leukemia, lymphoma, testicular cancer, and thyroid cancer the most common among 15- to 24-year-olds, and breast cancer and melanoma most common in patients ages 25-39.

Other UTSW authors include Simon C. Lee, Laura Howe-Martin, Suzanne Holm, and Kelli N. Triplett. Another author is Ryan Campbell of Children’s Health. The authors reported no conflicts of interest.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

“In prior studies we found there are intrinsic differences among melanomas in their ability to metastasize or spread. Some are efficient metastasizers that readily form distant tumors whether you take them out surgically or not, while others are inefficient metastasizers that spread more slowly and that can be cured through surgery,” said Dr. Sean Morrison, Director of CRI and a Howard Hughes Medical Institute (HHMI) Investigator. “Since metastasis is a major determinant of clinical outcomes, we have focused for several years on understanding why some melanoma cells are better at it than others.”

Scientists have long known that most cancer cells die when they attempt to metastasize from a primary tumor to other parts of the body. Those that are able to survive during metastasis must undergo poorly understood metabolic changes.

A previous study conducted by the Morrison lab found one factor that limits the ability of melanoma cells to spread to other parts of the body is the high level of oxidative stress cancer cells experience during metastasis when they enter the bloodstream. Recently, another study at CRI in Dr. Ralph DeBerardinis’ lab found that more aggressive lung cancer cells consume higher levels of lactate. Based on these findings, scientists in the two labs hypothesized that some melanoma cells might be better at metastasizing if they were better at consuming lactate.  

To test this hypothesis, researchers used techniques developed by the Morrison laboratory for studying the metastasis of human melanoma cells in specialized mice and techniques developed by the DeBerardinis lab to label and track the use of nutrients in tumors. The researchers discovered that efficient metastasizers take up more lactate because they have higher levels of a lactate transporter on their cell surface, called monocarboxylate transporter 1 (MCT1), as compared with inefficient metastasizers.

Researchers involved in the study include (from left) Drs. Brandon Faubert, Alpaslan Tasdogan, Sean Morrison, and Ralph DeBerardinis.

“Efficient metastasizers are able to take up more lactate, which allows them to increase their production of antioxidants that help them to survive in the blood,” said Dr. Alpaslan Tasdogan, lead author of the study and a postdoctoral researcher in the Morrison lab. “The findings in our paper, along with those made previously by the DeBerardinis lab, strongly suggest that increased lactate uptake by cancer cells promotes disease progression. This correlates with clinical data showing that patients with higher levels of MCT1 in their cancers have worse outcomes.”

In the study, published in Nature, melanomas growing in mice that were treated with an MCT1 inhibitor led to fewer melanoma cells in the blood and fewer metastatic tumors. These data raise the possibility that MCT1 inhibitors, if given to patients before their cancer spreads, could reduce the proportion of patients who develop distant metastases, which are associated with systemic disease and much less likely to be curable.

“This paper makes a compelling case for analyzing metabolism in tumors,” said Dr. DeBerardinis, Professor at CRI and an HHMI Investigator. “It’s a great example of how assessing tumor metabolism can identify differences that correlate with cancer aggressiveness. Then you can identify an activity related to metastasis, inhibit it with a drug, and reduce metastasis in the mouse. That’s remarkable.”

Dr. Morrison is a Professor of Pediatrics at UT Southwestern, a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, and a member of the National Academy of Medicine. He also holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern and Mary McDermott Cook Chair in Pediatric Genetics.

Dr. DeBerardinis is a Professor of Pediatrics at UT Southwestern, where he is Chief of the Division of Pediatric Genetics and Metabolism and holds the Joel B. Steinberg, M.D. Chair in Pediatrics and is a Sowell Family Scholar in Medical Research. He is also affiliated with the Eugene McDermott Center for Human Growth and Development and the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. At CRI, Dr. DeBerardinis is the Director of the Genetic and Metabolic Disease Program and is a Robert L. Moody, Sr. Faculty Scholar.

Dr. Tasdogan is a German National Academy of Sciences Leopoldina Postdoctoral Fellow.

The National Institutes of Health, HHMI, CPRIT, the Robert A. Welch Foundation, and donors to the Children’s Medical Center Foundation supported this work.

 About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas, the flagship hospital of Children’s Health. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism. For more information, visit: cri.utsw.edu. To support CRI, visit: give.childrens.com/about-us/why-help/cri/

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Payal Kapur, M.D.

“Clear cell renal cell carcinoma is the poster child of tumor heterogeneity as multiple, different populations of cells with different methods of behavior can be found in any particular tumor,” says Payal Kapur, M.D., a professor of pathology and urology at UT Southwestern, co-leader of pathology for the Kidney Cancer Program, and a co-author of the study. “Some of these cells develop aggressive traits and spread whereas others do not really progress, and it can be quite different from patient to patient.”

In the years since the Human Genome Project, technologies for deciphering the genetic code have vastly improved, enabling scientists to decode the genetic sequence of individual patients and their tumors. While much knowledge has been gleaned from this type of research, this approach has not reached clinical practice as it is expensive and requires specific expertise, says Qi Cai, M.D., Ph.D., an assistant professor of pathology and first author of the study.

Using tissue staining techniques that have been widely used for more than a century, Kapur and her team analyzed tumor samples from 549 patients. Specifically, they characterized how the cells are arranged within the tumor, what each individual cell looks like and how the tumor interacts with the surrounding tissue. They measured 33 parameters that they defined within these three categories. Then, to see if these tumors were able to grow in a foreign site, the team implanted tiny tumor samples into the kidneys of mice.

Illustration of the nine distinct patterns of ccRCC morphology based on extensive analysis of tumor architecture, cytology, and microenvironment. Thirty three cancer cell variables were defined which were then grouped into these nine patterns. This enabled the identification of aggressive phenotypes and shed light on tumor evolution.

Analyzing information about drug treatments the patients had received and how well they worked, the researchers were able to associate specific tumor characteristics with the drugs that worked best against those types of cells. “Most medicines for metastatic kidney cancer today do not directly act on tumor cells,” explained James Brugarolas, M.D., Ph.D., a professor of internal medicine, Director of the Kidney Cancer Program, and a co-author of the study. “Thus, it is not surprising that information about the tumor neighborhood could inform treatment response.”

Kapur and her team of experts in artificial intelligence, data analytics, oncology, and radiology have developed the first comprehensive catalog of ccRCC and an evolutionary model. By analyzing tumor composition (how the different subtypes occur together in individual patient tumors) across tumors of different size and grade, the team was able to develop an evolution trajectory of ccRCC progression, says Satwik Rajaram, Ph.D., an assistant professor of bioinformatics and pathology in the Lyda Hill Department of Bioinformatics, the Center for Alzheimer’s and Neurodegenerative Diseases, and a co-author of the study.

“This remarkable team with expertise across a broad array of fields has provided unique insight into ccRCC,” says Brugarolas. “This type of innovative approach illustrates how we continue to learn more about, tailor treatments to, and improve patient outcomes for kidney cancer here at UTSW.”

Payal Kapur holds the Jan and Bob Pickens Distinguished Professorship in Medical Science, in Memory of Jerry Knight Rymer and Annette Brannon Rymer and Mr. and Mrs. W.L. Pickens

James Brugarolas holds The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D.

Additional study authors are Alana Christie, Qinbo Zhou, Ellen Araj, Suneetha Chintalapati, Jeffrey Cadeddu, Vitaly Margulis, Ivan Pedrosa, Dinesh Rakheja, Renee McKay, all of UT Southwestern.

