On this page we describe current and recent fellow research projects to highlight the variety of research opportunities (clinical, laboratory, quality improvement) in oncology, hematology and stem cell transplant/immunology.

The table presents a summary of research mentors and areas of research our fellows have participated in during the last 8 years.

Applicants to our fellowship program are encouraged to explore individual UT Southwestern Faculty pages for each of these faculty mentors for further information regarding their research activities and interests.

 

SUMMARY OF FELLOWS' RESEARCH :

Carrye Cost, M.D. (Chief Fellow, Third Year Fellow 2010-2011)

Infection remains one of the leading causes of death in pediatric oncology patients. Consequently patients with febrile neutropenia during cancer therapy are often admitted to the hospital for empiric antibiotic therapy. Yet, data demonstrate that only 30% of patients have documented bacteremia with febrile episodes. Therefore, the majority of patients receive broad spectrum antibiotics that expose them to the risks of microbial resistance, nosocomial infection, and drug toxicity. This aggressive supportive care may be unnecessary in some. To have safe and accepted alternative options for managing febrile neutropenia, risk criteria to identify a group at low-risk of bacteremia is needed. Furthermore, while viruses are known to be the most common cause of fever in immunocompetent children, the prevalence of respiratory viral infection in febrile oncology patients is poorly defined. I am going to prospectively study children with febrile neutropenia admitted over a 12 month period, using viral multiplex PCR, to define the incidence of respiratory viral infections and duration of viral shedding in this group. I will also evaluate cytokine expression on the day of admission and correlate expression with bacterial, fungal, and viral infections. I will collect clinical data including vital signs, blood counts, most recent chemotherapy during each admission. My aims are:

• Develop a predictive risk model for bacteremia utilizing respiratory viral infections identified by multiplex PCR, cytokine expression profiling, and clinical factors in pediatric cancer patients with febrile neutropenia
• Evaluate the time course of respiratory virus shedding as measured by PCR in pediatric oncology patients with febrile neutropenia

This information will allow us to identify us to a population that is at low-risk for bacterial infection that can be potentially managed with shorter hospitalizations or outpatient antibiotics.

Amy Fowler, M.D. (Third Year Fellow 2010-2011)

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and survival has improved dramatically to approximately 80%.  However, there remain disparities in survival between various ethnic groups, with the Latino population having survival rates up to 10% lower than Caucasians.  One possible explanation involves pharmacogenomics of chemotherapy metabolism.  Mercaptopurine (6-MP) is a medication that is extremely important to the chemotherapy regimen for children with ALL.  6-MP metabolism is complex, but thioguanine methyltransferase (TPMT) is an enzyme known to be particularly important.  Genetic polymorphisms in the TPMT gene cause alteration of the TPMT enzyme activity, and therefore differences in effectiveness and toxicities.  Patients with almost no TPMT enzyme activity have severe myelotoxicity.  Patients with lower than normal TPMT, have some myelotoxicity, but have improved survival rates compared to patients with wild-type (WT), or normal TPMT.  There is significant heterogeneity of TPMT enzyme activity within patients with WT genetics, and there is some evidence that patients with higher enzyme activity also have a higher risk of relapse.  I am interested to know if the Latino population has a greater number of patients with a higher than normal TPMT enzyme activity, who may not achieve the desired anti-leukemic effect with standard 6-MP dosing, and who may also have an increased risk of relapse.  I am also interested in quality improvement, and have begun an initiative to improve provider adherence to established protocol guidelines for dose adjustment of oral chemotherapy during treatment for ALL. 

The objectives of my research are:

• To compare average absolute neutrophil count (ANC) during ALL maintenance therapy  between Latinos and Caucasians
• To measure TPMT enzyme activity in both Latino and Caucasian children with ALL.
• To improve physician adherence to protocol dose modification guidelines in children with ALL.

These projects may identify a population with higher than normal TPMT enzyme activity, which may benefit from alternative chemotherapy strategies, while also addressing the problem of poor provider adherence to published dose adjustment guidelines.

