Dr. Aristizabal will study racial/ethnic diversity in pediatric oncology clinical trial enrollment at Rady Children’s Hospital San Diego. The purpose of the study will be to identify disparities in the current racial/ethnic/age/sex representation in pediatric cancer treatment trials, to help identify under-represented populations that may benefit from potential targeted attention and to categorize the main reasons why parents decide to enroll or not enroll in clinical trials.

Compared with other childhood leukemias, T-cell acute lymphoblastic leukemia (T-ALL) has thus far defied risk stratification. Since 20 – 25 percent of T-ALL patients will have resistant disease, finding ways to identify these high-risk patients up-front is an important step in improving their overall survival. Unfortunately, no molecular markers have yet been shown to significantly correlate with clinical outcomes.

However, next-generation RNA sequencing allows identification of novel gene fusions that may play important roles in the pathogenesis of leukemia as well as to potentially identify high-risk disease. Dr. Balagtas will evaluate the functional oncogenic role of a novel gene fusion, FAM133b/CDK6 in the Jurkat T-ALL cell line. He expects that his efforts will yield additional insight into the molecular basis of leukemogenesis in T-ALL, thus facilitating the design of molecularly targeted therapies. A novel gene fusion may also help to identify high-risk T-ALL patients, allowing early intensification of therapy and, hopefully, improved survival.

In view of significant risks for late effects, pediatric oncologists recognize their obligation to develop strategies to screen for the adverse events that occur in childhood cancer survivors. The activities described below represent a critical developmental step in enhancing services available to long-term survivors of childhood cancer at the Vannie E. Cook Jr. Children’s Cancer and Hematology Clinic through the Passport for Care (PFC) program. Passport For Care is a Web-based clinical decision support tool that uses a survivor’s history of treatment exposures to deliver individualized screening guidelines, risk information, and patient information at the point of care.

Currently, with an overall cure rate of 80 percent, 1 in 300 young adults will be survivors of childhood cancer. Unfortunately, a large proportion of these survivors will suffer from life-altering chronic illnesses and have shortened life expectancies as a result to damage sustained to their brains, lungs, heart, or kidneys from cancer therapy. One of the more harmful, yet effective, treatments is radiation therapy. With two-thirds of survivors having received irradiation to some portion of their body, understanding the mechanism of irradiation injury is necessary to improve the quality of life for these individuals who beat cancer as a child or young adult.

Multivariate data analyses have the potential to enrich the use of the complex plethora of data gathered in the care of critically ill patients, with the goal of identifying risk factors associated with increased mortality. In 2010, Dr. Chaudhury proposed a retrospective data review of the outcomes of stem cell transplant patients who were admitted to the Pediatric Intensive Care Unit (PICU). This study was designed to identify predictors for mortality in this cohort of patients. more on this research summary >

Brain tumors are the second most common form of cancer during childhood. Brain tumors account for 16.6% of all cancers diagnosed among children younger than 15 years. 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. Survivors may be at increased risk for specific late effects, including: neurocognitive deficits, endocrine deficiencies, growth failure, and stroke. more on this research summary >

During the four years preceding this application, the Division of Pediatric Hematology-Oncology at Rainbow Babies & Children’s Hospital has successfully recruited several new faculty members, who together have established a new research initiative focused on the biology of Cdk5. To date, this research team has identified a novel role for this kinase in T cell biology and the relevance of this kinase as a therapeutic target in several childhood cancers, including leukemia. This research team currently seeks to translate this knowledge into a clinical application, starting with a ‘first in children’ Phase I trial with a novel inhibitor of Cdk5. more on this research summary >

For parents of kids undergoing chemotherapy, sometimes the bald hair, new medications or risk of infection is not nearly as distressing as the idea of their child not eating. Malnutrition has been reported in 10-50 percent of pediatric patients at the time of diagnosis.

Hypothesizing that poor nutritional status correlates with delays in chemotherapy and increases the incidence of hospitalization for fever and neutropenia, Dr. Gupta plans to evaluate newly diagnosed pediatric oncology patients treated at the University of Arizona Health Science Center. Evaluating each patient’s nutritional status at diagnosis and prior to the beginning of each chemotherapy cycle, she will study whether malnutrition and obesity negatively affect treatment outcomes.

Aim 1: Perform comparative oncogenomic anaiyses across the human-mouse species barrier of childhood B-lineage tumors, on the one hand, and tumor cell lines and primary tumor samples from double-transgenic LMP1/MYC mice, on the other. Methods involve global gene expression profiling on Affymetrix microarrays, survey of copy number changes across the human and mouse oncogenomes, and bioinformatics approaches including GeneGo analyses. more on this research summary >

Neurocognitive impairments are a well known complication associated with pediatric brain tumors. Evidence also demonstrates that even patients who have undergone surgical resection only (without adjuvant therapy) often experience long-term neurocognitive deficits. Significant treatment advances have resulted in elevated rates of survival and a paradigm shift towards improvement long term quality of life in pediatric brain tumor survivors. As neurocognitive deficits are often related to quality of life and long term functioning, the early identification and treatment of residual neurocognitive deficits is expected to improve a range of outcomes in these children. more on this research summary >

Acute myeloid leukemia (AML) is the second most common leukemia in children. Unlike acute lymphoblastic leukemia, for which therapy cures more than 80 percent of patients, AML is very difficult to treat: only about 50 percent of children survive long-term despite the use of very potent chemotherapy. One of the challenges in studying AML and cancers in general is that we do not understand very well why some cancer cells escape the toxic effects of chemotherapy.

We have undertaken a systematic strategy to understand this phenomenon better, utilizing cutting edge molecular biology techniques and computational analyses to Identify, Confirm and Validate proteins which are Functionally Active during Cancer Treatment (FACTs). < br/>< br/> During preliminary work, Dr. Porter looked for genes that make ARA-C, a commonly used chemotherapy, better at killing cells. Discovering a gene called WEE1, during a second experiment Dr. Porter confirmed that the gene is a FACT in AML cells treated with ARA-C. There is a new drug that inhibits WEE1, and Dr. Porter now aims to hypothesize that WEE1 plays a critical role in AML cell survival in the presence of ARA-C, and will further explore the role of WEE1 in treating AML. more on this research summary >

Hematopoietic stem cells (HSCs) are responsible for maintaining the supply of blood cells throughout the life of an individual. Two fundamental properties of stem cells are self-renewal, or the ability to make more stem cells, and quiescence, or the maintenance of a low metabolic state. These essential stem cell properties are regulated by cues from the environment in which the HSCs reside, which consists of specialized "niches" in the bone marrow. The maintenance of these properties is crucial, as dysregulated HSC function can lead to serious blood disorders, including bone marrow failure and leukemia. more on this research summary >

The successful outcome of HSCT has been greatly enhanced in the last 40 years by improvements in techniques and by progressive understanding of HLA histocompatibility and typing, improvement in supportive care management and by the development of effective immunosuppressive agents. Cyclosporine and tacrolimus have been critical for the improved outcome that has been observed over the last three decades for both solid organ transplantation and HSCT.

Dr. Shah will study the impact of genetic polymorphisms of CYP3A5 on Tacrolimus concentration in immediate post stem cell transplant period. Dr. Shah’s objectives are to determine whether there is a major impact on the Tacrolimus drug level in the pediatric stem cell transplant patient with different CYP3A5 genotype; determine whether a difference in CYP3A5 genotype between the donor and recipient make any impact on the Tacrolimus level; and examine whether the CYP3A5 genotype difference eventually makes any major impact on Acute GVHD or Tacrolimus toxicity.

Coming soon.

Neuroblastoma is the most common extra cranial solid tumor in children. High-risk neuroblastoma is distinctively aggressive and resistant to chemotherapy, with treatment results remaining unsatisfactory for the past 25 years in spite of using the most aggressive therapies. At least 50% of all neuroblastoma cases belong to this category. All neuroblastoma cells have glycoprotein called GD2 on their surface. more on this research summary >

There is an urgent need for new treatment options for poorly responsive and relapsed patients, because 20 percent of infants, children and adolescents will die from their disease or complications of treatment. Furthermore, new drugs with fewer side effects able to replace older, more toxic compounds, are important for long term survival in pediatric patients. more on this research summary >

The incidence of different forms of cancer varies by race and ethnicity. American Indians (AI) and Alaskan Native (AN) children have the lowest cancer incidence among different races. White children has significantly higher incidence of cancer (173.21 per million) than African American (117.87 per million); Asian/Pacific Islander (131.43 per million), and AI/AN (97.32 per million)[1]. Moreover, New-Mexico American Indian children has lower incidence of cancer compared to Alaska Natives, but both share relative lower rate of lymphomas and CNS tumors, and higher rate of retinoblastoma when compared to white Americans [2]. The same findings were similarly presented in adult population with some exception for kidney cancer among the AI/AN population[3].

Various studies showed ethnic immunobilogical disparities between African Americans and white Americans, affecting post-solid organ transplant infection [4], and prostate cancer [5] outcome. The assessment of immunobiological disparity among pediatric patients of minor populations and its correlation with the differ cancer incidence and outcome is not expressed in the literature. My focus is to explore the immunobiological disparity among the New Mexico Native American children with cancer and correlate it with the treatment outcome. more on this research summary >

Dr. Andolina is currently a second year pediatric hematology/oncology fellow within the hospital's Division of Hematology, Oncology and Stem Cell Transplantation. Prior to this, he received his medical degree from the University of Virginia School of Medicine and went on to complete his residency in pediatrics at Children's Memorial.

Our hospital's rigorous three-year training program places young physicians like Dr. Andolina on dual tracks by emphasizing the development of top-notch clinical expertise as well as the hypothesisdriven investigative skills necessary for a career in academic medicine. In their second and third years, fellows dedicate a significant amount of time to advance laboratory or clinical research of their choosing, which is a demanding undertaking that depends on talent, creativity and critical thinking. The third year of training is also a time when fellows prepare research abstracts for presentation at scientific meetings and manuscripts for publication...

Neuroblastoma is the third most common cancer affecting children. Over the past two decades, many advances have been made in improving treatment of many childhood cancers. Unfortunately, children with advanced-stage neuroblastoma continue to do poorly, with approximately two-thirds succumbing to their disease, despite very intense treatments. Often, children will go into remission only to have their neuroblastoma tumors return, resistant to all currently available treatments. To improve the outcome of children with neuroblastoma, new therapies need to be developed. The best way to accomplish this is through a better understanding of neuroblastoma pathophysiology and the mechanisms it uses to circumvent treatments.

My research involves understanding the signaling pathways used by chemotherapy to kill neuroblastoma cells, with the goal of determining ways by which these cells alter the pathways to survive through treatment. The MYCN gene plays a vital role in the outcome of children with neuroblastoma: the presence of extra copies of MYCN in the neuroblastoma cells (called MYCN amplification) portends a bad prognosis in these patients. However, how MYCN impacts the physiology of the neuroblastoma cell and leads to resistance to therapy is currently unknown...