This research was funded by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP130603, National Institutes of Health (NIH) grant P50CA196516, and an endowment from Brock Fund for Medical Science Chair in Pathology and the Jan and Bob Pickens Distinguished Professorship in Medical Science. The UT Southwestern Kidney Cancer Program is supported by the National Cancer Institute (NCI) through a Specialized Program of Research Excellence (SPORE) award and by CPRIT.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – Dec. 10, 2019 – Federal regulations may keep lung cancer patients out of clinical trials simply because these patients are on medications that might affect the electrical system of the heart. Drilling into the details quickly turns up reasons to think these regulations may be preventing a substantial proportion of patients from participating in clinical trials. There may be alternatives, and researchers and physicians should explore them.

These are the conclusions of a team of researchers from UT Southwestern Medical Center that included members of the Harold C. Simmons Comprehensive Cancer Center. Their findings, published in the journal Clinical Lung Cancer in November, might help break down barriers for patients to participate in important, potentially lifesaving clinical trials. The barriers currently exclude thousands of patients.

“This issue comes up all the time in my practice,” said Dr. David Gerber, who treats lung cancer patients and is a Professor of Internal Medicine and Population and Data Sciences. He is one of the study’s authors and has been studying clinical trial eligibility criteria for a decade.

Clinical trial eligibility criteria are designed to limit risks to study participants. But, according to Dr. Gerber, these criteria may be excessive in places.

“The criteria are not as thoughtful as they could be,” Dr. Gerber said. “We keep cutting and pasting from earlier studies, basically doing the same things over and over without justifying them or deciding if they’re rational.”

Using a database of more than 280,000 Veterans Health Administration patients with lung cancer, the study found that more than 25 percent of lung cancer patients were prescribed medications with potential cardiac risk, and almost 10 percent were taking multiple such medications. Dr. Gerber noted that even if these medications are not having cardiac effects on patients, simply receiving the medications may bar patients from clinical trials. Furthermore, when cardiac effects are noted, the actual risk to patients is often measured over a 40-year period. Because most lung cancer patients are over 70 years old, a 40-year range of possible risks may be less relevant.

“Lung cancer is a serious and possibly life-threatening condition,” Dr. Gerber said. “When we design clinical trials, we need to consider potential benefits as well as theoretical risks.”

Dr. Carlos L. Arteaga, Director of the Simmons Cancer Center and Associate Dean of Oncology Programs, said studies like Dr. Gerber’s are urgently needed because less than 2 percent of adult cancer patients in the U.S. are enrolled in clinical trials that can benefit the patient and advance scientific knowledge. He said clinical trials for lung cancer are particularly important because lung cancer is the leading cause of cancer deaths in Texas and the nation.

“Studying barriers to clinical trials can be as important as creating a new clinical trial itself. Patients can’t benefit from trials they can’t access,” said Dr. Arteaga, also Professor of Internal Medicine who holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology. “Dr. Gerber’s work is one of the first steps in making clinical trials more accessible.”

Dr. Mark Link, a cardiologist and Professor of Internal Medicine who worked on the study, said the seemingly excessive caution around the drugs stems largely from a medical crisis in the late 1990s. A new drug created to treat gastric motility disorders such as diarrhea, vomiting, and severe constipation showed positive effects on the gastrointestinal tract but serious threats to the heart.

“This new drug was widely used and very effective. It worked extremely well, but then the reports started coming in of QTc prolongation of this drug, and it was taken off the market,” said Dr. Link, who holds the Laurence and Susan Hirsch/Centex Distinguished Chair in Heart Disease.

QTc prolongation is the blip on an electrocardiogram, the iconic machine on the medical TV shows that charts each heartbeat with a beep and a fever chart line. The space between the highest peaks on the EKG line is known as the QTc interval. It is the moment the heart is preparing to beat again. It’s a crucial step in cardiac health – in staying alive – so the threats caused by the gastric motility disorder drug prompted the FDA to zero in on other drugs that affect QTc prolongation. The fallout included strict rules stating that patients taking drugs that prolong – or even might prolong – QTc intervals cannot enter clinical cancer trials.

The most common QTc-prolonging medications that the study found to be potential barriers to clinical trials included antibiotics, psychiatric medications, and cardiac medications.

Other researchers who contributed to the study were Dr. Tri Le, a hematology-oncology postdoctoral fellow; Dr. Sawsan Rashdan, Assistant Professor of Internal Medicine; Dr. Carlos Alvarez, Associate Professor of Population and Data Sciences; and Dr. Hui Yang, a Chief Analyst at Texas Tech University Health Science Center.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – Dec. 9, 2019 – UT Southwestern researchers have developed a software tool that uses artificial intelligence to recognize cancer cells from digital pathology images – giving clinicians a powerful way of predicting patient outcomes.

The spatial distribution of different types of cells can reveal a cancer’s growth pattern, its relationship with the surrounding microenvironment, and the body’s immune response. But the process of manually identifying all the cells in a pathology slide is extremely labor intensive and error-prone.

“As there are usually millions of cells in a tissue sample, a pathologist can only analyze so many slides in a day. To make a diagnosis, pathologists usually only examine several ‘representative’ regions in detail, rather than the whole slide. However, some important details could be missed by this approach,” said Dr. Guanghua “Andy” Xiao, corresponding author of a study published in EBioMedicine and Professor of Population and Data Sciences at UT Southwestern.

The human brain, Dr. Xiao added, is not good at picking up subtle morphological patterns. Therefore, a major technical challenge in systematically studying the tumor microenvironment is how to automatically classify different types of cells and quantify their spatial distributions, he said.

The AI algorithm that Dr. Xiao and his team developed, called ConvPath, overcomes these obstacles by using AI to classify cell types from lung cancer pathology images.

Here’s how it works: The ConvPath algorithm can “look” at cells and identify their types based on their appearance in the pathology images using an AI algorithm that learns from human pathologists. This algorithm effectively converts a pathology image into a “map” that displays the spatial distributions and interactions of tumor cells, stromal cells (i.e., the connective tissue cells), and lymphocytes (i.e., the white blood cells) in tumor tissue.

Whether tumor cells cluster well together or spread into stromal lymph nodes is a factor revealing the body’s immune response. So knowing that information can help doctors customize treatment plans and pinpoint the right immunotherapy.

Ultimately, the algorithm helps pathologists obtain the most accurate cancer cell analysis – in a much faster way.

“It is time-consuming and difficult for pathologists to locate very small tumor regions in tissue images, so this could greatly reduce the time that pathologists need to spend on each image,” said Dr. Xiao, who also has an appointment in the Lyda Hill Department of Bioinformatics and is a member of both the Quantitative Biomedical Research Center (QBRC) and the Harold C. Simmons Comprehensive Cancer Center at UTSW.

The ConvPath software – which incorporates image segmentation, deep learning, and feature extraction algorithms – is publicly accessible at https://qbrc.swmed.edu/projects/cnn/.

Dr. Guanghua “Andy” Xiao

The study’s lead authors include Shidan Wang, QBRC Data Scientist II; Dr. Tao Wang, Assistant Professor of Population and Data Sciences and in the Center for the Genetics of Host Defense; and Dr. Donghan M. Yang, QBRC Project Manager. Other co-authors from UT Southwestern include Dr. Yang Xie, Professor of Population and Data Sciences, a Professor in the Lyda Hill Department of Bioinformatics, and Director of the QBRC, and Dr. John Minna, Professor of Pharmacology and Internal Medicine and Director of the Hamon Center for Therapeutic Oncology Research. Dr. Minna holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology.

The study was supported by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – Nov. 20, 2019 – Juan Cueto did not feel sick, but he was losing weight rapidly and was devastated with the knowledge that he had two life threatening diseases, cancer and a liver disease.

Doctors in another state told him there was no treatment; only a liver transplant would cure him of the primary sclerosing cholangitis he was diagnosed with in 2012. He was told this liver disease could lead to bile duct cancer – and it did.

“It was very frustrating. I felt like, ‘How long do I have?’ You start thinking about your kids, your future. Your life is going down,” said Mr. Cueto, a 46-year-old electrical engineer who lives in Frisco.