Nicholas Fustino, M.D. (Third Year Fellow 2010-2011)

Germ cell tumors are a heterogeneous group of neoplasms occurring in neonates, infants and children, and represent 16% of all cancers diagnosed in 15-19 year old adolescents. The biological basis of pediatric germ cell tumors is not known, representing a significant barrier to improved care. We are currently unable to risk-stratify patients using biomolecular data and therefore most children are treated with chemotherapy regimens commonly used in adults. Though these regimens achieve relatively high overall survival, they also incur significant toxicity--including deafness, infertility and renal damage. Better understanding of the molecular mechanisms of pediatric germ cell tumors is critical not only to tailoring therapy, but also to the development of more specific, less toxic, targeted therapies. I am investigating biological pathways which we believe to play a critical role in germ cell tumorigenesis. Using real-time quantitative polymerase chain reaction (PCR) analysis, I am characterizing the expression of over 160 genes potentially involved in embryonic signaling pathways of human germ-cell tumor subtypes. In addition, I am utilizing high-resolution comparative genomic hybridization to identify genomic copy number variations (CNVs) associated with germ cell tumorigenesis. The goals of this study are to identify the critical CNVs associated with adverse outcomes, as well as to identify promising pathways for novel targeted therapies. Furthermore, I will be evaluating micro-RNA expression, which has become a powerful tool in determining the underlying mechanisms of germ cell tumor development. Significant potential exists to improve treatment of germ cell tumors in children. The specific biologic basis of these cancers needs to be elucidated if we are to improve cure rates, decrease toxicity, and improve overall quality of life for these children.

Raven Cooksey, M.D. (Second Year Fellow 2010-2011)

Brain tumors are the second most common form of cancer during childhood.  In the United States, an estimated 2200 children and adolescents are diagnosed with a brain tumor annually.  With current five-year survival rates of 73.3% for children with brain tumors, the majority of these will become long-term survivors.  Numerous treatment modalities are utilized in the care of children with brain tumors, namely surgery, chemotherapy, and radiation.  Survivors may be at increased risk for specific late effects, including: neurocognitive deficits, endocrine deficiencies, growth failure, and stroke.  These late effects can have dramatic effect on quality of life and life expectancy.  A growing body of literature suggests that cranial radiation also portends an increased risk for early development of cardiovascular risk factors (dyslipidemia, central obesity, hypertension) and insulin resistance.  This constellation of findings cluster into what is known as metabolic syndrome, and is associated with an increased risk for type II diabetes mellitus and atherosclerotic disease.  Metabolic syndrome may represent the connection between childhood cancer survivorship and increased long-term risk of cardiovascular disease associated with significant morbidity and mortality, specifically in survivors treated with cranial radiation.  My study will evaluate a cohort of brain tumor survivors treated with radiation for components of the metabolic syndrome.  They will be compared to a group of survivors who did not receive cranial radiation.  Our primary aim is to compare the frequency of metabolic syndrome between these two groups.  Secondary aims include evaluating the individual components of metabolic syndrome, as well as investigation of novel biomarkers of insulin resistance and chronic inflammation in these two groups. 

Scott Furlan, M.D. (Second Year Fellow 2010-2011)

Pattern recognition receptors (PRRs) are proteins found in cells of the innate immune system that recognize pathogen-associated molecular patterns and initiate intracellular signals that upregulate transcription of genes responsible for an immediate immune response to infection. Preliminary work in our laboratory has shown that mice deficient in a critical signaling element of a subset of PRR family, the Toll-like receptors (TLRs), fail to expand their white blood cells normally in response to infection.  This observation lends itself to the notion that PRRs are not only able to recognize pathogens, but can also alter hematopoiesis.

• Determine the role of the PRRs in regulating hematopoiesis during viral and bacterial infections.
• Characterize PRR interaction between bone marrow stromal cells and hematopoietic precursors during acute infection.
• Evaluate the transcription of PRR-dependent cytokines and hematopoietic growth factors during acute infection.