High-risk Neuroblastoma is responsible for 15% of childhood cancer mortality. Despite intensification of cytotoxic therapy and the use of multimodality treatments, survival rates have not changed appreciably in the past 15 years. Furthermore, there is a markedly increased treatment related morbidity and mortality.

High-risk neuroblastoma is a radiosensitive tumor and local control can be achieved with doses of 21 Gy. Currently, external beam radiation therapy is considered an essential component of high-risk neuroblastoma therapy, and the current Phase 3 trial is exploring doses of 36 Gy for patients with gross residual disease following attempts at surgical resection (COG ANBL0532). more on this research summary >

Neuroblastoma is the third most common cancer affecting children. Over the past two decades, many advances have been made in improving treatment of many childhood cancers. Unfortunately, children with advanced-stage neuroblastoma continue to do poorly, with approximately two-thirds succumbing to their disease, despite very intense treatments. Often, children will go into remission only to have their neuroblastoma tumors return, resistant to all currently available treatments. To improve the outcome of children with neuroblastoma, new therapies need to be developed. The best way to accomplish this is through a better understanding of neuroblastoma pathophysiology and the mechanisms it uses to circumvent treatments.

My research involves understanding the signaling pathways used by chemotherapy to kill neuroblastoma cells, with the goal of determining ways by which these cells alter the pathways to survive through treatment. The MYCN gene plays a vital role in the outcome of children with neuroblastoma: the presence of extra copies of MYCN in the neuroblastoma cells (called MYCN amplification) portends a bad prognosis in these patients. However, how MYCN impacts the physiology of the neuroblastoma cell and leads to resistance to therapy is currently unknown...

More information available on Dr. Beaupin's page more on this research summary >

Dr. Bernardi is a chief fellow in the department of pediatrics, section of hematology-oncology, Baylor College of Medicine. He studies cancer pharmacology, experimental therapeutics and drug development. He has been researching the identification and evaluation of novel therapeutic targets for medulloblastoma, including the use of shRNA genetic screens. more on this research summary >

Dr. Borinstein ‘s laboratory investigates epigenetic alterations in Ewing’s Sarcoma (ES) malignant tumor of bone and soft tissue that most often occurs in teenagers and young adults. Although localized ES is often curable, new treatment strategies are desperately needed for patients who present with metastatic disease. Epigenetic alterations are changes that contribute to the regulation of genes within in a cell that does not result in the change in DNA sequence. more on this research summary >

Dr. Butros is an Associate Professor of Pediatrics and the director of the Pediatric YES Clinic at the University of New Mexico. The Hyundai Hope on Wheels grant will support the following planned activity in our Young Enduring Survivors (YES) Clinic. To date, they have been able to start and maintain the database effort and to continue to provide evidence-based medicine in the field of childhood cancer survivorship. They also disseminate this information to patients and primary care providers in the community.

Dr. Butros has analyzed 146 leukemia survivors from the database for growth hormone and other hormone deficiencies, and found a significant risk for growth hormone deficiency in survivors of T cell leukemia. These results were presented in a poster session at the recent 2010 American Society of Pediatric Hematology/Oncology. She plans to add to the database this year to get to a statistically significant number of T cell leukemia survivors for publication. The goal is to have enough T cell leukemia survivors in the database to submit my results for publication by the end of the academic year 2010–2011. more on this research summary >

Dr. Cauff is involved in clinical research in Pediatric Hematology/Oncology. He is an active member of the Children’s Oncology Group. The Children's Oncology Group (COG) is a worldwide research group supported by the National Cancer Institute (NCI) with the mission “to cure and prevent childhood and adolescent cancer through scientific discovery and compassionate care”. All of Dr. Cauff’s new oncology patients are entered into the Children’s Oncology Group registry and enrolled on clinical trials, if appropriate. In 2008, the Division of Pediatric Hematology/Oncology registered 17 patients on active COG treatment protocols and 49 patients on biology and banking protocols. There are 60 active COG treatment and biology studies open for patients at Joe DiMaggio Children’s Hospital. more on this research summary >

Scott J. Diede, MD, PhD is currently an Attending Physician in the Division of Hematology/Oncology at Seattle Children’s Hospital, an Acting Clinical Instructor in the Department of Pediatrics at the University of Washington, and a Research Associate in the Clinical Research Division at the Fred Hutchinson Cancer Research Center. He received his undergraduate degree in chemistry, MD, and PhD all from the University of Chicago, and completed residency in General Pediatrics and a fellowship in Pediatric Hematology/Oncology at Seattle Children’s Hospital.

One mechanism by which cells obtain a cancerous phenotype is through aberrant DNA methylation. DNA methylation is a form of normal gene regulation that is heritable through successive cell divisions, and previous work has shown that cancer cells can exploit this mechanism to silence tumor suppressor genes through promoter hypermethylation. more on this research summary >

Dr. Fluchel is an exceptionally talented physician scientist whose research interests are focused on treatment costs and outcomes, particularly for underserved populations. He has made great progress at University of Utah since his appointment as Assistant Professor in Pediatrics July 1, 2007. Mark received his MD degree from Vanderbilt University and then completed his pediatric residency in 2003 at Seattle Children’s Hospital, University of Washington. Mark then completed his fellowship training in Pediatric Hematology-Oncology at Children’s Hospital of Philadelphia (University of Pennsylvania) in June, 2007. more on this research summary >

Traditionally, treatment of pediatric cancer has relied on the use of combinations of chemotherapy and radiation. For some types of pediatric cancers these agents have proven highly effective and can even achieve a cure, but this success comes with a cost including decreased growth, abnormal hormone levels, decreased fertility, and the risk of new secondary cancers from treatment. In addition, many children present with disease that is resistant to even high doses of chemotherapy and radiation.

more on this research summary >

Neuroblastoma is the most common extra-cranial solid tumor in children and accounts for nearly 10% of all childhood cancers. In the United States approximately 600 new cases are identified each year. Despite steady advances in chemotherapy treatment, patients with high-risk advanced disease continue to have poor survival. Efforts to change the natural disease outcome of advance Neuroblastoma with aggressive treatment regimens that included high dose therapy and stem cell transplantation have not significantly improved survival for all patients. With current methods of treatment survival for a child greater than 1 year-old with advanced stage Neuroblastoma is 40-50%. more on this research summary >

The Children’s Hospital of New York-Presbyterian at Columbia University has one of the largest pediatric oncology programs in the United States. Residing within this division is the Pediatric Cancer Foundation Developmental Therapeutics Program (PCFDTP) led by Dr. Julia Glade Bender. The PCFDTP has demonstrated scientific leadership in the field of translational antiangiogenic research through investigations of novel agents which inhibit tumor blood vessel growth by blocking vascular endothelial growth factor. Preclinical work is conducted in the Pediatric Tumor Biology laboratory and clinical translation is carried out by the PCFDTP which strives to deliver patient-centered care while offering innovative approaches not ordinarily available in the community through participation in early phase clinical trials. This interplay between laboratory studies and clinical investigation gives us the unique opportunity to introduce and advance new treatments for children with cancer. Columbia University continues to be one of only 21 Phase 1 institutions supported by the National Cancer Institute and the Children's Oncology Group (COG). Our institution is the only so designated center caring for children and adolescents with cancer in the New York, New Jersey, Connecticut tri-state region. Our program is also an active member in both the New Approaches to Neuroblastoma Therapy (NANT) and Therapeutic Advances in Childhood Leukemia (TACL) Consortia with Dr. Glade Bender serving as the Institutional Principal Investigator. more on this research summary >

Dr. Gordon is a fellow in pediatric hematology/oncology at the University of Mississippi Medical Center. Her research investigates the use of two drugs used to treat acute lymphocytic leukemia (ALL), which strikes almost 25 percent of the children diagnosed with cancer each year in the U.S. Dr. Gordon is investigating ways to decrease the side effects associated with one of the chemotherapy drugs used to treat ALL called Vincristine. more on this research summary >

Neuroblastoma is a tumor of the nervous system in children. It has been noted that children of a younger age (less than 1 year) do much better in terms of survival than older children. Age has been one of the criteria to classify these children to the three groups of low, intermediate or high risk. The treatment and prognosis differ among these groups with only a third of the high risk patient surviving long term.

The human body fights against infection as well as tumors using the immune system. The immune system functions by two different pathways, the innate and the adaptive. The innate system is nonspecific and is the primary defense in infants. As the child grows, the adaptive system develops which produces a specific response and defense. It has been noted in previous studies that components of the innate system are more active in fighting against neuroblastoma. more on this research summary >

TARGETED I-131 MIGB THERAPY FOR NEUROBLASTOMA Neuroblastoma is a cancer of the peripheral nervous system and the most common tumor in children. Approximately 600 patients are diagnosed per year. One of the most difficult parts of treating neuroblastoma is that it often initially responds to chemotherapy, radiation and surgery but eventually comes back. The survival at five years from diagnosis is less than 40%. For patients who experience a relapse of their neuroblastoma, the survival is generally accepted to be less than 20%.

The commitment to clinical research in the Cook Children’s Hematology and Oncology Center stems from the desire to provide hope for our patients and a chance for a cure. For many patients, this hope is delivered in the form of clinical trials where patients have access to the most cutting edge treatments. One such treatment is 131I-metaiodobenzylguanidine (MIBG) which is a radioactive target of neuroblastoma. This drug is infused intravenously and goes to the tumor sites, even those that cannot normally be detected, and delivers a radiation dose over an extended period of time directly to tumor cells. The remainder of the radioactive material is then eliminated from the body. The therapy requires specialized facilities for delivery and monitoring of the patient and caregivers to assure that the radiation is being eliminated at the proper rate. The monitoring of the radiation exposure to the whole body is called dosimetry and is performed by nuclear medicine physicists. They measure the radiation emissions from the patient over time as collected by a Geiger counter mounted above the patient bed. Patients are in isolation during for 3-5 days after the infusion until their radiation levels reach a certain threshold. Their visitation from family members is restricted to appropriate exposure levels and then is increased over time as the radiation emissions decrease. MIBG has been shown to be an effective agent in relapsed and refractory neuroblastoma with response rates up to 40% in a heavily pretreated population. more on this research summary >