Mr. Cueto’s prospects changed dramatically when he moved to Texas in 2016 and found a team of specialists at UT Southwestern who could address both issues in one surgery.

Dr. Parsia Vagefi brought the new surgical protocol for bile duct cancer and liver disease when he came to UT Southwestern in 2018 as Associate Professor of Surgery and the Ernest Poulos, M.D. Distinguished Chair in Surgery. The surgery protocol would give Mr. Cueto a new liver by transplant and surgically remove the bile duct. Of the 7,000 liver transplants that take place nationwide every year, only 1 percent address bile duct cancer in the same surgery.

Dr. Vagefi told Mr. Cueto, “It’s a little bit of a Hail Mary pass, but sometimes Hail Marys work.”

UT Southwestern had the expertise, but Mr. Cueto had to wait for a liver to become available. A man he knew suffered from a similar condition, and he was alarmed to see his health decline rapidly. The man was near death when he received a partial liver transplant from a living donor.

“That really scared me too,” said Mr. Cueto who has a teenage son and a daughter in college.

To be eligible for transplant, doctors would need to ensure that cancer had not spread anywhere else in his body. Oncologists from the Harold C. Simmons Comprehensive Cancer Center put Mr. Cueto on a carefully planned treatment plan of radiation and chemotherapy.

His medical oncologist, Dr. Muhammad Beg, said the careful monitoring that comes with every patient plan was particularly important for Mr. Cueto with scans receiving extra scrutiny.

“We monitor patients very closely with scans. Patients need to fit very specific criteria before they are considered for transplant. Part of this process is a detailed discussion of their scans in a multidisciplinary tumor board,” said Dr. Beg who is an Associate Professor of Internal Medicine and Dedman Family Scholar in Clinical Care. “We also ensure that chemotherapy and radiation is given following strict criteria and proven protocols.”

Dr. Vagefi said many patients in this situation nationwide do not make it to transplant because their cancer spreads. After imaging in Radiology, UT Southwestern doctors did an endoscopy to ensure cancer had not reached Mr. Cueto’s lymph nodes.

“There were a lot of people involved getting him to transplant,” Dr. Vagefi said. “It was a true multidisciplinary effort.”

In July, Mr. Cueto got the call. A liver had become available.

“I was super scared,” he said. “You have to be strong and hope for the best.”

Dr. Vagefi said the first phase of the surgery focused on making sure cancer had not spread elsewhere in Mr. Cueto’s body. Any sign of spread would halt the operation, he would not get a new liver, and he would be back to square one.

“We inspected the entire abdomen to make sure there is no evidence of microscopic spread, and we sampled certain lymph nodes that surround the liver,” Dr. Vagefi said. “We sent those to the Department of Pathology, another area of expertise that we have at UT Southwestern that helped contribute to this team effort. They look at those slides right away and they can tell us whether there is spread of the cancer or not. If there’s spread then we abort the case.”

Another potential recipient was ready, per the protocol’s requirement, to receive the liver if Mr. Cueto’s case was aborted. But one after another, the results came back. No cancer had spread. Dr. Vagefi moved on to the transplant and surgical removal of the bile duct.

“We cut out the recipient’s bile duct in its entirety. We didn’t want to leave any of that behind for the chance of harboring cancer or developing cancer in the future,” he said. “But we still needed a way to drain the donor liver bile duct so we had to reroute the bowl and connect it to the donor bile duct and allow it to drain. That added another level of complexity to the case.”

Dr. Vagefi said he found radiation oncologists had worked with tremendous precision; radiation treatments were tightly focused in a specific area. This meant that blood vessels were not radiated any more than necessary, leaving an ample amount of blood vessels for reconnection. No bypasses were needed. Veins, an artery, the new bile duct were delicately sutured in the surgery’s final steps.

Hours later Mr. Cueto woke up in the recovery room, and Dr. Vagefi came to his bedside. He was too groggy to remember Dr. Vagefi’s exact words, but he remembers him saying everything went well. He would have no restrictions going forward.

“I was so happy. It was like my second birthday,” Mr. Cueto said. “I feel like I was in the right place at the right time. It was a very professional team, very well organized.”

Blood tests and follow up appointments show Mr. Cueto enjoying a strong recovery. He looks forward to having his 21-year-old daughter home for the holidays and has begun building a vintage video game replica in the garage with his 15-year-old son.

“I feel great,” he said. “I felt like somebody was looking out for me, and they were making the best decisions for me. I didn’t have any doubt that I was in the right place at the right time.”

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – Oct. 29, 2019 – Sandra McKinney grew so attached to the Simmons Cancer Center at UT Southwestern that she decided to fly back for follow-up appointments instead of finding a new provider when she moved to New Jersey.

“The people are kind. The nursing staff is really kind,” she said. “I just felt like I could never be anything but joyous that I was there.”

The 59-year-old mother of two said she discovered a lump in her breast in January 2017. After visiting a local hospital, she received a phone call with a diagnosis of triple negative breast cancer.

“She told me I needed to find a surgeon and good luck and hung up the phone,” Mrs. McKinney said.

Triple negative breast cancer is particularly aggressive and challenging because it lacks the three hormones that oncologists typically use as a foothold for cancer treatments.

“I thought, ‘I’m going to do this, and I’m going to have a sweet attitude because I can control that,’” she said. “From the very start, I told my husband I was going to be kind and happy, and I was going to be the best patient they ever had.”

At the Harold C. Simmons Comprehensive Cancer Center Mrs. McKinney said she met people who shared her positive attitude and focus on what can be done.

“I felt relief because I felt like I’d found my people,” she said.

People like her oncologist Dr. Nisha Unni, a physician-researcher who is conducting clinical trials on breast cancer and triple negative breast cancer. Dr. Unni is working to identify with a much higher level of specificity how effective chemotherapy is and which patients are best suited for it. By delivering chemotherapy before – instead of after – surgery, she can analyze surgically removed tumors down to the molecular level. It’s a forward-looking approach paving the way for future treatments.

Mrs. McKinney remained focused on the future not just for her, but for her family. She elected for genetic testing at UT Southwestern to learn what might be in store for her and her two adult children.

“I have a daughter, and I didn’t want her to be sitting in the chair I was sitting in. I wanted to know and be at peace with that,” she said.

The genetic testing revealed she lacks a gene for another type of breast cancer commonly associated with triple negative breast cancer, but she has a variant of uncertain clinical significance for a gene for colon cancer. She shared the news with her children immediately, and they adopted regular screenings.

Now Mrs. McKinney looks forward to the upcoming weddings of both her daughter and her son and hopes for grandchildren soon. She’s never been a nature person, but as a new chapter of life begins, she said she is pleasantly surprised how much she enjoys walks in a nature preserve near her home.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – Oct. 9, 2019 – On Wendy Casper’s first day at the Simmons Cancer Center at UT Southwestern she met a fellow breast cancer patient, a volunteer.

The woman said her treatment was done, but she came back as a volunteer because she missed the Harold C. Simmons Comprehensive Cancer Center.

“I thought, ‘Well, that’s weird. Who would want to go back?’ But I get it now. I go over to the Simmons Cancer Center, and I feel comforted,” Ms. Casper said.

The Simmons Cancer Center helped her beat breast cancer and continue her career as a Professor and Associate Dean in the College of Business at the University of Texas at Arlington.

On Friday, Ms. Casper’s last day of infusion chemotherapy, she enjoyed a surprise reunion with Mary Ellen Garland, the volunteer who helped her on her first day of treatment. When told that Ms. Garland was there to see her, Ms. Casper’s jaw dropped and eyes widened.

“Oh, my God!” she gasped, bringing her hand to her mouth. “I would love to see her!”

Ms. Garland entered, and the two women embraced in a hug that exemplified the support cancer survivors give each other and the bonds built at the Simmons Cancer Center.

