SUMMARY OF FELLOWS' RESEARCH :

Mark Hatley, M.D., Ph.D. (Fourth Year Fellow 2009-2010)

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:                                                   

                    1)   To determine the sufficiency of miR-21 in tumorigenesis.
                    2)   To explore the necessity of miR-21 in tumorigenesis.
                    3)   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. (Chief and  Senior Fellow for 2009-2010)

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. (Senior Fellow 2009-2010)

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. (Senior Fellow 2009-2010)

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.

Amy Fowler, M.D. (Second Year Fellow 2009-2010)

Rhabdomyosarcoma (RMS) is a cancer that arises from muscle tissue, and is the most common soft tissue sarcoma that affects children. Currently, children are treated depending upon two types of information: tumor histopathology, and specific clinical information about how large the tumor is, where it is, and whether it has spread. Using this information children are treated according to their “risk group”, wherein children with “low risk” disease receive less toxic therapy, reserving more toxic therapy for those with higher risk disease. This approach has been helpful, but a significant fraction of children thought to have low or intermediate risk RMS have a relapse or a poor response to therapy, and most of these children ultimately die of their disease. In addition, treatment for children with high risk disease is usually ineffective and has not improved significantly in 20 years despite large clinical trials. A better understanding of RMS biology is therefore needed to improve treatment by more accurately targeting therapies to the appropriate risk populations and by identifying new targets for novel drugs. The aim of my project is to use newly developed technology to discover changes in the DNA of RMS tumors that more accurately predict the likelihood of cure and that suggest new targets for therapies. I am using a technique called array Comparative Genomic Hybridization (aCGH) to identify gains and deletions in samples of tumor DNA obtained from the Children’s Oncology Group. The goal of this technique is to identify interesting new oncogenes or tumor suppressor genes, which could improve risk stratification and ultimately treatment for this disease. Our lab has already identified several genes of interest and part of my project will be to elucidate the role of these genes in the oncogenesis of rhabdomyoscaroma.

Nicholas Fustino, M.D. (Second Year Fellow 2009-2010)

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.

Recent Graduates

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. (Chief Fellow 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.

Laura Klesse, M.D., Ph.D. (2008)

Pilocytic astrocytomas are the most common glioma in children.  Optic gliomas, a low grade pilocytic astrocytoma, are extremely common in children with Neurofibromatosis type 1, a genetic disorder associated with an increased risk of malignancy.  Optic gliomas can cause significant problems including growth disturbances, vision loss and progression.  Unfortunately, little is know about the biology of these tumors or how they are best treated.  Optic gliomas most commonly develop in children under the age of six and are treated with chemotherapy or radiation – our current best option.  Since these therapies are given to children with actively developing brains, however, they carry significant risk for long term problems, including developmental delay, growth failure and increased risk of a second cancer.  To better understand the biology of optic gliomas, in order to identify better treatment options, we have created mouse models of Neurofibromatosis that allow us to selectively ablate NF1 in specific cells. We removed NF1, the gene for Neurofibromatosism, from astrocytes of the optic nerve, as astrocytes are the cells from which optic gliomas appear to form.  In mice where NF1 is ablated from astrocytes alone, optic gliomas do not form.  When we delete NF1 from astrocytes and remove one copy of NF1 from the surrounding cells, optic gliomas do form.  These two mouse models provide for a unique opportunity to identify the factors that are critical for driving astrocytes to proliferate aberrantly and form gliomas.  By understanding how these tumors form, and the signaling mechanisms which underlie their development, we hope to identify novel target that we can use to develop better therapies. 

J. Allyson Niece, M.D. (Chief Fellow 2008)

My research interest is in the histocytic disorders, specifically hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH).  I am completing a retrospective chart review in the three largest pediatric academic medical centers in Texas for HLH.  I will be compiling data from Texas Children’s Hospital in Houston, Children’s Medical Center of Dallas and Christus Santa Rosa Medical Center at the University of Texas-San Antonio. In addition, I will be conducting a prospective screening study of children in the pediatric intensive care unit (PICU) at Children’s Medical Center Dallas.  I hope to identify early markers of HLH to hasten diagnosis and initiation of therapy.  My research is funded through an Amgen grant for the academic year 2007-2008.

Jason Litten, M.D. (2008)

Hepatoblastoma is a rare embryonal tumor of the liver in children associated with particular cytogenetic aberrations and genetic syndromes.  I am working in Gail Tomlinson’s Laboratory at The Hamon Center for Therapeutic Oncology Research at UT Southwestern with our institutional hepatoblastoma tissue bank.  Our laboratory is describing the putative role of a novel candidate gene in hepatoblastoma.  We believe that this gene is central to the development of hepatoblastoma and may be a target for future therapeutic interventions.  In addition to direct involvement in all components of this project, my particular role is investigating epigenetic phenomena that contribute to this gene’s expression in normal and hepatoblastoma tissue.  I am supported by a grant from The Saint Baldrick’s Foundation – http://www.stbaldricks.org/#.

Tamra Slone, M.D. (2007)

Acute lymphoblastic lymphoma (ALL) is the most common malignancy of childhood and infection is one of the most common causes of morbidity and mortality in these children.  Ten percent of children with ALL develop temporary insulin-dependent hyperglycemia during treatment and are at increased risk of infection.  The prevalence of obesity has more than doubled in the past two decades in the U.S. as has the incidence of diabetes and pre-diabetes.  We hypothesize there is also a subgroup of children with ALL who have pre-diabetes (impaired glucose tolerance and/or impaired fasting glucose) and are also at increased risk of infectious complications.  My clinical research project is a prospective study in which I am evaluating children with ALL during induction chemotherapy for the development of pre-diabetes and infectious complications.  I am also developing a phase II study incorporating Alimta, a multi-targeted antifol, into the treatment protocol for relapsed ALL with the support of the Children's Oncology Group's relapsed ALL committee.

Cindy Neunert, M.D. (2007)

I am interested in hemostasis and thrombosis and ITP with specific interests outlined below:
1) Elective surgery in patients with hemophilia has increased since the introduction of factor concentrate.  Despite the increase in both major and minor procedures there are no guidelines established for hemostatic coverage during these procedures.  I recently completed a retrospective review on port a cath procedures and plan to look at additional minor procedures. 
2)  Idiopathic Thrombocytopenic Purpura is one of the most common diagnoses bringing children to the attention of pediatric hematologist.  The platelet count is currently considered the best marker for risk of intracranial hemorrhage and is used as outcome measure in research.  We propose that development of a valid and reliable bleeding severity score will assist in improved clinical outcome measures.

Jennifer Wright, M.D. (2007)

My research is in late cardiac toxicity from anthracyclines.  The two areas I am specifically interested in are the use of cardiac MRI to evaluate cardiac function in survivors and sub-clinical toxicity in survivors who received low doses of anthracycline.  I'm currently analyzing the data from cardiac MRIs done in young adult survivors of ALL as part of an NIH sponsored study on cardiovascular risk factors and fitness.  Additionally, I'm about to open a cardiac toxicity study for survivors of ALL treated on a local protocol that received 60 or 150 mg/m2 of daunorubicin.  These patients, who have been off therapy for up to 17 years, will have an echocardiogram and cardiac MRI performed to find the incidence of sub-clinical toxicity and to compare echo and MRI.  If we find that there are a substantial number of patients with cardiac toxicity, we will also do genetic polymorphism testing for allele mutations known to be associated with heart disease.