J. Anthony Graves attended Bucknell University from 1987 to 1991 and graduated with a B.A. in Biology and a minor in Black Studies. He started graduate school in his hometown of Pittsburgh, PA at Carnegie Mellon University. He studied yeast genetics in the lab of Dr. Susan Henry and graduated in 1996 with his doctor dissertation entitled, Analysis of the Role of the OPI1 Gene Product in the Negative Regulation of the Phospholipid Biosynthetic Pathway of Saccharomyces cerevisiae. Next, he matriculated at The Johns Hopkins University School of Medicine. He completed his first year of training and then did a two year research fellowship at Johns Hopkins in the laboratory of Dr. Chi Van Dang where he studied various aspects of Myc biology, including its impact on apoptosis. He returned to the medical program in 1999 and graduated with his M.D. in 2002. He started his residency in 2002 in Pediatrics at the Children’s Hospital of Pittsburgh, and continued at the same hospital for his fellowship in Pediatric Hematology/Oncology. Following the completion of his fellowship, Dr. Graves joined the faculty at the Children’s Hospital of Pittsburgh of UPMC. Under the mentorship of Dr. Edward Prochownik, he again has focused his studies on the Myc oncoprotein as well as the role of the regulation of reactive oxygen species in tumorigenesis. Currently he is a Hyundai Hope on Wheels Scholar and a Harold Amos Medical Faculty Development Scholar sponsored by the Robert Wood Johnson Foundation. He is married to his wife Becky and has two children: Isaac (age 7) and James (age 7 months). more on this research summary >

Dr. Haertling was recruited to our training program largely due to her interest in a career as a physician-scientist targeting the improvement in the quality of life of children with oncologic and hematologic disorders. Dr. Haertling’s training provides an excellent platform on which to build a solid research career. She completed her Doctor of Osteopathic Medicine at A.T. Still University in Kirksville, Missouri and her pediatric residency at Saint Louis University’s Cardinal Glennon Children’s Medical Center in St. Louis. While in her residency, she participated in a quality improvement project focused on the effectiveness of pain management of hospitalized patients before and after the institution of a standardized admission protocol. This experience combined with the additional clinical training she received as a first year fellow at Children’s Memorial has allowed her to refine her skills and interest in the development of assessment tools to further evaluate parameters which impact the quality of life of pediatric cancer patients.

During the next two years Dr. Haertling will pursue a hypothesis driven clinical research project under the mentorship of Stewart Goldman, MD, Medical Director of Neuro-oncology, and a committee of three faculty members. Dr. Haertling’s research project will look at the issue of fatigue, a problem that impacts the quality of life of many pediatric cancer patients, but has not been widely studied. As such, there is a critical need to examine a way to minimize the fatigue and other problems associated with cancer and its treatment that many children experience. Such research can lead to improved risk-based care specific to each individual’s cancer diagnosis and treatment. Dr. Haertling will compliment her research activities by enrolling in the Master of Science in Clinical Investigation (MSCI) at Northwestern University. more on this reseach summary >

More available in PDF Dr. Harrison Proposal

Dr. Keller is a board-certified pediatric oncologist and NIH R01-funded investigator specializing in the development of more effective, less toxic therapies for the childhood muscle cancer, rhabdomyosarcoma, and the childhood brain tumor, medulloblastoma. His special interest is advanced disease that has spread beyond the initial location of the cancer. Dr. Keller is investigating whether the genes thought to be responsible for the initial tumors are also important when the disease progresses, thereby identifying targets for new medical therapies.

One would like to think that tangibly better treatments for rhabdomyosarcoma, medulloblastoma and other childhood cancers can be found in a matter of years, instead of tens of years. Finding new treatments starts with research, perhaps even a new research approach to identifying effective new treatments. The Pediatric Preclinical Testing Initiative at the Pediatric Cancer Biology Program at the Oregon Health & Science University focuses on finding molecules in childhood cancers that can be directly turned off or on by drugs so that the tumor stops growing. Behind our novel approach is the use of genetically-engineered mice. Our Pediatric Preclinical Testing Initiative uses mice modified from before birth so that at a certain age, and in a certain tissue, the same mutations found in a child’s cancer are activated in the mouse. These special mouse models of childhood cancer can be used to test a treatment to see whether the tumor growth and spread (metastasis) can be reversed. The specific aspect of these mice having normal immune systems is a real plus, too, because white blood cells play an important role in how tumors evolve and respond to therapy. more on this research summary >

Dr. Kumar is principal investigator for COG studies at University of Kansas Medical Center and involved in clinical research in Pediatric Hematology/Oncology. Her patients are offered disease appropriate clinical trials through COG and are enrolled on current leading edge cancer treatment trials, identifying causes of childhood cancer and contribute to research to improve quality of life and survivorship. more on this research summary >

Dr. Jennifer Levine is one of two 2010 Hyundai Scholars from Morgan Stanley Children’s Hospital of New York-Presbyterian. She is the medical director at the Center for Survivor Wellness, Division of Pediatric Oncology, Columbia University and an assistant professor of pediatrics at Columbia University Medical Center. Dr. Levine is also an attending physician at both Morgan Stanley Children’s Hospital of New York-Presbyterian and Stamford Hospital in Stamford, Connecticut.

Dr. Levine’s research focuses on the survivors of childhood cancer, investigating the long-term complications of oncology treatment, conducting outcomes research and developing new programs and methods to provide supportive care to pediatric cancer survivors throughout their childhood and adolescence and into adulthood. more on this research summary >

A diagnosis of cancer in a child is overwhelming and terrifying. Families are required to become experts in medical terminology, understand complicated procedures, and make decisions under stressful situations. They also must navigate a complex regimen of medications both at home and in the hospital. Timely medication administration at home is vital to treating these diseases. If medications are not taken properly, adverse effects may occur, or the disease may not be treated effectively and recur. Medications can interact with food or other medications if not taken at the right time. Communication between families and health care providers is essential to making certain that children receive their medications accurately, especially at home. more on this research summary >

Dr. Madigan’s research involves developing combinatorial personalized therapy for childhood leukemia. This project involves a multidisciplinary team of scientists. Drs. Catherine Madigan and William Roberts are involved in clinical research on childhood leukemias at Rady Children’s Hospital and UCSD. Other investigators span a wide combination of disciplines, such as control theory, artificial intelligence, theoretical physics, statistical mechanics and optimization methods, computational modeling of metabolic and signaling networks, disease models and therapeutic interventions. More specifically, Andrew McCulloch (UCSD Bioengineering) has relevant expertise in bioengineering and systems biology, Giovanni Paternostro (Burnham Institute for Medical Research) in biomedicine and systems biology, Philip Duxbury (Michigan State University) in statistical mechanics and control and optimization in physics, Carlo Piermarocchi (Michigan State University) in quantum control and optimization, Jorge Cortes (UCSD Engineering) in control and optimization in engineering. Additionally we have recently added a collaborator with vast expertise in statistical analysis of clinical and omics data, Nicholas J. Schork, Director of Biostatistics and Bioinformatics, The Scripps Translational Science Institute. more on this research summary >

Dr. Mohamed’s research is in the area of palliative care, described as “medical care that lessens pain or the side effects from treatment of a disease, such as cancer.” Palliative care helps make patients more comfortable at every stage of an illness. There may be ongoing issues with symptom control associated with therapy and/or progression of high risk cancer. These problems may include pain, nausea, anorexia, fatigue, immobility and depression. General practitioners who wish to direct the care of children with life-threatening or life-limiting conditions must become familiar with pediatric palliative care. more on this research summary >

Dr. Nhlane is involved with clinical research in Pediatric Hematology/Oncology. He is an active member of the Children’s Oncology Group (COG) and the Nevada Cancer Research Foundation (CCOP). He completed his fellowship in Pediatric Hematology Oncology in June 2009 at Memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital (University Hospital of Columbia and Cornell). Dr Nhlane is an attending physician at Children’s Center for Cancer & Blood Disease of Las Vegas and works directly with Dr. Jonathan Bernstein, the Principle Investigator for the COG in Nevada.

As a member of the COG and CCOP, Dr. Nhlane must maintain the highest standards for treating children with cancer and follow COG-defined protocols to prove scientific, medical and ethical scientific expertise. All of Dr. Nhlane‘s cancer patients are evaluated for clinical trials if appropriate and he oversees their treatment plans to guarantee research protocols are meticulously followed to ensure the best possible patient outcomes. Statistics from these patients are used to develop standardized, evidence-based protocols for childhood cancer patients’ world wide. more on this research summary >

Javier E. Oesterheld received his Bachelor of Science degree from Lehigh University in Bethlehem, Pennsylvania. He attended medical school at the Universidad Central Del Caribe, Puerto Rico and completed his residency at the University of Medicine and Dentistry of New Jersey - Newark. Dr. Oesterheld completed his hematology/oncology fellowship at Columbia University, Morgan Stanley Children's Hospital New York. He is currently part of the Hematology/Oncology team at Levine's Children's Hospital where he was named Director of Developmental Therapeutics in July 2009. more on this research summary >

Andrea Orsey is a pediatric hematologist/oncologist, and lead physician of Cancer Support Services at Connecticut Children’s Medical Center. Dr. Orsey holds a M.D. from the University of Connecticut School of Medicine and a M.S.C.E. with an emphasis on clinical trials from the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. Dr. Orsey also holds a B.S. in physical therapy from McGill University and has been a licensed physical therapist in the state of Connecticut since 1996.

Dr. Orsey is an active member of the Cancer Control Committee of the Children’s Oncology Group, an international research group composed of over 200 hospitals that treat children with cancer. As a faculty member of the Department of Pediatrics of the University of Connecticut School of Medicine and the Graduate School of Clinical and Translational Research at the University of Connecticut, Dr. Orsey has been a co-investigator in several studies focused on assessing and managing pain for children with sickle cell disease. more on this research summary >

Dr. Othman’s research explores dissecting mechanisms of lymphocyte recruitment at the blood-brain barrier. Pediatric brain tumors continue to be the Achilles’ heel for researchers and clinicians engaged in discovering novel therapeutic strategies and improving the lives of pediatric oncology patients. In particular, medulloblastoma (MB) is the most common malignant brain tumor of childhood. Originating from embryonal neuroepithelial cells, MB often exhibits an aggressive growth pattern. It frequently invades surrounding CNS structures such as the regional subarachnoid and ventricular spaces, and can cause widespread seeding of the subarachnoid space. MB is one of only a few brain tumor types with a systemic metastatic potential including extraneural spread, principally to the bone marrow. To-date, available treatment options for MB remains highly problematic. Conventional multi-modality therapies such as surgery, radiotherapy and chemotherapy can all cause significant brain injury manifesting as long-term neurocognitive defects in many patients of all ages. New directions in the development of anti-tumor therapy are therefore needed. One such new direction is cell-mediated immunotherapy, in which tumor-specific lymphocytes are targeted to destroy tumor cells while preserving normal tissues. more on this research summary >

Dr. Pauly's research will involve studying the BCL-2 family of proteins with regard to their anti-apoptotic and pro-apoptotic roles in a cell life cycle. My initial project will be working with a druge that inhibits BCL-2 and BCL-XL and studying the impact of this drug on cells that are deficient in the downstream proteins of BCL-2 and BCL-XL in an effort to understand potential side effects of the drug. The long term plan of her research is to then study this drug in childhood lymphoma and/or leukemia. more on this research summary >