“I get it now, what you said to me last year, when you said that you came back here,” Ms. Casper said as the two clasped hands. “I feel connected now to everybody that understands this journey, and everybody here has been so good to me – and it all started with that day I met you almost a year ago.”

“This is where health care is supposed to be,” Ms. Garland said with a wide smile.

“That’s definitely what I found. So many times I realized, I never had this kind of medical care before,” Ms. Casper said. “I never had this level of attention and care for my well-being.”

Ms. Garland said it meant a lot to hear that her volunteer work helped someone else, and that someone remembered her from her first, overwhelming day as a cancer patient.

“It’s always gratifying because you are in such a spin when you first have this happen,” she said. “You don’t remember anything. You just think, everybody’s nice, everybody’s trying to help you, so to be remembered specifically is very gratifying. … It is a very supportive environment. That is truly what I think this thing is all about.”

The reunion was a happy ending to Ms. Casper’s yearlong fight against cancer that came on suddenly. More than a decade of mammograms showed nothing, and Ms. Casper had no history of breast cancer in her family, so a diagnosis of breast cancer in late 2018 “came out of nowhere.”

A doctor in Tarrant County told her, “I hate to do this over the phone, but you have cancer.”

Staff at the first hospital she spoke with seemed less focused on her as a patient and more focused on the reconstructive breast surgery she would eventually need. She wanted a team that treated her differently from this. People kept recommending Dr. Marilyn Leitch, a breast surgeon at the Simmons Cancer Center. Dr. Leitch is a Professor of Surgery and holds the S.T. Harris Family Distinguished Chair in Breast Surgery, in Honor of A. Marilyn Leitch, M.D.

“Everyone kept saying this is the best breast surgeon,” she said. “The day I came to see her my life changed, and it was like, ‘Everything’s going to be ok.’ My anxiety was way down, and I just felt so much safer. I felt like everything was going to be ok.”

The doctors and staff focused on her as a person and moved to make her treatment as quick and easy as possible. She said she felt like a priority when she could hear the scheduler working the phones to advance her appointments.

“She kept saying, ‘Escalate, escalate. She’s a new diagnosis, she needs to get in right now.’ She was on the phone doing that for like 40 minutes, and she got off the phone and had all these appointments for me,” Ms. Casper said. “I was just completely overwhelmed with gratitude.”

Wendy Casper and her husband Roger Duval

Ms. Casper’s husband, Roger Duval, said he also noticed how attentive the entire team was.

“They made sure we were introduced to the nurses,” he said. “There was just this complete package feeling that we were definitely with competent people who were totally focused on your needs. Every single individual we interacted with has been focused and competent and careful.”

Ms. Casper had chemotherapy, radiation, and surgery to treat the cancer. She temporarily lost her hair to chemotherapy but did not get the mental fogginess of “chemobrain” – a side effect that she feared would interfere with her scholarly work as a professor.

She said the cancer team helped her with each step of treatment.

“People have just taken care of me in a way that I had never experienced before in the medical system,” she said. “It really helped keep my spirit up. I really felt like I had really been cared for as a human being.”

Ms. Garland was part of that, and she was there at the beginning – as an example of someone giving back. Ms. Casper said she is already at work on her own way of giving back. Ms. Casper, who has a Ph.D. in organizational psychology, studies ways to improve the health and well-being of employees. She said she will now study how cancer patients in outpatient treatment juggle their schedule and cancer care.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

The study published today in Science Immunology suggests that giving the two therapies as short course, first-line treatment might work better than the current practice of providing one treatment early and the other treatment only if tumors relapse.

(l-r) Drs. Chuanhui Han, Yang-Xin Fu, and Zhida Liu

“This study reveals the importance of the proper combination and timing of tyrosine kinase inhibitors and immunotherapy such as the programmed death-ligand 1 (PD-L1) inhibitor, also known as immune checkpoint blockade. If borne out by future research, these findings might open new treatment avenues for many cancer patients,” said corresponding author Dr. Yang-Xin Fu, Professor of Pathology, Immunology, and Radiation Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center.

“Many cancers have high and abnormal tyrosine kinase activities. Tyrosine kinase inhibitors, or TKIs – which target specific cancers – are a common first-line treatment for rapidly shrinking tumors such as those associated with kinase-driven breast cancer and lung cancer. But tumor relapse or resistance often occurs. The standard of care is to use TKIs first and then use immunotherapy such as PD-L1 inhibitors after relapse occurs,” Dr. Fu explained. “Our study showed that immunotherapy should be used together with the TKIs as the first-line – not second-line or third-line – treatment. We also demonstrated that the dose and timing of the TKI is important.”

The team, which included first authors and postdoctoral researchers Drs. Zhida Liu and Chuanhui Han, also found that hypofractionated TKI (HypoTKI) – giving a high dose over a short time – was more effective in mouse models of breast cancer and lung cancer than standard hyperfractionated TKI (HyperTKI) – lower doses over a longer time. Compared with standard therapy, the high-dose/short time TKI approach appeared to significantly reduce tumor burden and limit relapse with fewer side effects.

Earlier studies that found increased side effects when TKI and PD-L1 were given together had used HyperTKI rather than the HypoTKI provided in this investigation, said Dr. Fu, a physician-scientist who holds the Mary Nell and Ralph B. Rogers Professorship in Immunology.

The researchers found that TKIs work in part by activating both innate and adaptive immunity – that is, both of the body’s immune systems. The innate immune system is activated as soon as a threat is identified. Adaptive immunity is the body’s response to threats it has learned to recognize, Dr. Fu explained.

PD-L1 inhibitors are thought to enhance adaptive immunity to overcome the ability of some tumor cells to develop resistance to TKIs, he added.

Compared with standard HyperTKI therapy, the HypoTKI approach triggered greater innate immune sensing and a more potent release of type I interferon and other cytokines through an innate immunity signaling pathway to enhance tumor-specific T cell infiltration and reactivation. The researchers also found that HypoTKI was more potent than HyperTKI in limiting tumor relapse in a host immune response-dependent manner. More importantly, they observed that PD-L1 blockade could further enhance the anti-tumor effectiveness of HypoTKI treatment in advanced large tumors and limit the relapse. The timing of the dose of the drugs was important, he said.

The study is among the first to find that this class of TKIs can trigger the innate immune response, Dr. Fu said. “We think there might be a threshold effect with HypoTKI in which the treatment more effectively alerts the innate immune system. It appears that higher-dose/shorter duration TKI treatment may spark a more potent anti-tumor response by better triggering the innate immunity system.”

In one series of experiments, the researchers found that tumors were completely resistant to anti-PD-L1 therapy alone, so-called monotherapy. When HypoTKI was given by itself, it markedly reduced tumor burden initially, but all tumors relapsed eventually.

When the two treatments were given concurrently and early, it resulted in the best tumor regression and most mice showed no relapse over more than two months of follow-up. Tumor relapse in mice usually occurs within two to three weeks.

“The maximum synergistic effect of combination therapy depends on the timing of the anti-PD-L1 treatment. When it was started within three days of TKI administration, there was total tumor regression and only two of eight tumors relapsed,” Dr. Fu said.

Almost no synergistic effect was seen if PD-L1 inhibitors were provided a week after TKI therapy.

“Our study demonstrates that HypoTKI and PD-L1 blockade can work in combination to effectively control advanced large tumors, increase overall survival, and reduce tumor relapse. These data suggest that proper timing – giving the two agents together at the start of treatment – provides maximum synergistic anti-tumor effects in these tumors and should be studied further,” Dr. Fu said.

UTSW co-authors include Research Associate Dr. Chunbo Dong, Drs. Zhenhua Ren, Changzheng Lu, Longchao Liu, Anli Zhang, all postdoctoral researchers in the Fu laboratory; Eric Hsu and Casey Timmerman, both students in the Medical Scientist Training Program that grants dual M.D./Ph.D. degrees; Dr. Mingyi Chen, Associate Professor of Pathology; and Dr. Jian Qiao, Assistant Professor of Pathology. Former laboratory manager Yang Wang and former postdoctoral researchers Aijun Shen, and Yang Pu also participated.