Carrie Laborde, M.D. (Second Year Fellow 2010-2011)

Lymphoblastic leukemia/lymphoma is the most common hematologic malignancy in children comprising 25% of all cancers in children.  Central nervous system adverse events occur in 5-18% of all these patients excluding those with primary CNS disease.   Events include methotrexate neurotoxicity, posterior reversible encephalopathy syndrome, hypertensive encephalopathy, ischemic or hemorrhagic stroke, and central sinovenous thrombosis.  

It is hypothesized that all pediatric leukemia/lymphoma patients are at risk for an impaired neurocognitive function compared to the general population.  Areas such as learning, working memory and concentration may be affected.  Even so, it is not standard to routinely perform neurocognitive testing on all children after completion of therapy.  Identified risk factors include younger age, female gender and certain therapies, like cranial radiation; however, little is known about the contribution of an acute CNS event during therapy on long-term neurocognitive outcome. Current research is ongoing to identify ways to adjust leukemia/lymphoma treatment to limit potential neurotoxicity without impairing survival.  I aim to identify the long-term neurocognitive burden of acute CNS events with the goal of improving screening and interventions for these children.  I  hypothesize that children with CNS events during therapy will have a worse neurocognitive outcome compared to those that have not had events.

I will conduct a retrospective review of all leukemia/lymphoma patients in our institution over the past 10 years to determine the timing of CNS events, associated medications, presenting symptoms and current status.  Patients identified with CNS events at least one year prior to enrollment and who have completed therapy will be asked to participate in this study and undergo testing of intellectual and adaptive functioning using the validated Adaptive Behavioral Assessment Evaluation and Wechsler Intelligence Test. Control groups will include leukemia/lymphoma patients without CNS events and patients without cancer but have had sinovenous thrombosis or stroke.  By including a group of patients at risk for neurocognitive dysfunction, such as children with a history of stroke but not cancer, we may be able to generalize these results beyond lymphoma/leukemia patients in future studies.

Ellen Plummer, M.D. (Second Year Fellow 2010-2011)

Iron deficiency anemia remains one of the leading mineral deficiencies worldwide, affecting nearly 700,000 toddlers and 7.8 million females of reproductive age in the United States. In addition to the symptoms associated with iron deficiency anemia such as fatigue and increased work demand on the heart, this condition has adverse effects on cognitive abilities with potentially lasting ramifications. While oral iron therapy is the initial treatment of choice, approximately 20% of patients fail to have an adequate response to this mode of iron delivery, primarily due to poor compliance and/or untoward side effects such as upset stomach and constipation.  For those patients who are poorly responsive to oral iron therapy, investigation into alternative methods of iron delivery is needed to help correct the condition and prevent complications. Intravenous iron offers a potentially safe and effective alternative.  Historically high molecular weight iron dextran has been avoided secondary to risk of anaphylaxis, however, newer preparations of intravenous iron exist. Based on studies in patients with chronic kidney disease, inflammatory bowel disease, and even pregnancy, these preparations appear both safe and effective in replacing iron stores, though they have not yet been well studied in otherwise healthy children. While there are various preparations available, low molecular weight iron dextran, such as InFed, offers a comparable side effect profile to iron sucrose and iron gluconate with the added benefit of being able to infuse as a total dose infusion.  In collaboration with Dr. Buchanan and Dr. Crary, I will perform a prospective descriptive study to demonstrate the safety and efficacy of low molecular weight iron dextran in children with iron deficiency anemia who have failed oral iron therapy.

Recent Graduates

Mark Hatley, M.D., Ph.D. (2010)