Dr. Joanna Perkins is a pediatric hematologist/oncologist at Children’s Hospitals and Clinics of Minnesota in Minneapolis. She joined the professional staff at Children’s in September, 2003 after completing her fellowship in pediatric hematology/oncology/BMT at the University of Minnesota. She also received her bachelor’s degree in psychology, her doctorate from the School of Medicine, and her master’s degree in clinical research at the University of Minnesota. Her research has focused on the long-term effects of treatment for childhood cancer. She lives with her husband Ron and two sons (Alex and Nick) in Apple Valley. more on this research summary >

Pediatric brain tumors continue to be the Achilles' heel for researchs and clinicians engaged in discovering novel therapeutic strategies and improving the lives of pediatric oncology patients. In particular, medulloblastoma (MB) is the most common malignant brain tumor of childhood. Originating from embryonal neuroepithelial cells, MB often exhibits an aggressive growth pattern. It frequently invades surrounding CNS structures such as the regional subarachnoid and ventricular spaces, and can cause widespread seeding of the subarachnoid space. MB is one of only a few brain tumor types with a systemic metasatic potential including extraneural spread, principally to the bone marrow. To-date, available treatment option for MB reamins highly problematic. Conventional mutli-modality therapies such as surgery, radiotheraphy and chemotherapy can all cause significant brain injury manifesting as long-term neurocognitive defects in many patients of all ages. A new direction in the development of brain tumor therapy is therefore the incorporation of biological agents that are capable of targeting specific tumor signaling pathways to maximize treatment efficacy while reducing toxicity at the same time. more on this research summary >

Down syndrome (DS) is the most prevalent chromosomal disorder in the population and associated with alterations in development in a range of organ systems. The Centers for Disease Control and Prevention estimates DS to occur in approximately 1 in 733 newborns in the United States. Children with DS may be variably afflicted with a range of conditions including cognitive challenges, congenital heart defects, endocrinopathies, autoimmunity, orthopedic problems, and hematologic disorders. Children with DS therefore represent a unique population in which to study acute leukemia. These children are ten to twenty times more likely than age-matched peers to develop leukemia, making them an excellent model for the study of leukemogenesis. In addition to their propensity to develop leukemia, DS children have other underlying metabolic abnormalities that may contribute to their development of leukemia including their decreased intrinsic antioxidant activity and inability to process free radicals.

Dr. Pope's work on analysis of multiple genes in key pathways influencing the ability to repair DNA damage and metabolize free radicals. They are studying genes with known functional polymorphisms that are common in the population, many of which are associated with increased risk of cancer or of heart disease, often an endpoint for free radical damage. more on this research summary >

Dr. Rubin’s project is development of a comprehensive sarcoma research clinical program. Progress in the treatment of Ewing’s sarcoma, the second most common bone tumor in children and adolescents, has improved survival from about 10% in the period before chemotherapy was introduced to about 75% today for patients with non-stage 4 localized tumors. However, for stage 4 patients (those with metastatic disease) the survival rate is significantly worse and therapy for stage 4 patients is very toxic and can lead to significant short- and long-term adverse effects. Multi-disciplinary care is indispensable for these patients. The recent development of new molecular technologies and imaging modalities has led to a rethinking of the diagnosis, classification, and treatment opportunities for patients with Ewing’s sarcoma.

Dr. Elyssa Rubin is a junior faculty at CHOC Children’s Hospital in Orange County, CA and a member of the CHOC Cancer Institute. Dr. Rubin completed her fellowship in pediatric hematology/oncology at CHOC Children’s in 2009 and joined the staff and faculty of the CHOC Children’s Hospital Cancer Institute and the University of California, Irvine (UC Irvine). Dr. Rubin’s fellowship research centered on sarcoma work with Dr. Bang Hoang, a surgical orthopedic surgeon. Her work involved determining the mechanism involved with osteogenic sarcoma at a basic science level. With new innovative therapeutics now becoming available, the need for a truly multi-disciplinary team that involves radiologists, radiation oncologists, medical oncologists, surgical pathologists, sarcoma pathologists, sarcoma orthopedic surgeons, and general pediatric surgeons has never been more relevant. more on this research summary >

Dr. Shad leads a collaborative team composed of pediatric oncologists, pediatric oncology nurses, social workers, psychologists, patient advocates, nutritionists, clinical research associates, chaplains and art therapists – all of whom provide care to the 80% of children who will survive cancer into adulthood. However, no treatment is without undesirable effects. As childhood cancer survivors grow into adolescents and young adults, some are at risk of developing complications related to the very treatments that saved their lives. No longer can pediatric oncologists walk away from the responsibility of monitoring these survivors for late effects of treatment; most of which appear years after remission or cure, and range from physical to educational to psychological issues. more on this research summary >

Dr. Thakar completed her Pediatric Hematology-Oncology Fellowshit at the Fred Hutchinson Cancer Research Center and University of Washington in Seattle, WA, in 2008. She was recently recruited to the Medical College of Wisconsin for her first faculty position in January 2010. Since her arrival in Milwaukee, she has designed bone marrow transplant clinical trials and translational research projects geared toward overcoming relapse in pediatric patients with high-risk malignancies. Her goal as a Pediatric Oncology and Stem Cell Transplant physician is to continue searching for curable and less-toxic means to treat relapsed patients. more on this research summary >

In recent years, much has been learned about gene regulation of the developing brain. Among the many genes involved, the “hedgehog” family of genes appears to have a pivotal role in the embryonic development in mammals including humans. Likewise, significant data has accumulated regarding the biology and genetics of medulloblastoma. It is evident that certain genes and “signaling” pathways regulate the development of medulloblastoma. Previous data has shown that the dysregulation of sonic hedgehog and Gli signaling pathways are a significant contributor to this malignant process. more on this research summary >

As advances in medicine and technology improve the survival of children with cancer, attention to health-related quality of life and progress in symptom management has not kept pace with advances in disease-directed therapies. This disparity creates a population of children who are living with cancer but who suffer from inadequate symptom control. The paucity of systematic research in symptom management leads to a lack of evidence or standards on which to base interventions, which leads, at least in part, to suboptimal supportive care.

Fatigue is frequently reported to be the most incapacitating of symptoms, preventing children from partaking in meaningful life experiences, thereby impairing quality of life. In a cross-sectional retrospective survey of parents of children who died of cancer, at Dana Farber Cancer Institute/ Children’s Hospital Boston ( DFCI/ CHB) led by Dr. Joanne Wolfe, 96% of children experienced some degree of fatigue, with 49% of children suffering significantly from it.1 Through further analysis of these data, with an additional cohort of parents from Children’s Hospital of St Paul and Minneapolis, we have found that suffering from fatigue is associated with suffering from pain, dyspnea, anorexia, nausea/vomiting, anxiety, sadness, or fear (P<0.05) and with side effects from pain or dyspnea treatment (P<0.05).2 more on this research summary >

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although a majority of children can be cured, a significant proportion relapse. While biologic markers like the Philadelphia chromosome, age at diagnosis, and initial peripheral blast count prospectively identify some patients at a high risk for relapse, many patients have no identifiable biologic markers for increased relapse or toxicity risk. Further improvements in ALL outcomes may occur by risk stratification based on new paradigms. more on this research summary >

Dr. Yankelevich’s project title is “Development of Optimal Production, Cryopreservation, and Recovery of Mature Autologous Dendritic Cells in Preparation for a Phase I Study of Dendritic Cell-Based Vaccine in Children with Recurrent High Glade Gliomas.”

In spite of multimodal therapy, including maximal safe neurosurgical resection followed by radio-chemotherapy and maintenance chemotherapy, malignant or high-grade gliomas (HGG) continue to have a dismal prognosis both in children and adults. The preclinical, and the early clinical evidence have demonstrated a therapeutic potential of (DC)-based immunotherapy for HGG. Vaccination with tumor antigen-loaded DC’s generated in vitro has been shown to elicit antitumoral CTL responses responses in vivo and to induce tumor regression in some patients with gliomas. One of the critical steps in the DC-based immunotherapy is the ability to cryopreserve and subsequently revive sufficient numbers of functionally active clinical grade DC for sequential vaccination. DMSO is the most commonly used cryoprotectant with majority of DC studies using it at the concentrations of 10% or higher. However, DMSO at such concentration is toxic to cells, so it can negatively affect cell survival and function. Our preliminary results and recent literature reports suggest that using 5% DMSO vs. 10% DMSO may result in a better preservation of cells. The other advantage of using the lower concentration of DMSO is that it reduces the exposure to the patient. It will also enable us to reduce or avoid further manipulations with DC after thawing. more on this research summary >

Dr. Andolina is currently a second year pediatric hematology/oncology fellow within the hospital’s Division of Hematology, Oncology and Stem Cell Transplantation. Prior to this, he received his medical degree from the University of Virginia School of Medicine and went on to complete his residency in pediatrics at Children’s Memorial.Our hospital’s rigorous three-year training program places young physicians like Dr. Andolina on dual tracks by emphasizing the development of top-notch clinical expertise as well as the hypothesis driven investigative skills necessary for a career in academic medicine. In their second and third years, fellows dedicate a significant amount of time to advance laboratory or clinical research of their choosing, which is a demanding undertaking that depends on talent, creativity and critical thinking. The third year of training is also a time when fellows prepare research abstracts for presentation at scientific meetings and manuscripts for publication in peer-reviewed journals. While our seasoned physicians and scientists are dedicated to guide, teach and inspire those who seek out their knowledge, they too look to these emerging young physicians with great hope that one day they will uncover answers to some of medicine’s most challenging questions. Hyundai’s continued support will help ensure the professional development of pediatric physician-scientists such as Dr. Andolina who will care for childhood cancer patients today well into the future.

Neuroblastoma is the third most common cancer affecting children. Over the past two decades, many advances have been made in improving treatment of many childhood cancers. Unfortunately, children with advanced-stage neuroblastoma continue to do poorly, with approximately two-thirds succumbing to their disease, despite very intense treatments. Often, children will go into remission only to have their neuroblastoma tumors return, resistant to all currently available treatments. To improve the outcome of children with neuroblastoma, new therapies need to be developed. The best way to accomplish this is through a better understanding of neuroblastoma pathophysiology and the mechanisms it uses to circumvent treatments. My research involves understanding the signaling pathways used by chemotherapy to kill neuroblastoma cells, with the goal of determining ways by which these cells alter the pathways to survive through treatment. The MYCN gene plays a vital role in the outcome of children with neuroblastoma: the presence of extra copies of MYCN in the neuroblastoma cells (called MYCN amplification) portends a bad prognosis in these patients. However, how MYCN impacts the physiology of the neuroblastoma cell and leads to resistance to therapy is currently unknown. My research will examine the interactions of the MycN protein with its antagonists such as Mxi1, and how these interactions are involved in the development of resistance to treatment with chemotherapeutic agents. We will examine how these proteins interact with known cell death pathways and what they do to modulate responses to therapy.By elucidating these interactions, we hope to develop targeted therapies that bypass blockades, thereby resulting in improved outcomes for children with advanced-stage neuroblastoma.