The study received support from the National Institutes of Health and the Cancer Prevention and Research Institute of Texas (CPRIT).

The authors report no disclosures.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

The finding builds on a December 2018 study by the same researchers who found that antiviral drugs do not increase the risk of liver cancer recurrence, as was previously feared.

Dr. Amit Singal

Dr. Amit Singal’s study was published in the journal Gastroenterology on July 30. Dr. Singal is an Associate Professor of Internal Medicine, Medical Director of the UT Southwestern Liver Tumor Program, and Clinical Chief of Hepatology. He collaborated on these studies with Dr. Caitlin Murphy, Assistant Professor of Population and Data Sciences and Internal Medicine. They are both members of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Their studies overturn prior misconceptions that made doctors reluctant to prescribe direct-acting antivirals to treat hepatitis C in patients with a history of liver cancer. Many doctors previously believed that hepatitis C, for all its harmfulness, activates the immune system when it infects the liver, and the immune system kept liver cancer recurrence at bay.

But this notion appears to be false. Drs. Singal and Murphy studied nearly 800 patients from 31 medical centers across the country and found that the drugs are not only safe, they decrease death from cirrhosis and liver cancer by 46%.

“Not only are these drugs safe in this patient population, but we have now demonstrated that they are helpful,” Dr. Singal said. “Our study changes the paradigm from you could treat a patient’s hepatitis C to you should treat it.”

Dr. Caitlin Murphy

Dr. Carlos L. Arteaga, Director of the Simmons Cancer Center, said the study’s scope and impact are something that can only be produced by a National Cancer Institute-designated Comprehensive Cancer Center.

“Dr. Singal had more patients involved in the study than any other participating site. As an epidemiologist, Dr. Murphy brought rigor to the data that removes prior doubt on this issue,” he said.

Dr. Murphy said previous studies compounded the misunderstandings of direct-acting antiviral therapy because they, among other things, failed to account for the timing of therapy relative to liver cancer diagnosis, did not include a comparison group, or did not properly consider clinical differences among patients.

The new study is a significant contribution because it clears the path to beneficial drug treatment.

“Hepatitis C therapy is so important because it provides a cure,” Dr. Singal said. “You take oral medications for two or three months, with minimal to no side effects, and you’re done. You’re cured of hepatitis C. There’s less than a 1% chance of relapse if you’re cured of hepatitis C.”

Defeating hepatitis C is an important step because infection can otherwise lead to cirrhosis – scarring of the liver – which can be deadly. Cirrhosis can increase the risk for liver cancer, which also may be fatal. Curing hepatitis C with antivirals breaks the first link in a deadly chain of events and can lead to improvement in liver function among those who have previously developed cirrhosis.

Hepatitis C rapidly made its way into the American blood stream in the 1970s and 1980s when intravenous drug use spiked and blood products were not screened for the hepatitis C virus. Hepatitis C infected 2 to 3% of the baby boomer population, the largest generation in U.S. history. Millions were affected.

The disease can lie dormant for 25 to 30 years and resurface as a life-threatening specter years after someone has stopped using drugs and turned to a healthy lifestyle. Hepatologists saw an alarming spike in cirrhosis as baby boomers aged. By 2017, The New York Times called hepatitis C “an enormous public health problem.” In 2018, the Centers for Disease Control and Prevention announced there were nearly 2.4 million people living with hepatitis C in the U.S.

“Dr. Singal’s and Dr. Murphy’s study reports a welcome, fact-based way to oppose the adverse effects of hepatitis C infection in various demographic groups,” Dr. Arteaga said. “Their findings will have a global, lifesaving impact on how hepatitis C is treated. It is particularly important to Texas because the liver cancer incidence rate in Texas is the highest in the nation.”

Dr. Arteaga said the study is also important because liver cancer is highest among the Hispanic population in Texas, and research-based advances in reducing cancer in underserved groups are a Simmons Cancer Center priority.

The Simmons Cancer Center stands among only 32 U.S. cancer research centers named by the National Cancer Institute as a National Clinical Trials Network Lead Academic Participating Site.

The authors declared financial interests with the manuscript.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – Aug. 5, 2019 – Dr. Woodring Erik Wright, Professor of Cell Biology, passionate educator, and scientific trailblazer in the fight against aging and cancer, died on Aug. 2. He was 70.

A faculty member since 1978, Dr. Wright dedicated decades of research to studying the relationships between aging and cancer and focused on the role of the end caps of chromosomal DNA, called telomeres, in these processes.

Together with longtime collaborator Dr. Jerry Shay, Dr. Wright explored molecular mechanisms that regulate telomere shortening and telomerase activity. The laboratory partners leveraged these mechanistic insights into studies on how telomere shortening contributes to human aging and pursued a variety of approaches to transform their insights to develop treatments for cancer and age-related diseases.

“Woody and I collaborated for over 30 years and published many highly cited papers together. His two most cited papers were both published in Science (1994 and 1998) and have been referred to by other authors 5,700 and 3,450 times, respectively,” said Dr. Shay, Professor of Cell Biology, who holds The Southland Financial Corporation Distinguished Chair in Geriatrics. “Woody was exceptionally good at developing new methods and coming up with insightful ideas on how to advance a project. We worked well together and complemented each other’s strengths. He will be missed by me and all his former students and postdoctoral trainees.”

Dr. Wright received the Lyndon Baines Johnson Research Award from the American Heart Association, a Research Career Development award from the National Institutes of Health, a Method to Extend Research In Time (MERIT) Award from the National Institute on Aging, an AlliedSignal Award for Research on Aging, the Hayflick Award from the American Aging Association, and an Ellison Medical Foundation Senior Scholar Award in Aging. He also served on the Scientific Advisory Board of the Buck Institute for Research on Aging.

Together with longtime collaborator Dr. Jerry Shay (right), Dr. Wright explored molecular mechanisms that regulate telomere shortening and telomerase activity.

In addition to being a distinguished researcher with UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, Dr. Wright had heroically waged a 13-year battle with multiple myeloma, a type of rare blood cancer, at the Cancer Center. In the midst of his success in illuminating the role of telomeres, Dr. Wright was diagnosed in 2006 with multiple myeloma and volunteered to take part in one of the nation’s first clinical trials of CAR-T therapy. “I don’t know if it’s because of what I went through or if it’s a normal part of aging, but I have a strong desire to give back,” he had explained in a 2018 interview.

Born June 21, 1949, Dr. Wright received his Bachelor of Arts degree, summa cum laude, from Harvard College in 1970, a Ph.D. under the direction of Dr. Leonard Hayflick in 1974, and an M.D. from Stanford University School of Medicine in 1975. He joined the UT Southwestern faculty as an Assistant Professor following a postdoctoral fellowship at the Pasteur Institute in Paris with Dr. Francois Gros. Dr. Wright became an Associate Professor in 1985 and was promoted to Professor in 1992. At UTSW, he had previously held the Southland Financial Corporation Distinguished Chair in Geriatric Research.

Dr. Wright garnered national and international attention to his work through more than 140 seminars and lectures at major universities and meetings throughout the U.S. and the world, more than 320 published articles, reviews, and book chapters, and 27 patents related to methods for the diagnosis, treatment, and analysis of telomere length, telomerase activity, and other anti-cancer therapies.

Dr. Wright also was a committed and passionate educator. He mentored more than 35 graduate students and 70 postdoctoral fellows during his long and distinguished career. His excellence in the classroom was recognized by Outstanding Teacher Awards in 1993, 1994, 1999, 2008, and 2012. More than four decades of former medical students will remember the songs he wrote and performed to explain topics he was lecturing on in medical histology.