MicroRNAs (miRNAs) are evolutionarily conserved, endogenous, non-protein coding, approximately 22 nucleotide single-stranded RNAs that negatively regulate gene expression in a sequence-specific manner [1-3].  MiRNAs that bind with perfect complementarity to the protein encoding messenger RNA (mRNA) target the mRNA for destruction, and miRNAs that bind with imperfect complementarity to the 3’ untranslated region (UTR) of the mRNA target repress mRNA translation.  MicroRNAs have been implicated in tumorigenesis.  Specifically, the expression of miR-21 is increased in glioblastoma and many carcinomas including lung, breast, stomach, prostate, colon, hepatocellular and pancreatic [4-6].  Several tumor suppressors have been identified as putative targets for miR-21 including PTEN, PDCD4, Maspin, RECK, TIMP3 and TPM1 [6-10].  Increased expression of miR-21 is associated with poor survival and poor therapeutic outcome in colon adenocarcinoma and non-small cell lung cancer [11, 12].  More experiments are needed to determine if miR-21 has a direct function in tumorigenesis or tumor progression or is simply differentially modulated in these tumors.  As well, it is tempting to speculate that miRNA expression signatures in pediatric tumors could have diagnostic and therapeutic implications.  The specific aims of my research are as follows:                                                   

• To determine the sufficiency of miR-21 in tumorigenesis.
• To explore the necessity of miR-21 in tumorigenesis.
• To identify miRNAs regulated in Ewing’s sarcoma.

These studies will provide insights into the microRNA regulatory mechanisms involved in tumorigenesis and will be an important step toward the possible therapeutic manipulation of microRNAs as an approach for tumor therapy.

Amanda Blair, M.D. (2010)

Hemochromatosis occurs as a result of iron overload and iron accumulation in vital organs. Although hemochromatosis can be an inherited condition, most patients develop the clinical signs and symptoms related to iron overload as a consequence of chronic transfusion of packed red blood cells (PRBCs).  It is well-known that children with thalassemia and sickle cell disease can suffer from the consequences of iron overload related to transfusions over a long period of time, often many years.  We do not know if patients who receive multiple transfusions over a shorter period of time, such as occur in children receiving chemotherapy for cancer, share the same long-term toxicities.  As the long-term survival rate for children treated for cancer continues to improve, it is possible that more children will be at risk for developing the clinical sequellae of iron overload.  There currently are no published studies documenting transfusion patterns in children treated for cancer.  Additionally, there is no documented or established threshold for transfusion volume that invariably puts children at risk for development of iron overload. 

The objectives of my research project include (1) systematic investigation of transfusion practices in the pediatric oncology population at Children’s Medical Center Dallas, (2) determination of high risk, heavily transfused patient groups, (3) examination of high risk patient groups for iron levels and organ toxicity and (4) determination of the transfusion volume threshold that puts children at risk for development of iron overload. 

Puja Gupta, M.D. (2010)

Vascular endothelial growth factor A (VEGF) is a primary stimulant of angiogenesis in both normal and pathological settings. Solid tumor development and progression is dependent on angiogenesis, a process considered a hallmark required to sustain cancer. In the tumor microenvironment, VEGF promotes endothelial survival, functions as a powerful permeability factor and modulates the recruitment and function of immune cells. Thus, inhibition of VEGF activity in tumors is a major focus of many academic and biotech research groups. The FDA has approved the use of therapies targeting the VEGF pathway, such as bevacizumab (Avastin). However, significant questions remain as to the most efficacious strategy to inhibit VEGF receptor activation in tumors. The development of the anti-VEGF antibody, r84, has opened a new avenue of research. r84 selectively blocks VEGF-induced VEGFR2 activation, but allows VEGF to signal through VEGFR1. My project focuses on the function and downstream signaling pathway of VEGFR1 in effort to better understand the efficacy and potential safety benefits of targeting the VEGF pathway with r84.

Platelet-derived growth factor receptor (PDGFR) plays a key role in the development and progression of lung cancer. Increased tumor PDGFR expression is associated with a more aggressive phenotype and worse clinical outcomes. A number of new targeted cancer therapies, including imatinib and sunitinib, inhibit PDGFR. However, these non-specific tyrosine kinase inhibitors block a number of signaling pathways. This lack of specificity makes it difficult to isolate the therapeutic effect of PDGFR inhibition. A novel PDGFR- human and mouse specific monoclonal antibodies will allow us to test the hypothesis that both anti-tumor and anti-stromal/vascular properties contribute to treatment effect on tumor xenografts models.