I am dedicated to improving the care of pediatric sarcoma patients through clinical and translational research. My fellowship training at The Children’s Hospital of Philadelphia (CHOP) has provided me with an excellent starting point for a career in pediatric oncology. My fellowship research project focused on the discovery of novel therapeutics in pediatric neuroblastoma. CHOP currently has one of the premier programs in the country for caring for patients with neuroblastoma. I will use the neuroblastoma model developed here as a guide to develop a world-class sarcoma program. Our sarcoma program will integrate outstanding patient care with scientific advancement, and hopefully bring novel therapies from the bench to the bedside. During the period of time I am supported by the Hyundai Scholar Award, I will establish a pediatric sarcoma patient database needed to initiate this program. I will also continue to contribute to a growing body of knowledge on solid tumors, particularly sarcomas. Receiving the Hyundai Scholar Award will serve as a launching point for my career. The CHOP Oncology Clinic sees approximately 50-60 new sarcoma patients each year. I will build a database to capture information about our patients’ care – including diagnosis, treatment plans, surgical approaches, complications from therapy, and supportive care. In addition, I will integrate this clinical information with other biological information, including tumor pathology, molecular genotyping, and expression profiling. By taking advantage of our division’s vast experience with this particular patient population, there is certainly much to be learned by examining this large dataset. I will use this information to develop standards of care for our patients. In addition, I will use this information to implement novel programs, both therapeutic and supportive, for our sarcoma population. Because many sarcoma patients are adolescents and young adults, we plan to develop an Adolescent/Young Adult (AYA) clinic in collaboration with the University of Pennsylvania, to care for these and other cancers that affect this population. In addition to data collection and analysis, I also plan to move carefully selected novel therapies for pediatric sarcoma patients to the clinic. This will require careful collaboration with other investigators such as Drs. Womer and Peter Adamson at CHOP, and Drs. Arthur “Chip” Staddon and Keith Flaherty at Penn, as well as the pharmaceutical industry as new, targeted agents are developed. The above-mentioned individuals have extensive experience with clinical trials, and moving new drugs through the pipeline.

Today, 75 to 80 percent of children with cancer will be cured of their disease. This astonishing feat represents over 30 years of progress in the development of cancer research and treatment protocols, each built on knowledge gained from earlier studies. Survival from childhood cancer, however, comes with unintended consequences. As many as two thirds of the survivors of childhood cancer have, or are likely to develop, treatment-related diseases and disabilities. Although children often tolerate the immediate side effects of cancer treatment better than adults, these young, growing patients are more vulnerable to problems that may emerge in subsequent years as a result of their treatment. As knowledge of these problems grows, treatment regimens are being modified and intervention strategies developed to alleviate them. Increasingly, physicians are recognizing the need to screen and treat patients in order to protect their quality of life and to diminish the secondary economic and social implications of these problems as they progress toward adulthood, establishing long-term relationships, and entering the work force. In addition, many pediatric oncology centers are initiating specific Late Effects Programs to address the needs of survivors of childhood cancer.

Dr. Cauff is involved in clinical research in Pediatric Hematology/Oncology. He is an active member of the Children’s Oncology Group. The Children's Oncology Group (COG) is a worldwide research group supported by the National Cancer Institute (NCI) with the mission “to cure and prevent childhood and adolescent cancer through scientific discovery and compassionate care”. All of Dr. Cauff’s new oncology patients are entered into the Children’s Oncology Group registry and enrolled on clinical trials, if appropriate. In 2008, the Division of Pediatric Hematology/Oncology registered 17 patients on active COG treatment protocols and 49 patients on biology and banking protocols. There are 60 active COG treatment and biology studies open for patients at Joe DiMaggio Children’s Hospital. Dr. Cauff oversees all policies, procedures and treatment plans to make sure that the research protocols are rigorously followed to insure the best outcomes. Data from his patients is used to develop standardized, evidence-based protocols for pediatric cancer patients. This data is also periodically published in national medical journals.

Metastatic neuroblastoma remains a difficult disease to treat with survival rates of less than 40 % despite aggressive therapy. N-MYC, a transcription factor found in neuroblastoma that portends a poor prognosis, is often amplified in these children. The treatment of recurrent or refractory disease includes myeloablative chemotherapy, radiation therapy, and stem cell transplant. This treatment plan is highly toxic, and has remained relatively unchanged for a number of years. A better understanding of the mechanisms regulating neuroblastoma growth and N-MYC activity is likely to lead to better approaches to treatment. The observation that neuroblastoma occurs more frequently in children with high birth weights has led to the speculation that growth factors such as IGF-I may be important in the pathogenesis of neuroblastoma. IGFI is a small peptide that signals through a specific membrane tyrosine kinase receptor, the insulin-like growth factor-I receptor (IGF-IR), and has an important role in cell survival and proliferation. Signals are transduced through either the ras/MAPK or PI3 kinase/Akt pathways. The mammalian target of rapamycin (mTOR) is a downstream element of the PI3 kinase/AKT pathway that plays an important role in the regulation of cell growth, proliferation, motility, and survival. Given that cell survival and proliferation are key aspects of malignant cells, the IGF-I signaling pathway and mTOR present intriguing avenues for neuroblastoma research. mTOR can be blocked by rapamycin, a commercially available drug that is already approved for use in children. Analogs of rapamycin exist, including temsirolimus, which is currently being investigated in a number of adult cancers. My previous work has been through collaboration with Dr. Billie Moats-Staats at the University of North Carolina at Chapel Hill investigating the impact of mTOR blockade in neuroblastoma. We inhibited mTOR signaling in neuroblastoma cell cultures by treating them with rapamycin or temsirolimus and found that this decreased both neuroblastoma cell number and N-MYC activity. This work has resulted in two publications in the medical literature.

Dr. Druley is a board-certified pediatrician and faculty member in Pediatric Hematology and Oncology at St. Louis Children’s Hospital. He is a general oncologist who also participates in the care of bone marrow transplant recipients. His research is based in the hypothesis that much of pediatric cancer predilection and treatment is heavily influenced by the unique combination of rare inherited DNA polymorphisms within each person. Dr. Druley’s research is conducted in Washington University’s Center for Genome Sciences, which is composed of a multidisciplinary group of investigators focused on utilizing the latest genomic technologies to improve the understanding of a wide array of fundamental genetic processes and their roles in human diseases. Dr. Druley has helped design and validate new high-throughput DNA sequencing technology and plans to use this technology to characterize the degree of germline DNA variation inherent in a variety of diseases, particularly pediatric cancer. The long term goals are to better understand the pathophysiology of pediatric cancer as well as to identify all of the pertinent germline variants within a pediatric cancer patient prior to starting therapy in order to provide a genetically customized treatment plan designed to maximize anti-cancer activity while minimizing toxicity and morbidity.

Acute Myeloid Leukemia (AML) is a disorder of normal blood cell development. Approximately one thousand children are diagnosed with AML each year in the United States. Their survival using conventional therapies hovers near 50%, which lags considerably behind survival for acute lymphoid leukemia and has changed only modestly in the last decade. This outcome is clearly unacceptable, and reinforces the need for both new insights into AML pathogenesis and new therapeutic targets. Because AML occurs when mechanisms of normal blood cell development are altered, we must better understand these mechanisms, how they are altered in AML and how we can overcome these alterations to improve outcomes for our patients. At the heart of AML development are mutations in genes that direct hematopoiesis, an exquisitely regulated and flexible process whereby hematopoietic stem and progenitor cells produce more mature cells found in our peripheral blood. The most commonly observed chromosomal translocations seen in AML involve the RUNX1 locus and genes that encode members of the myeloid translocation gene (MTG) family of proteins. These translocations encode fusion proteins composed of RUNX1 and MTG domains that can, at once, impair hematopoietic development, enhance hematopoietic stem and progenitor cell self-renewal capacity, and antagonize the machinery that corrects new mutations as they arise. From this fertile ground, a fully malignant leukemia cell can emerge. In our laboratory, we are working to understand how MTG proteins and their proleukemic derivatives influence the machinery governing hematopoietic stem and progenitor cell self-renewal and how these relationships are regulated. We believe this will lead us to novel targets for therapeutic development that improve survival for patients with AML. Without the generous support of the Hyundai Hope On Wheels program, our shared mission to cure every pediatric cancer patient could not be realized.

Cancer is the chief cause of non-accidental death in children younger than 15 years of age. Thankfully, the prognosis for children with cancer has greatly improved in the past several decades. The average survival rate for these children is now approximately 75%, up from only 5% in the 1960s. Nonetheless, approximately 2,500 children are expected to die of the disease this year. Researchers believe that an improved understanding of pediatric cancer epidemiology—who suffers from it and why—is the key to eventually finding a cure for the approximately 12,500 to 13,000 children who are expected to be diagnosed with cancer this year. Advances in our understanding of the epidemiology of various adult cancers have led to important cancer screening and early detection recommendations; however, much more research is needed in the epidemiology of childhood cancer in order to develop prevention strategies for children who are vulnerable. Statistical studies have also been used to characterize the socio-economically unique aspects of South Texas, or the area known as the Rio Grande Valley (RGV). This area is largely Hispanic (88.2% in 2000 Census) and has almost three times the national average of its population living below the poverty level (35.4% as compared to 12.4% in 2000). In RGV environmental exposure to chemicals is high, considering the importance of farming to the region. There is a general assumption among epidemiologists that cancer risk is increased in Rio Grande Valley, however this has not been proven. The Vannie E. Cook Jr. Children’s Cancer and Hematology Clinic (VECCC) in McAllen, Texas was established in 2001 and was the first in South Texas to provide complete care for children dealing with cancer and blood disorders. The clinic is affiliated with Baylor College of Medicine and Texas Children’s Hospital. Patients are now no longer forced to leave for treatment in various places like Houston, San Antonio and Corpus Christi. Because of this, a large portion of the pediatric cancer cases in South Texas are now centrally located within one location. Experience in VECCC gave us an opportunity,for the first time, to conduct an epidemiological study in pediatric oncology in South Texas.