Funeral arrangements are being made with Wade Family Funeral Home in Arlington: 4140 W. Pioneer Parkway, Arlington, TX 76013. Visitation will be held 6 to 8 p.m. Wednesday, Aug. 7. A memorial service begins at 4 p.m. Thursday, Aug. 8.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Resources

• Radiation treatment for kidney cancer
• Video: Definitive radiation treatment for kidney cancer and metastases
• Clinical trials

DALLAS – Aug. 1, 2019 – Investigators at UT Southwestern Medical Center’s Simmons Comprehensive Cancer Center, who are members of the Kidney Cancer Program, report an innovative strategy for treating advanced kidney cancer. In a longitudinal study published today in the International Journal of Radiation Oncology, Biology, Physics, researchers show how the use of a powerful, targeted radiation technique called stereotactic ablative radiotherapy (SAbR) can effectively treat metastatic disease while delaying the need for systemic (drug) treatments, which often come with side effects.

Metastatic kidney cancer is uniquely challenging because the disease can act so differently from one patient to the next. When a tumor metastasizes and spreads to other parts of the body, it does so with varying degrees of severity. Some kidney cancer patients have oligometastatic disease, from the Greek word oligos meaning “few,” and have a small number of metastases. With a limited number of tumors, investigators discovered that it is possible to control the disease by tightly targeting the tumors with high doses of radiation that kill the cancer.

Dr. Raquibul Hannan

In the study, 47 patients received ablative radiation to a combined 68 tumors, resulting in control rates of over 90 percent two years after the radiation therapy. Most patients received one course of radiation with some receiving up to three rounds to target tumors that appeared after the initial SAbR treatment, according to Dr. Raquibul Hannan, radiation oncology co-leader of the Kidney Cancer Program and co-corresponding author of the study – along with Drs. Robert Timmerman and James Brugarolas. Remarkably, two and a half years later, nearly 40 percent of patients did not need any additional treatment beyond SAbR. While this follow-up time is relatively short, the results suggest that for some patients, radiation alone may be enough to control their disease long term. This finding could have a significant impact on patients’ quality of life, since radiation therapy was well tolerated, while systemic, or whole-body drug treatments like targeted therapy and immunotherapy often include a myriad of unpleasant and even toxic side effects.

While metastatic disease could not be ultimately controlled with local radiation alone for some patients, SAbR delayed the use of systemic therapy by 15 months, on average. Importantly, the duration and effectiveness of subsequent drug treatment was seemingly unaffected by SAbR, suggesting that SAbR may provide a survival benefit to patients and preserve their quality of life while leaving the door open for follow-up therapies, if needed.

“This is a potential paradigm shift in how we view and treat advanced disease by outright delaying the use of systemic therapy until otherwise necessary,” Dr. Hannan said.

Dr. Robert Timmerman

Dr. Timmerman, a SAbR pioneer and Fellow of the American Society for Radiation Oncology, echoed the novelty of the approach. “What is truly innovative is the use of SAbR to control the cancer not just initially, but while it remains oligometastatic,” he said. “To my knowledge, this is the first time that SAbR was used in such a manner in any cancer type.”

The study builds on a long-standing tradition of pioneering radiation therapy approaches at UT Southwestern, where the largest series of avant-garde SAbR treatment for kidney cancer was recently reported (Wang et al., 2017).

“This is an approach worth considering for selected patients,” said Dr. Brugarolas, Director of the UT Southwestern Kidney Cancer Program. “The study shows how multidisciplinary care can bring new treatment options for our patients.”

The oligometastatic treatment paradigm is being evaluated in a prospective phase two clinical trial (NCT02956798) led by Drs. Hannan and Brugarolas, which is currently accruing patients at UT Southwestern. “A national study is also under consideration,” Dr. Hannan added.

Dr. Hannan is an Associate Professor of Radiation Oncology and Immunology. Dr. Timmerman, Professor of Radiation Oncology and Neurological Surgery, holds the Effie Marie Cain Distinguished Chair in Cancer Therapy Research. Dr. Brugarolas, Professor of Internal Medicine, holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Also contributing to the study were Dr. Yuanyuan Zhang, Jonathan Schoenhals, Alana Christie, Dr. Osama Mohamad, Chiachien Wang, Dr. Isaac Bowman, Dr. Nirmish Singla, Dr. Hans Hammers, Dr. Kevin Courtney, Dr. Aditya Bagrodia, Dr. Vitaly Margulis, Dr. Neil Desai, Dr. Aurelie Garant, and Dr. Hak Choy. Dr. Hammers is a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine, and Drs. Bagrodia and Desai are both Dedman Family Scholars in Clinical Care. Dr. Choy holds The Nancy B. and Jake L Hamon Distinguished Chair in Therapeutic Oncology Research.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – July 24, 2019 – A new molecular mechanism discovered by UT Southwestern researchers indicates that drugs currently used to treat less than 10 percent of breast cancer patients could have broader effectiveness in treating all cancers where the drugs are used, including ovarian and prostate cancers. The new study also revealed a potential biomarker indicating when these drugs, called PARP inhibitors, can be unleashed in the fight against cancer.

“These findings could increase the patient population benefiting from these drugs by two, three, or four-fold. Up to 70 percent of breast cancer patients could now be good candidates,” said Dr. W. Lee Kraus, Director of the Green Center for Reproductive Biology Sciences at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. “We have found that PARP inhibitors can act by a mechanism that is different from those previously identified, which rely on BRCA-dependent DNA repair pathways.”

This research helps explain why breast cancer patients can be responsive to PARP inhibitors even if they don’t have BRCA gene mutations.

The Kraus team’s findings were published in the journal Molecular Cell on July 24.

PARP inhibitors were approved by the FDA in 2014 for the treatment of ovarian cancers containing BRCA mutations, rare genetic mutations that disable a DNA repair pathway in cancer cells. The FDA also approved PARP inhibitor for breast cancer treatment in 2018. In their current use, doctors prescribe PARP inhibitors to disable a second DNA repair pathway, making it difficult for cancer cells to survive.

Dr. Kraus’ lab discovered that while this war on DNA repair is being waged, PARP inhibitors are also battling for dominance elsewhere in the cancer cell. It is an important, effective fight previously unknown to science. The PARP inhibitors also attack the machinery that makes proteins, called ribosomes.

“Cancer cells are addicted to ribosomes. Cancer cells grow fast and must make proteins to support cell division and other essential processes going on in the cell. If you can slow down or inhibit the production of ribosomes, then you can slow down the growth of the cancer cell,” Dr. Kraus said.

This new understanding changes the way that scientists and clinicians think about PARP inhibitors and their clinical applications, which previously have been focused on DNA repair pathways since the initial discoveries in 2005. It took more than a decade to get PARP inhibitors approved by the FDA. New applications of PARP inhibitors based on Dr. Kraus’ discovery could reach patients much quicker because three PARP inhibitor drugs are already approved and in use.

“The historical view is that cancers need the mutated BRCA gene to be sensitive to PARP inhibitors. That’s what most scientists and clinicians thought,” Dr. Kraus said. “But what the field is now coming to realize is that’s just not true.”

The realizations Dr. Kraus mentioned come from recent laboratory science, preclinical studies, and clinical trials throughout the nation that show additional signs of PARP inhibitors’ effectiveness in the absence of BRCA mutations. But a clear molecular explanation for these effects has been lacking – until now. 

The new study maps out this molecular pathway in its entirety and identifies a potential biomarker, a clinical test, that might indicate which patients may benefit from PARP Inhibitors. The biomarker is based on a protein called DDX21, which is required for the production of ribosomes in small subcellular compartments called nucleoli. The presence and function of DDX21 in the nucleolus requires PARP-1, the target of PARP inhibitors. Treatment with PARP inhibitors blocks DDX21 function and causes it to leak out of the nucleolus and disburse throughout the nucleus, thus inhibiting ribosome production. High levels of DDX21 in the nucleolus indicate cancers that might be the most responsive to PARP inhibitors.