Hanumantha "Chinni" Pokala, M.D. (2010)

My research focuses on infectious complications in pediatric cancer patients. I am currently working on a project exploring rates of invasive fungal infections (IFIs) at Children’s Medical Center of Dallas over the last 5 years. These infections are more severe than bacterial infections and harder to treat. There is significant morbidity and mortality due to the infections themselves, the toxicity of antifungal therapy, and the changes that are often made in the child’s cancer therapy. An increase in the incidence of IFI has been noted at pediatric centers. In addition to known risk factors, there are reports of outbreaks of fungal disease during times of hospital construction. Children’s Medical Center of Dallas has undergone construction for the past several years. During this time, there has been a perceived increase in cases of IFI.

I am performing a retrospective chart review of our patients with hematologic malignancies who started therapy in 2004-2008.  These are the patients who were at the highest risk for developing an IFI. Each patient’s chart will be reviewed for the known risk factors and when they occurred in the context of the hospital construction project. Additional information will be collected on patients who develop IFI.  This will allow a more accurate assessment of any impact hospital construction may have had in the incidence and character of IFI at Children’s Medical Center during this time. I hope this will help in the development of strategies for prophylaxis or preemptive therapies for children with cancer.

Cristina Tarango, M.D. (2009)

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL Ab), increased risk for thrombosis, and pregnancy morbidity.  Circulating aPL Ab are associated with deep venous thrombosis, pulmonary embolism, and stroke in children and adolescents as well as in adults.  The mechanism(s) by which antiphospholipid antibodies cause such devastating disease is still unknown.  In vitro studies indicate that the endothelium is a critical direct target of aPL Ab, which upregulate endothelial cell adhesion molecule expression and procoagulant activity. My project is investigating the molecular basis and disease implications of endothelial dysfunction caused by aPL Ab, using cell culture and mouse models to identify the necessary receptor(s) for aPL Ab actions on endothelium. It is anticipated that the new knowledge gained can then be effectively translated into novel prophylactic or therapeutic strategies to combat the devastating impact of APS on the health of the mother, the fetus, and the newborn.

Martha Stegner, M.D. (2009)

Pilocytic astrocytomas are the most common brain tumor diagnosed in children.  While children diagnosed with these tumors have a very good survival rate, the treatment can often lead to significant long-term complications.  We know very little about the molecular basis of this cancer.  I am currently doing research to better understand the molecular mechanisms that lead to the growth and progression of these tumors.  In order to accomplish this, I am using pilocytic astrocytoma tumor samples from the UT Southwestern pediatric tumor bank.  Each of these samples is clinically annotated, thus allowing us to identify molecular alterations that influence the clinical behavior of these tumors.  I am using a technique called array Comparative Genomic Hybridization (aCGH) to find gains and deletions of genes in the tumor DNA.  I have identified several genes with recurrent alterations in these tumors.  Along with colleagues in my laboratory, I am studying the oncogenic potential of the most promising of these genes, using astrocytes in cell culture and mouse models.   The overall goal of this research is to discover new oncogenes and tumor suppressor genes that could potentially be targets of novel therapies for pilocytic astrocytomas and other cancers.

Tim McCavit, M.D. (2009) 

I am interested in quality of care and outcomes research in pediatric hematology and oncology.  Currently, I am studying quality of care outcomes in sickle cell disease.  Sickle cell disease is a common disorder of hemoglobin, the oxygen-carrying protein of red blood cells.  Children affected by sickle cell disease suffer from a variety of health problems of which severe, recurrent, and episodic pain is the most common.  Hospitalization for pain and other sickle-cell-related problems occurs frequently in sickle cell disease.  We are currently studying a variety of quality of care related outcomes for these hospitalizations.  Additionally, 10% of children with sickle cell anemia, the most common form of sickle cell disease, have a stroke by age 18.  We are studying the impact of a stroke prevention program introduced in the late 1990’s on the rate of hospitalization for stroke in the United States.  My long term research interests include the development of useful clinical practice guidelines, the development of more effective models of care delivery for children with sickle cell disease, and studying the epidemiology of sickle cell disease.

Research Opportunities