Cancer is the leading cause of disease-related deaths among children 1 to 14 years of age, and acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although cure rates for pediatric standard risk ALL have dramatically increased in recent years, it is unlikely that additional minor changes using the available drugs will provide any significant further improvement in survival. The development of new drugs which more selectively kill cancer cells may provide an opportunity to continue to increase survival rates in children with leukemia. Additionally, subsets of patients respond unfavorably to current treatment protocols. Pediatric patients with early relapse also have very low survival rates. In fact, only 10- 30% of patients with early bone marrow relapse on therapy maintain are able to maintain a second remission. Thus, there continues to be a significant need for new treatment strategies to offer ALL patients who relapse or have high risk cancer. Finally, pediatric cancer survivors have a significant risk of both short-term and long-term toxicities associated with currently used chemotherapy agents. Approximately two of every three pediatric cancer survivors will have at least one adverse late effect (growth delay, infertility, organ dysfunction, cognitive function) and one in four will experience a late effect that is severe. Hence, new therapies that are less toxic are needed to replace some of the standard chemotherapeutic agents or provide increased effectiveness when used with currently used drugs.

The research proposal will be a pilot study evaluating the optimal timing of presentation of the subject of Late Effects associated with cancer therapy. Late effects of therapy are critically important to the overall health of the childhood cancer survivor. Families often times are focused on active treatment and the late effects are forgotten or not viewed as important in the face of the ongoing challenge of defeating cancer. Unfortunately, this does not diminish their importance. Determining the most receptive time for presentation of these late effects will be the goal of this study. We will be focusing on three subgroups of patients: recently diagnosed (3-6 months after diagnosis), recently completed therapy (3-6 months after completion of therapy) and long term off therapy (over 18 months off therapy). We will be utilizing surveys to interact with the families at these time points to determine when the optimal time for presentation of the subject regarding Late Effects of cancer treatment would be.

As a result of therapeutic advances, survival rates for childhood cancer have improved considerably in recent decades, and the majority of the 20,000 children in the United States who are diagnosed with cancer each year will become long-term survivors. Therapeutic strategies in pediatric oncology today are increasingly using “risk-based” therapy that seeks to deliver effective anti-neoplastic therapy with reduced toxicity to the patient. Nonetheless, untoward health outcomes known as “late effects” are often recognized in survivors of cancer therapy. Some of these issues affect the developing child while others may not surface until adulthood. Research focused on long-term survivors of childhood cancer has allowed us to anticipate certain organ-specific complications, including learning impairment, abnormal growth and development, gonadal and reproductive abnormalities, and the development of secondary malignancies. Although research to identify chemotherapy regimens that minimize late effects without compromising survival rates is ongoing, interventions that identify and manage late effects continue to be important components of the treatment of childhood cancer survivors.

Complementary and alternative medicine (CAM) is defined as interventions that are not traditionally available in hospitals nor taught in medical training programs. Recent surveys have demonstrated that a large number of pediatric oncology patients are using some form of CAM therapy and the use of these agents seems to be on the rise. Some of the more common therapies include dietary changes, nutritional supplements, herbal remedies, massage, acupuncture, chiropractic therapy, and vitamin therapy. There are a number of reasons patients and parents are choosing to utilize CAM therapies including managing side effects, maintaining some control of their treatment, and understandably trying to ‘do everything’ for their child. An enormous amount of unreliable information on CAM in oncology is available in the media and internet, where CAM products are widely marketed and available. While most of these therapies have not been rigorously studied, some have shown benefit to patients. However, the limited evidence that does exist is for adults and may not translate to children. With the rising number of children using these therapies, experts from around the world are advocating a need for research into all aspects of CAM therapies. Drug interactions have been shown to cause morbidity and mortality in patients with cancer. Due to the large number of medications patients receive, these drug interactions may occur more frequently than currently reported. Some interactions increase toxicity while others decrease the effectiveness of the medication. In addition to the interactions between conventional medications, CAM therapies may potentiate or even cause additional unintended problems. Knowledge of CAM’s true effects (good and bad) in children with cancer is slowly evolving. Therefore, it is important to first understand the scope of the issue so that pediatric oncologists can improve patient safety. Interestingly, most CAM use is not disclosed to the pediatric oncologist making patient safety an even greater issue. In one study the primary reason cited for not disclosing CAM use was that the parents were simply not asked about the use. This further highlights the need for further study within a pediatric oncology clinic.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, accounting for 5-8% of childhood cancers. The two major subtypes of rhabdomyosarcoma (RMS) are the alveolar (ARMS) and embryonal (ERMS) forms. Alveolar rhabdomyosarcoma accounts for approximately 20% of all cases. The alveolar subtype has been associated with more aggressive disease, increased rates of metastasis and an unfavorable outcome. Two specific gene abnormalities have been identified in alveolar rhabdomyosarcoma. These abnormalities involve genetic rearrangements of PAX3 or PAX7 and Forkhead (FKHR) genes which are normally involved in muscle development and cell division, respectively. These rearrangements produce abnormal, cancer causing fusion proteins that seem to be important for tumor formation, although the mechanism is not fully understood. Tumors involving the PAX3-FKHR genetic defect result in higher risk disease. RNA interference, RNAi, has emerged as a leading candidate strategy to suppress disease genes. Small inhibitory molecules (microRNAs) can be designed to specifically target any gene based on its DNA sequence. My research will focus on the development of an RNAi viral vector to suppress PAX3-FKHR in cells and in mouse models of ARMS. The primary goal of this research is to reduce PAX3-FKHR protein and decrease or eliminate ARMS tumor growth through PAX3-FKHR targeted inhibition. RNAi therapy will provide further insight in the development of ARMS and provide a potential therapeutic tool in adjunct to current therapies for this more aggressive form of rhabdomyosarcoma.

Pediatric brain tumors remain amongst the most common malignancies in childhood, second only to leukemia, representing 20% of all childhood cancers in the United States. Although significant strides have been made in therapies for other pediatric malignancies, mortality for patients with brain tumors remains high. The mainstay of therapy for CNS tumors has been a combination of surgery, chemotherapy, and radiation. High dose chemotherapy with stem cell transplant has been proposed as an alternative to radiation, in very young children and for relapsed patients. Stem cell transplantation however is not without significant side effects as well as transplant related mortality. Busulfex has historically been used in the setting of conditioning regimens for stem cell transplants, and has been shown to be effective therapy for pediatric brain tumors both in vitro and in vivo. Busulfex is a unique agent in that it crosses the blood brain barrier, reaching concentrations in the central nervous system (CNS), nearly equal to that in the plasma. Capitalizing on this property, we propose that Busulfex can be an affective agent for pediatric brain tumors at a lower dose, thus obviating the need for stem cell transplant. Children who are between the ages of 2 and 21 years of age with any histological proven recurrent or progressive CNS tumor are eligible for this study. Following enrollment, patients will undergo stem cell harvesting as a precautionary measure. Patients will then receive Busulfex as a 24 hours infusion every 4 weeks for 6 cycles, provided that they maintain the required blood counts. Should their blood counts not recover within 42 days following the infusion, they will receive their previously harvested stem cells. The main objective of this trial is to determine the maximum tolerated dose of Busulfex given as a 24 hour infusion to patients with recurrent, progressive, or refractory primary brain tumors. As secondary aims, we hope to learn more about the pharmacokinetics of a continuous infusion of Busulfex, and to obtain data regarding progression free survival and event free survival when Busulfex is used at submyeloablative doses in children with recurrent, progressive, or refractory brain tumors.

Acute leukemia is the most common malignancy in children. High risk leukemia patients have a poor outcome despite the most intensive treatment currently available. More intensive treatment is not an option, because it has a dose limitation due to major side effects to normal cells and leukemia cells acquire resistance to chemotherapy. Also, long term leukemia survivors show many side effects from chemotherapy and radiation therapy. Leukemia cells are believed to arise from leukemia stem cells (LSC). It is known that LSC are responsible for leukemia maintenance and relapse; therefore, it remains urgent to develop novel treatments to target LSC specifically. This treatment approach is also significant for children to spare normal cells from toxicities, since most leukemia survivors suffer from long term side effects from current treatments. Although extensive efforts have been made to develop LSC targeted treatments, there are very few LSC targeted treatments available to date since only a few LSC are identified. Unique LSC markers have not been identified in childhood leukemia and different leukemia may have different LSC, since childhood leukemia is a heterogeneous disease. The goal of this project is to identify LSC in different types of childhood leukemia, which will lead to clinical development of new LSC targeted therapies. This project will be conducted by a multidisciplinary team. I am fortunate to have excellent mentors and collaborators, including Dr. Jan Nolta, Stem Cell Program, Dr. Kit Lam, Hematology/Oncology, James Chan, Center for Biophotonics Science and Technology, and Laurel Beckett, Biostatistics, CTSC.

Almost 80% of all children and adolescents diagnosed with cancer are long term survivors, and the majority are considered cured. This success has largely been due to the use of more intensive therapy using a combination of different chemotherapeutic agents, surgery, and radiation. However, no treatment is without cost! As childhood cancer survivors become adolescents and young adults, some of them are at risk of developing complications related to the very treatment that saved their lives. No longer can pediatric oncologists walk away from the responsibility of monitoring these survivors for late effects of treatment, most of which appear years after completion of treatment, and range from physical to educational to psychological issues. The Late Effects Clinic was established six years ago as part of the general pediatric oncology program at Lombardi, and was initially staffed by just one pediatric oncologist. In addition to addressing specific issues related to late effects, we started putting together comprehensive “Off-Therapy” summaries for all patients who finished treatment in our program, as it was evident that this was the most important piece of information we needed to provide patients and their primary care providers. As the clinic became established, our patients’ families came forward and started helping with funding of staff and research projects. In 2005, a generous grant from the Hyundai Motor Corporation helped us to hire a nurse practitioner and to expand the clinic into a Cancer Survivorship Program. This funding has continued over the last four years and allowed us to grow as a program to provide better care for childhood cancer survivors, not just patients from Georgetown, but from the Greater Washington area and beyond. It has also allowed us to initiate research in childhood cancer survivorship.