The Kraus team found the new pathway and potential biomarker by examining a wide spectrum of breast cancer cells, some of which naturally have low levels of PARP. The low-PARP-level cells behaved like cells in which PARP activity was reduced by PARP inhibitors. The discovery builds on 15 years of PARP research so intense that Dr. Kraus’ laboratory team put a molecular model of PARP-1 on his birthday cake.

“We started by trying to identify new molecular mechanisms and pursued this line of inquiry. We didn’t know where the study would lead,” he said. “We started as pure basic scientists, but as the study progressed the clinical relevance became more evident.”

The next step is clinical trials Dr. Kraus is currently developing with UT Southwestern oncologists who treat breast and ovarian cancers.

Dr. Carlos Arteaga, Director of the Simmons Comprehensive Cancer Center, asked Dr. Kraus to speak about this potential new application of PARP inhibitors at the Wendy and Emery Reves International Breast Cancer Symposium on Sept. 20 and 21.

“This is a stellar example of our commitment to translational research; Dr. Kraus sought and secured Institutional Review Board approval for clinical trials with PARP inhibitors before the article was even published. This speaks to the commitment of the Cancer Center to bringing the benefits of our basic science discoveries in cancer directly to patients,” Dr. Arteaga said.

Dr. Kraus is a founder and consultant for Ribon Therapeutics, Inc., which studies PARP inhibitors, and he holds a patent covering reagents used in this research. 

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – July 16, 2019 – Dr. Phil Evans is so deeply involved in nonprofit cancer groups that a luncheon with the National Breast Cancer Foundation was a routine item on his calendar. But the event turned out to be anything but ordinary. Dr. Evans was stunned with a Lifetime Achievement Award.

“I was just floored. I couldn’t believe it. It was just such a surprise,” said Dr. Evans, a Professor of Radiology who serves as Chief of the Breast Imaging Division.

The Frisco-based breast cancer charity honored him in May for his decades of work with and on behalf of breast cancer patients, including his recent efforts to help raise $40 million for a new breast center at Parkland Memorial Hospital. Scheduled to open in 2021, the center will more than double the number of breast cancer patients visits from 40,000 to 100,000.

National Breast Cancer Foundation founder and CEO Janelle Hail said Dr. Evans’ work on the fundraising campaign coupled with his reputation as a compassionate and attentive doctor made him ideal for the award.

“For 40-plus years, Dr. Evans has devoted his career to improving the health of women. As a diagnostic radiologist, he has fought tirelessly to screen and diagnose women early while serving on the medical staff and also as a leader at one of our most prestigious partner hospitals, Parkland,” she said.

The National Breast Cancer Foundation is just one of many organizations that Dr. Evans has worked with to advance cancer care. He served as President of the Society of Breast Imaging and of the American Cancer Society. He also joined several committees of Susan G. Komen, the prominent breast cancer foundation based in Dallas.

“That’s the way you get things done,” he said.

When Dr. Evans talks about the nonprofit groups, he quickly gets into the details of their organizational structure, history and goals. It’s a testament to how heavily involved he is. He cites nonprofit work and patient groups as medicine’s major partners in cutting the breast cancer mortality rate in recent decades. Breast cancer deaths dropped 39 percent from 1989 to 2015, according to the American Cancer Society.

His affable demeanor, well known among the nonprofit groups, extends into patient care.

Frisco resident Linda Neal, a patient of his for more than two decades, said she trusted him so much she followed him from one hospital to the next and later had her own daughter become one of his patients.

“I just have absolute trust in him and his knowledge,” she said explaining that patients appreciate his warm smile and calming voice. “His bedside manner is probably the best I’ve ever had in any physician – ever.”

Dr. Evans also works closely with other physicians and within institutions to advance breast cancer care. In 2013, D Magazine named him one of “The Dallas Dozen,” the magazine’s annual list of 12 influential people in Dallas. The magazine described that year’s distinguished group as people who “would rather be in the trenches getting things done.”

Dr. Evans currently serves on the Planning Committee for the Wendy and Emery Reves International Breast Cancer Symposium. The premier event, hosted by UT Southwestern Simmons Cancer Center, will spotlight the most recent progress in breast cancer research and clinical care. Dr. Evans recruited two speakers for the September symposium: Dr. Debra Monticciolo, President of the American College of Radiology, and Dr. Robert Nishikawa, an artificial intelligence expert at the University of Pittsburgh.

“It’s a world-class group of people coming for this symposium,” Dr. Evans said. “It’s the real cutting-edge people in breast cancer.”

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

The authors of the study published this month in the Journal of Clinical Oncology investigated why many cancer clinical trials fail to enroll enough patients. The researchers sought to identify potential interventions – i.e., solutions – to improve the situation.

Research in the Department of Population and Data Sciences investigates ways to improve health care delivery on a population level. Its studies often involve breaking a problem into its component steps, identifying potential barriers at each step, and developing a list of possible interventions for future study. In this specific project, the researchers approached suboptimal clinical trial enrollment – a significant national concern – as a health care delivery issue.

Dr. Celette Sugg Skinner

“Cancer clinical trials are meant to result in treatment advances. However, their potential benefits are diminished by suboptimal trial participation, both by patients and by clinicians and their organizations,” said Dr. Celette Sugg Skinner, Chair and Professor of Population and Data Sciences and corresponding author of the study. Dr. Skinner is also a member of the Harold C. Simmons Comprehensive Cancer Center and holds the Parkland Community Medicine Professorship.

Nearly half – 40 percent – of cancer trials fail to reach targets for accrual, the medical term for the number of patients who have completed or will complete the trial. Fewer than 2 percent of adults with cancer enroll in trials, and last year no trials were offered in 36 percent of physician-owned and 14 percent of hospital-owned oncology practices, she said.

In order to help ensure results will reach statistical significance, clinical trials are designed to enroll a calculated number of patients, she explained. “Before we can figure out how to improve accrual in trials, we need to better understand the entire process and challenges along the way.”

Dr. Simon Craddock Lee

To gain this understanding, lead author Dr. Simon Craddock Lee, Associate Professor in the Department, conducted in-depth interviews with 10 key oncology physicians, nurses, and research staff in leadership positions across nine states.

“Nationally, we know there are large numbers of cancer patients and relatively few of them are in clinical trials,” Dr. Lee said. “Most of the research to date has focused on the idea that the problem must be that patients don’t know about clinical trials.”

That mindset led to a research emphasis on improving communication so that patients are aware of trials and understand the risks and benefits as well as reaching out to underrepresented populations and ensuring messages are culturally appropriate – all worthy goals. However, this study identifies another group of problems, he explained.

The researchers found that emerging therapies and the changing landscape of oncology have introduced complexity, he continued. Specifically, oncology practices encounter barriers to (1) staying aware of available trials, (2) identifying eligible patients, (3) introducing the idea of trial participation vs. standard treatment to those patients, and (4) enrolling and caring for them throughout clinical trials.

These steps have become more complicated due to emerging discoveries in the realm of precision oncology, which seeks to determine the best treatment based on patient genetic, environmental, or lifestyle factors. For example, whereas trials in the past would enroll all patients with stage 2 breast cancer, current trials often are designed to enroll only patients with certain biomarkers.

“As eligibility criteria become more numerous and specific, the likelihood of any patient meeting all criteria goes down,” Dr. Lee explained. “Because oncology practices are not reimbursed for determining and documenting enrollment, trial accrual is threatened as these tasks become more costly and time-consuming.”

The authors suggest that addressing challenges to trial accrual may involve changes in trial-specific reimbursement, as well as incentives for administrative and infrastructure costs.

Dr. David Gerber

“Our next goal must be to enhance logistic, infrastructure, and policy support to translate oncology discoveries into high-quality cancer care,” said co-author Dr. David Gerber, a Professor of Internal Medicine and Population and Data Sciences. Dr. Gerber serves as Associate Director for Clinical Research and co-Leader of the Experimental Therapeutics Program in the Simmons Cancer Center.

