Nanoparticles Shrink and Kill Cancer Tumors

What if an oncologist could inject small particles into a patient that quickly seek cancer tumors, and just as quickly start a chain reaction in which tumor cells enter a death spiral?

And unlike traditional radiation treatments, which can harm both healthy and cancerous tissues indiscriminately, what if these chemical nanoparticles killed cancer cells only, leaving healthy ones intact and functioning normally?

David A. Boothman, PhD

Triggering a so-called “kiss-of-death” reaction within cancer cells is now within reach of the laboratories of David A. Boothman, PhD, Professor of Radiation Oncology and Pharmacology; and Jinming Gao, PhD, Professor of Pharmacology. Both researchers are associated with the Harold C. Simmons Comprehensive Cancer Center.

 Dr. Boothman and his colleagues in the Cell Stress and Cancer Nanomedicine Program at UT Southwestern are developing nanoparticles specifically designed to target cancer cell resistance and recovery responses to “stressful insults,” such as those occurring after chemotherapy or radiation therapy.

The program has developed nanoparticles capable of delivering a novel class of two known drugs, one of which, ß-lapachone, is derived from the bark of the Lapacho tree found in the South American rain forest. These drugs can selectively and quickly kill cancer cells that have elevated levels of an enzyme called NQO1, found mostly in abundance in solid tumors.

Dr. Boothman teamed up with David Gerber, MD, Assistant Professor of Internal Medicine, to develop a clinical trial ongoing within the Simmons Cancer Center to analyze the safety of using the bark-derived drug, known as Arq761, a derivative of ß-lapachone. Early on, Dr. Gerber also became interested in what the natural product did in the body as it targets elevated NQO1 levels that are typically higher in patients with breast, prostate, non-small cell lung, pancreatic, and colon cancers.

The UT Southwestern group, along with Paul Hergenrother, PhD of the University of Illinois Urbana-Champaign, reported in Cancer Research (Online, April 25, 2012) that a new drug was as effective or more against human solid cancers, including pancreatic cancers. This new drug, deoxynyboquinone, was better at exploiting NQO1 for cell death responses.

But before Arq761 could be studied in humans, Drs. Boothman and Gerber needed a suitable animal model. Enter the work of Rolf Brekken, PhD, Associate Professor of Surgery and Pharmacology. Dr. Brekken’s laboratory, which is focused on pancreas, breast and lung cancer is working to understand the microenvironment inside tumors and how the extracellular matrix affects tumor growth and drug activity. The work of Drs. Brekken and Boothman has demonstrated efficacy of this class of agents against human pancreatic cancers.

Once the drug was successfully delivered in animals with pancreatic or lung cancers, Dr. Boothman demonstrated that cancer cells quickly produced massive levels of hydrogen peroxide as a by-product. Once flooded with hydrogen peroxide, NQO1 cancer cells experienced a dramatic level of genetic damage that ultimately caused a unique form of cell death.

“We hope to personalize this therapy by determining a cancer’s NQO1 levels before treatment. We are already rapidly gaining ground in charting the resistance-based stress response mechanisms that kick into place when cancer cells are confronted by a toxic threat,” Dr. Boothman said. “The next challenge is to make treatments even more specific to certain cancers on an individualized or personalized level by eliminating these resistance (DNA repair) factors.”

Dr. Boothman recently received a Pancreatic Cancer Network Innovator Award from the American Association for Cancer Research for this targeted approach to treating pancreatic cancer. It is the first time that UT Southwestern has been given the award.

“Causing DNA damage specifically to cancer cells and then blocking their ability to repair themselves will hopefully increase the effectiveness of these novel therapeutic agents,” Dr. Boothman said. “When exposed to certain compounds, cancer cells try to repair and evade these treatments in order to survive and spread. Understanding these cell stress events at a molecular level, including the DNA repair inhibitors required for cancer cells to evoke a resistance pathway, has ultimately allowed us to exploit these pathways for improved cancer-selective therapies.”

Another important advantage for patients is that studies suggest this nanoparticle treatment could take only two hours to reach and treat their tumor targets. That compares to the repeated and prolonged infusions many chemo patients know and dread.

Speed is important in killing certain types of cancer, particularly those of the pancreas, which often are diagnosed only in later stages of the disease. Actor and Texan Patrick Swayze waged one of the more famous and public pancreatic cancer battles, dying 20 months after receiving a diagnosis of Stage IV pancreatic cancer in 2008.

“Considering the limited treatment options for pancreatic cancer, finding novel drugs to fight this dreaded set of diseases is the focused goal of researchers at UT Southwestern,” said James Willson, MD, Director of the Simmons Cancer Center.