Medulloblastoma is the most common malignant brain tumor in childhood. While many children can be cured with current therapies, over 1/3 still die from their cancer. Even for those who survive their disease, most suffer lifelong disability of variable degree. With continued research into novel therapies that cause less damage to the developing brain and nervous system, there is hope that more children will survive this disease with fewer long-term side effects. Previous work has shown that there are numerous signs that make medulloblastoma tumors more likely to recur, less likely to respond to current treatments. Tumor anaplasia is characterized by several specific microscopic features and is a sign of “high risk” medulloblastoma. High levels of the oncogene, MYC, have been associated both with “high risk” tumors and tumor anaplasia. MYC is a gene important for many normal cell functions, but is found to be abnormally expressed in many cancers. Little is known about what it does in medulloblastoma. In a model system using tumor cells forced to express high levels of MYC, cells grow more quickly and form larger tumors in animals. These changes mimic many features of anaplasia. In other cancers, MYC changes the levels of many thousands of other genes to make tumors more dangerous. We are using these experimental, high-MYC cells to try to learn the mechanisms underlying “high risk” disease by examining the changes in gene expression patterns. In this way, we may identify additional markers for use in treatment decisions as well as, hopefully, designing new treatments for patients with the worst tumors. Several groups of genes have already been identified and are undergoing additional study. For example, MYC seems to drastically change the make-up of the scaffolding that surrounds the tumor cells, the so-called extracellular matrix (ECM). Traditionally, research has focused on the cancer cells themselves and the pathways that are important for tumor growth and spread. In medulloblastoma, there is very little known about the role of the ECM. The make-up of the ECM varies greatly between different organs in the body and is often altered in malignancy. In many other cancers, this matrix plays important roles in cell survival and invasion. The matrix is also very important in normal brain development. Preliminary results indicate that the matrix in many medulloblastoma tumors is very different from that of normal brain and that the tumor cells themselves actively contribute to the ECM. This raises the possibility that targeting the matrix in medulloblastoma may damage tumor cells, but not normal nervous tissue, the goal of developing less neurotoxic therapies.

Acute Lymphoblastic Leukemia (ALL) is the most common cancer of childhood; about 2500 children are diagnosed with ALL each year in the United States. Outstanding clinical and basic research over the last two decades have led to a markedly improved survival; however almost 20% of children still succumb to this disease, mostly due to recurrence of the disease. The most common questions coming from children with ALL and from their parents are: “ why did I get leukemia”, “ will it ever come back” and “will I live a normal life after I complete the therapy”. We are still very far from being able to answer these questions with certainty and to be able to guarantee cure after therapy. I am convinced that the answer to these questions will derive from the study and understanding of the molecular mechanisms that make a blood cell proliferate uncontrollably and sometimes become resistant to the chemotherapy. Revealing these mechanisms will set the ground for the discovery of new targeted drugs, likely to be less toxic and to have less long term side effects for the survivors so that they can enjoy a long life just like anybody else. The laboratory I work in at the Columbia Medical Center is specifically interested in studying an aggressive subtype of ALL, called T cell ALL (T-ALL). T-ALL has a worse outcome compared to a more common subtype of ALL and requires radiotherapy in addition to chemotherapy. We are particularly interested in studying the role of NOTCH1 in T-ALL. NOTCH1 is a very important transcription factor that controls several steps of normal T-cell development and is mutated in more than half of patients with T-ALL. Abnormal activity of NOTCH1, due to the acquisition of mutations, leads to uncontrolled proliferation of a T-cell and development of leukemia.

As the number of pediatric cancer survivors grows, clinical research directed toward understanding and mitigating the acute toxicities and late-effects of cancer treatment becomes increasingly important. There are estimated to be 270,000 survivors of childhood cancer nationwide.1 Over 80% of childhood acute lymphoblastic leukemia (ALL) patients are expected to become long-term event-free survivors.2 While the successes in the treatment of childhood cancers are impressive, treatments remain non-specific and associated toxicities can be life-altering. Continued attention to decreasing the toxicity of treatment, both during therapy and with regard to chronic morbidities, is essential if we are to improve the quality of life of childhood cancer survivors. Skeletal toxicity has emerged as an important complication of therapy for childhood ALL. Increased rates of fracture and osteonecrosis have been noted in multiple patient cohorts. For example, a retrospective study of children with ALL treated at the Dana-Farber Cancer Institute (DFCI) demonstrated a 5-year cumulative fracture incidence of 28%, with median time from diagnosis of ALL to first fracture of 15 months, as well as a 5 year-cumulative incidence of osteonecrosis of 7%.3 While skeletal morbidity has been increasingly recognized as a major treatment-related toxicity of childhood ALL therapy, much remains to be elucidated about risk factors, long-term outcomes, the role of screening, proper management, and potential preventative and interventional strategies. Bone mass attained early in life is considered a major determinant of long-term bone health. A detailed understanding of how bone changes during and after leukemia therapy is needed in order to identify those at greatest risk of toxicity and to develop effective interventions that prevent significant morbidity and promote long-term bone health. We plan a prospective, longitudinal assessment of bone mineral density in children with ALL, utilizing peripheral quantitative computed tomography (pQCT), a modality with advantages over standard bone mineral content measurement techniques. Through use of pQCT, we hope to gain a detailed understanding of how bone mineral status and bony architecture changes over time in children during and after leukemia therapy. In exploratory analyses, we will examine the relationship between pQCT findings and risk of fracture and osteonecrosis, and between pQCT findings and 25-hydroxy vitamin D level. Vitamin D deficiency has been recognized as an important concern with regard to bone health, even for healthy children, emphasized by the recent American Academy of Pediatrics recommendation for increased minimal daily vitamin D intake. While children undergoing leukemia treatment may be at risk for vitamin D deficiency, the impact of vitamin D status with regard to acute and long-term skeletal morbidities has not been thoroughly explored in this population.

Fifteen out of every 100,000 children in the United States are diagnosed with cancer each year, and of these diagnoses, acute leukemia is the most common. Therefore, I have chosen to focus my research endeavors on chemotherapy for acute leukemia. While we have made enormous strides in our cure rates for acute leukemia over the past 40 years, patients who relapse still have a very poor prognosis. It is imperative that we develop new chemotherapeutic agents or novel combinations of chemotherapy in order to provide relapsed leukemia patients with better outcomes. As a result, I am working on multiple research projects in the hopes of creating more options for physicians and families in the event of a relapse of leukemia. The first involves combining two agents, asparaginase and sirolimus. Asparaginase is widely used for treatment of leukemia. Sirolimus is an immunosuppressive agent initially created to decrease rates of solid organ transplant rejection. Recently, it and other similar drugs are being studied as chemotherapeutic agents due to their ability to affect cell signaling and protein synthesis. To better study this combination of agents, I have created a clinical trial for use in patients with multiply relapsed leukemias. As a correlate to the clinical trial, I am developing a method of studying signaling pathways within leukemia cells. This method, phospho-flow, is being used in different institutions around the country in order to better understand the signaling pathways that occur within different types of cancer cells. Initially, I would like to use this technique to test the patient’s leukemia cells treated with the combination of sirolimus and asparaginase. By testing their cells before and after treatment, I will be able to determine how this combination of drugs actually leads to a decrease in protein synthesis and eventually cell death. Ultimately, as this technique becomes better developed, I foresee being able to test the cells of newly diagnosed leukemia patients against different types of chemotherapy. If we are able to determine which chemotherapy agents will lead to cell death in each patient, we will be able to target each patient’s therapy to increase the rates of cell death while minimizing toxicity by not using drugs that will not be effective.

St. Joseph’s Children’s Hospital’s (SJCH) Pediatric Molecular and Cellular Research Laboratory holds the vision for a pediatric cancer-free world and for researching and developing cutting-edge treatment methodologies that are least-painful and most-effective at treating pediatric cancer. Generous contributions from donors like Hyundai Motor America, partnerships with biotechnology companies, and our own investments have allowed SJCH to create a cutting-edge research program for pediatric cancer treatment. SJCH is proud to be a catalyst for such important work, and takes seriously the understanding that our research provides children with the possibility to live --- cancer-free. SJCH is very excited about the early study findings of our dedicated team of researchers. In the past five years under the leadership of our Director of Oncology Research Michael Lawman, Ph.D. and his team, SJCH has made tremendous strides in cancer immunotherapy. We respectfully submit Pediatric Oncologist Dr. Tung Wynn as our Hyundai Scholar to facilitate his co-investigation on “Post Transcriptional Silencing of Genes: A Novel Molecular Approach to the Treatment of Pediatric Cancers of the Cerebellum” which may indeed lay the groundwork for the development of a non-invasive and effective therapeutic protocol of medulloblastoma in children – the most common brain cancer. In recent years, much has been learned about gene regulation of the developing brain. Among the many genes involved, the “hedgehog” family of genes appears to have a pivotal role in the embryonic development in mammals including humans. Likewise, significant data has accumulated regarding the biology and genetics of medulloblastoma. It is evident that certain genes and “signaling” pathways regulate the development of medulloblastoma. Previous data has shown that the dysregulation of sonic hedgehog and Gli signaling pathways are a significant contributor to this malignant process. The inability to down-regulate sonic hedgehog signaling in certain neuron brain cells is the foundation for the development of tumors such as medulloblastoma. Currently, the treatment of medulloblastoma involves surgery, radiation therapy and chemotherapy. While these treatments are successful, they can potentially cause significant neurological defects and can alter growth and development of young children as well as cause short and long-term psychosocial behavioral problems.

Funding from this Hyundai Scholars grant will be used to support a project on the molecular basis of metastasis in Ewing’s Sarcoma Family of Tumors (ESFT). ESFT, including Ewing’s Sarcoma and peripheral primitive neuroectodermal tumor, are the second most common primary bone tumors of childhood and adolescence. Patients with localized tumors have long-term survival rates nearing 70% using aggressive multiagent chemotherapy, surgery and/or radiation therapy. Unfortunately patients with metastatic disease at diagnosis have survival rates below 20%. Recently, the ESFT-specific gene expression profiles molecularly defined a primitive neural crest-derived progenitor cell population as the histogenetic origin of ESFT. Neural crest cells are highly motile cells derived from neural epithelial cells and migrate extensively throughout the body during embryogenesis. Several genes involved in neural crest formation have been implicated in promoting carcinoma cells to migrate, invade and metastasize. This project aims to address the molecular basis of Ewing’s sarcoma metastasis by examining the expression of candidate genes involved in neural crest migration in Ewing’s sarcoma cell lines and tumor samples, and to examine the functional requirement of the neural crest migratory program in Ewing’s sarcoma invasion and metastasis. This project will be conducted with the help of Dr. Jing Yang, department of pediatrics, University of California San Diego.

I am dedicated to improving the care of pediatric sarcoma patients through clinical and translational research. My fellowship training at The Children’s Hospital of Philadelphia (CHOP) has provided me with an excellent starting point for a career in pediatric oncology. My fellowship research project focused on the discovery of novel therapeutics in pediatric neuroblastoma. CHOP currently has one of the premier programs in the country for caring for patients with neuroblastoma. I will use the neuroblastoma model developed here as a guide to develop a world-class sarcoma program. Our sarcoma program will integrate outstanding patient care with scientific advancement, and hopefully bring novel therapies from the bench to the bedside. During the period of time I am supported by the Hyundai Scholar Award, I will establish a pediatric sarcoma patient database needed to initiate this program. I will also continue to contribute to a growing body of knowledge on solid tumors, particularly sarcomas. Receiving the Hyundai Scholar Award will serve as a launching point for my career. The CHOP Oncology Clinic sees approximately 50-60 new sarcoma patients each year. I will build a database to capture information about our patients’ care – including diagnosis, treatment plans, surgical approaches, complications from therapy, and supportive care. In addition, I will integrate this clinical information with other biological information, including tumor pathology, molecular genotyping, and expression profiling. By taking advantage of our division’s vast experience with this particular patient population, there is certainly much to be learned by examining this large dataset. I will use this information to develop standards of care for our patients. In addition, I will use this information to implement novel programs, both therapeutic and supportive, for our sarcoma population. Because many sarcoma patients are adolescents and young adults, we plan to develop an Adolescent/Young Adult (AYA) clinic in collaboration with the University of Pennsylvania, to care for these and other cancers that affect this population.