The researchers will use this study to guide future investigations. Most immediately, they have surveyed more than 1,000 oncology providers, asking in-depth questions about the barriers identified in this study. Findings from that survey will help to identify strategies to ensure that clinical trials enroll the targeted number of patients.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – June 3, 2019 – A novel imaging test shows promise for identifying kidney cancer patients most likely to benefit from immunotherapy.

In a study published today in the Journal for ImmunoTherapy of Cancer, investigators with the UT Southwestern Medical Center Kidney Cancer Program developed a new test to illuminate kidney cancers that may respond to checkpoint inhibitors.

The strategy involved transforming an immunotherapy drug, atezolizumab (Tecentriq, Genentech/Roche Group), into a diagnostic tracer. Atezolizumab, which is used to treat lung, breast, and bladder cancer, binds to and disables PD-L1, a protein that cancer cells display on their surface to shut off approaching killer immune cells. By labeling atezolizumab with zirconium-89 (Zr⁸⁹), a radioactive metal generated using a cyclotron, the investigators were able to visualize atezolizumab using PET (positron emission tomography). As such, a single, very small dose of Zr⁸⁹-atezolizumab can be used to evaluate whether tumors deploy PD-L1 to suppress immune cells and whether drugs disabling this pathway may be effective.

(l-r): Drs. Xiankai Sun, James Brugarolas, and Alex Bowman with UT Southwestern Medical Center have pioneered a novel imaging test to identify kidney cancer patients most likely to respond to immunotherapy.

Currently, immunotherapy drugs benefit less than 50 percent of kidney cancer patients. With immuno-PET, or iPET, as a screening tool, the investigators hope to identify those patients who will benefit. Marking the first time this type of theranostic (drug turned into a diagnostic test) is deployed for kidney cancer, the approach opens a molecular window to what is going on inside a cancer patient.

In proof-of-principle experiments, a team led by Dr. James Brugarolas, one of the corresponding authors of the study and the Director of the UT Southwestern Kidney Cancer Program, showed that Zr⁸⁹-atezolizumab was able to illuminate kidney tumors with high levels of PD-L1. As part of the study, investigators selected tumors from two patients, one with high PD-L1 and another with low PD-L1, and transplanted them into mice. The mice were then injected with Zr⁸⁹-atezolizumab intravenously and evaluated by PET. As predicted from the mouse studies, the patient with the high PD-L1 tumor had substantial regression of his metastases when treated with nivolumab (Opdivo, Bristol-Myers Squibb), which targets the PD-L1 pathway.

"The development of tests predicting which patients respond to immunotherapy is critical,” said Dr. Hans Hammers, an immunotherapy expert with the Kidney Cancer Program.

Zr⁸⁹-atezolizumab was filed with the U.S. Food and Drug Administration by the Cyclotron and Radiochemistry Program led by Dr. Xiankai Sun at UT Southwestern, also a corresponding author of the study, and is now proceeding to evaluation in patients in a clinical trial at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.

The clinical trial is made possible through a $600,000 translational award to Dr. Brugarolas’ team by the V Foundation for Cancer Research. Support for the preclinical studies was provided through a Specialized Program of Research Excellence (SPORE) grant from the National Cancer Institute.

“We are hopeful that iPET will identify kidney cancer patients most likely to benefit from checkpoint inhibitors,” said Dr. Alex Bowman, Principal Investigator in the clinical trial, along with Dr. Brugarolas and Dr. Orhan Öz.

A second trial also is planned at the Simmons Cancer Center using Zr⁸⁹-atezolizumab to evaluate the impact of stereotactic body radiation therapy (SBRT) on PD-L1 expression in kidney cancer patients.

“SBRT has the potential to induce inflammation and activate an immune response, and we are excited to evaluate this therapy further in patients using iPET,” said Dr. Raquibul Hannan, a leader in radiation therapy for kidney cancer and Principal Investigator of the study. The SBRT trial will be funded by the Kidney Cancer Congressionally Directed Medical Research Program.

Dr. Brugarolas, a Professor of Internal Medicine, holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Dr. Hammers is an Associate Professor of Internal Medicine and a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine. Dr. Sun, an Associate Professor of Radiology and in the Advanced Imaging Research Center, holds the Dr. Jack Krohmer Professorship in Radiation Physics. Dr. Öz, a Professor of Radiology, holds The Wechun Pak Professorship of Bone Biophysics. Dr. Hannan is an Associate Professor of Radiation Oncology and Immunology. Dr. Bowman is an Assistant Professor of Internal Medicine. Also contributing to the study were Dr. Joseph Vento; Dr. Aditi Mulgaonkar; Layton Woolford; Kien Nham; Alana Christie; Dr. Aditya Bagrodia; Dr. Alberto Diaz de Leon; Dr. Renee McKay; Dr. Payal Kapur; Dr. Guiyang Hao; and Dr. Marianna Dakanali.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

DALLAS – May 23, 2019 – E-cigarette use is climbing among cancer patients and cancer survivors, according to a new study by a UT Southwestern Medical Center oncologist.

Dr. Nina Sanford’s study found that:

• E-cigarette use among people with a cancer diagnosis increased from 8.5 percent in 2014 to 10.7 percent in 2017.
• The increase happened even as conventional smoking remained stable.
• E-cigarette use is especially high among young cancer patients (under the age of 50). More than a quarter of them use e-cigarettes, and it keeps going up: 23 percent of cancer patients under 50 reported using e-cigarettes in 2014 compared with 27 percent in 2017.

“The gradual but steady increase is quite striking,” said Dr. Sanford an Assistant Professor of Radiation Oncology and doctor who specializes in treating cancers of the gastrointestinal tract. “The high prevalence of e-cigarette use among younger cancer patients and survivors is concerning.”

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Dr. Sanford’s analysis was based on data from the Centers for Disease Control and Prevention’s National Health Interview Survey, which included more than 13,000 cancer patients from 2014 to 2017. Her findings were published in the journal JAMA Oncology in February.

The study findings shed new light on e-cigarette use as the products gain increased attention ranging from federal government crackdowns on e-cigarette sales to claims that e-cigarettes can be used to quit traditional smoking.

Usage of e-cigarettes, also called “vaping,” has medical experts concerned because of the addictive nicotine and potentially harmful toxins they deliver. The battery-operated products produce an aerosol that users inhale into their lungs like traditional smoking.

Dr. Sanford said she seized on the opportunity to study the data because there is so little known about e-cigarette use in cancer patients.

“Because e-cigarettes are relatively new, we don’t have the long-term data on their side effects yet,” she said.

With so little known about e-cigarettes and what they do to the body, Dr. Sanford said the best bet is to avoid them all together. She noted that e-cigarettes often produce harmful chemicals such as lead, nickel, and acetaldehyde. Conventional smoking can impede healing from surgery and radiation therapy so it is possible that e-cigarettes could cause similar difficulties, she said.

Dr. Sanford said patients often ask about e-cigarettes, and she recommends staying away from all kinds of smoking instead of trying to substitute e-cigarettes for traditional cigarettes.

“I don’t encourage it, but I also am honest that the jury is still out on what the long-term effects of e-cigarette use are,” she said. “These are not an FDA-regulated product. There’s wide variation of what goes into them. When you pick up an e-cig in the store, you really don’t know what’s in it.”

Regulation of e-cigarettes has just begun and so have studies of the products. Dr. Sanford said medical experts need to know much more, and it will take decades to know if e-cigarettes cause cancer.

“It’s a new area, and there’s just no long-term data on e-cig use so there’s going to be a lot of controversy on what to do until more rigorous studies are published, particularly given the diverse entities involved, ranging from cancer organizations to e-cigarette companies,” she said.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.