Every year about 100 children are diagnosed with cancer at Arkansas Children's Hospital. The good news is that about 80% of these children will be cured, and will grow up to have full lives and families of their own. This statistic raises two questions: 1) How has this success rate been accomplished?; and, even more importantly, 2) What about the 20% who are not yet curable? The answers to both questions are essentially the same, and help to explain what we, in the Pediatric Oncology program at Arkansas Children's Hospital, have been doing to help in this battle over the past few decades, and what we will be doing in the future, with the help of research funding such as that provided by the Hyundai Hope on Wheels program. Although cancer is the second leading cause of death throughout childhood, it is fortunately relatively rare compared to its incidence in adults. Additionally, every type of childhood cancer is different, and even within similar types there are subtle variations which can make a dramatic difference in prognosis and treatment. The only way to maximize our understanding of the behaviors of specific types of childhood cancers, and to systematically evaluate new treatment options which might help improve the cure rate of those cancers, is by carefully designed and implemented clinical and laboratory research. The need for prospective clinical and basic research into childhood cancer was recognized by the pioneers in our field over 3 decades ago, who also realized that, because of the relative infrequency of childhood cancer, it would take a collaborative effort among all children's hospitals to achieve the goals of improving understanding and hopefully the cure rates of these cancers. Since the 1970's, we at Arkansas Children's Hospital have joined in this nationwide collaborative effort, by being members of the premier clinical trials groups for childhood cancer in this country. Currently, the Children's Oncology Group (COG) is the worldwide leader in clinical and laboratory research for childhood cancer, and we are a full member institution. As such, we are able to offer our patients not only the very best in cutting edge therapy options, but also to allow them to participate in research related to their own specific tumor type, in the hopes of not only optimizing their own chance of cure, but also to help the children in the next generation to also have a better chance of cure. By using this model for the past 30+ years, and by the generous participation of the patients and families who have been treated during that time period, we have progressed from an era when most children with cancer eventually died of their disease to the place where over 80% are cured.

The Hope on Wheels Donation will support a seminar to educate pediatric physicians about the latest developments in pediatric cancer research. The seminar will focus on late effects of childhood cancer. It will educate pediatricians in northeastern Oklahoma on these issues, i.e. insurance, etc. Oncologists at the hospital, including Dr. Bourland, will choose a presenter who is active in research to come to The Children's Hospital at Saint Francis and do a workshop/meeting for all pediatricians in Oklahoma. This will be billed as a joint presentation by Saint Francis and Hope on Wheels. There will be invitations sent to all pediatricians in Oklahoma. The money given to Dr. Bourland will pay for the fee of the speaker, travel, and for the costs of putting on the seminar, including a notebook that will be given to participants. The hospital will seek CME credit for this seminar.

Dr. Cauff is involved in clinical research in Pediatric Hematology/Oncology. He is an active member of the Children’s Oncology Group. The Children's Oncology Group (COG) is a worldwide research group supported by the National Cancer Institute (NCI) with the mission “to cure and prevent childhood and adolescent cancer through scientific discovery and compassionate care”. All his cancer patients are entered into the Children’s Oncology Group registry and into clinical trials if appropriate. He oversees all policies, procedures and treatment plans to make sure that the research protocols are rigorously followed to insure the best outcomes. Data from his patients is used to develop standardized, evidence-based protocols for pediatric cancer patients. This data is also periodically published in national medical journals.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While more than 85% of children diagnosed are now cured, survivors are at increased risk of obesity and adult cardiovascular disease compared with peers. Historically, radiation therapy to the brain was the most consistently identified risk factor for subsequent obesity. However, in an effort to reduce this as well as other growth, hormonal, and cognitive side effects, the use of cranial radiation in pediatric ALL treatment has decreased greatly over the past 20 years, replaced by a greater reliance on more intensive chemotherapy, including the use of a more potent type of steroid called glucocorticoids. In an earlier study, we found that the rates of obesity among children treated with contemporary ALL therapy (21%) remained significantly greater than population norms (Chow EJ, 2007). Children who received the highest cumulative dose of glucocorticoids were six-times more likely to be obese compared with the lowest dose level. Glucocorticoids affect body weight by altering the metabolism of sugars (e.g. carbohydrates) and fats, resulting in changes in body composition and fat distribution. In addition to the actual glucocorticoid dose and lifestyle factors such as diet and activity, we believe this risk of obesity following ALL therapy may be influenced by an individual’s underlying genetic make-up. Specifically, we are interested in exploring the influence of natural variations (termed polymorphisms) in the glucocorticoid receptor gene (NR3C1), some of which have been associated with obesity-related outcomes in the general population (van Rossum, 2004). To accomplish this, we propose to examine 200 ALL patients who have completed treatment at Seattle Children’s Hospital since 1990 to determine if selected NR3C1 polymorphisms are associated with a risk of obesity in this population. To determine if people with such polymorphisms actually have altered carbohydrate metabolism after receiving glucocorticoids, we have proposed to test for subtle differences in carbohydrate metabolism by using a modified version of the glucose-tolerance test among children currently being treated for ALL and receiving glucocorticoids.

While great strides have been made in the treatment of many pediatric cancers through the use of combinations of chemotherapy and radiation, these cures often come with a cost including decreased growth, abnormal hormone levels, decreased fertility, and the risk of secondary cancers from treatment. Furthermore, for an unfortunate group of patients even high doses of chemotherapy and radiation cannot cure their cancers. Bearing these thoughts in mind, I have focused the efforts of my research as a Hyundai Scholar on understanding factors that impact the immune response to tumors with the hope that immunotherapy can be improved to serve not only to augment chemotherapy and radiation in the treatment of pediatric cancers, but also as a potentially less toxic alternative. The immune system’s ability to specifically recognize an antigen makes it a potentially powerful and unique tool in the armamentarium of cancer treatments. Chemotherapy and radiation typically destroy both cancer cells and dividing normal cells, leading to both immediate and late-onset toxic effects on normal tissues in growing children. Immunotherapy, on the other hand, has the potential to distinguish healthy from cancerous tissue and selectively destroy cancer cells. However, immunotherapy has yet up to its full potential, due in large part to the ability of cancer cells to either direct cells into an inappropriate type of immune response or simply turn the cells of the immune system off. My postdoctoral research in the laboratory of my mentor, Dr. Jonathan Powell, has focused on identifying biochemical pathways that turn on and off T cells of the immune system. This research has identified a critical role for a process called DNA methylation in turning off T cells. By exposing T cells to chemicals that block DNA methylation, we observed that we are able to prevent the T cells from being turned off by exposure to tumor cells. These data provide important insight into developing drugs to enhance anti-tumor immune responses, which will be the focus of my work as a Hyundai Scholar. It is our hope that this work will allow us to develop effective vaccine based treatment regimens for pediatric cancers.

Oncogenes are genes that lead to the formation of tumors when over-expressed in a cell. While numerous such genes have been identified, one of the most extensively studied oncogenes is c-Myc. The c-Myc gene product is over-produced in a wide array of cancers including those of the breast and colon, as well as in leukemias and lymphomas. The c-Myc gene product functions as a global transcription factor, affecting up to 20% of all known genes, in species ranging from flies to humans. One significant result of high cellular levels of c-Myc is the generation of genomic instability, which is thought to be essential in the development of a tumor. One of the varied ways that c-Myc can cause genomic instability is by the production of free radicals and reactive oxygen species (ROS). Left unchecked, ROS can cause widespread cellular damage via protein, lipid, and nucleic acid oxidation; in the latter case, this can lead to permanent mutational changes and cancer. In my first line of research I am investigating whether the fact that c-Myc produces these damaging toxins is in anyway responsible for its ability to cause cancer. Specific mutations of the c-Myc protein have been generated; some of these mutants have lost the ability to generate ROS. I am taking those mutants, as well as those that are still capable of producing ROS, and putting them into mouse hematopoetic stem cells. I will subsequently use those cells to reconstitute the bone marrows of lethally irradiated mice and observe the mice for the development of lymphoma. It is my hypothesis that mutations that result in higher levels of cellular ROS will be more capable of causing cancer than those that do not. If this hypothesis is supported then it will lead to a far greater understanding of the mechanism by which c-Myc can cause a tumor in vivo.

Unfortunately, cancer treatment is not without lasting side effects. Patients may undergo a combination of chemotherapy, radiation therapy and/or surgery to battle their disease. The treatment itself requires one to conform to a sedentary lifestyle due to low levels of energy secondary to anemia and chemotherapy effects. The patients also must minimize interaction with peers and partake in a solitary lifestyle due to the high risk of infectious complications during treatment. These interventions leave lasting scars and deficits, both physically and psychologically, thus creating barriers for patients trying to reintegrate into normal social and physical activity after completion of therapy. In the fall of 2007, our cancer survivorship clinic conducted a pilot study evaluating the effects of organized physical activity on the health and well being of a group of adolescent cancer survivors. The 12 week program consisted of weekly group sessions which were overseen by professionally trained coaches. The purpose of the program was to provide an opportunity for the patients to re-engage in physical activity in a safe, nonjudgmental and supportive environment. The program encouraged patients to participate with family, friends and other cancer survivors.

The job of our immune system is to recognize foreign invaders and eliminate the threat while ignoring tissues within our own body. Although tumor cells exist because they have gone through many genetic mutations and therefore potentially can be recognized by the immune system as foreign invaders, they are, after all, derived from self tissues and the immune system may become tolerant to them. Balance between activation and unresponsiveness of the immune system against tumor cells ultimately determines whether a patient will succumb to cancer or overcome it. The immune system is highly dependent on the motility and recruitment of the individual immune cells in carrying out their proper function. The capacity to move around the body and to ensure timely and orderly physical interactions among various members represents a unique feature of the immune system. Until recently, how immune cells migrate within the body and how tumor cells may affect these processes are largely unknown. Historically, clinicians and scientists have relied on investigative tools that involve teasing apart individual cells away from their native environment to study their function in a test tube, obtaining static snapshots of where these cells migrate within the body through examination of fixed tissues under the microscope, or imaging whole organ inside the body without single-cell resolution (e.g. MRI, CT scan, and Ultrasound). While useful tools in uncovering many of the principle processes which govern how cells communicate with one another, these traditional investigative tools cannot fully reconstitute the myriad of environmental cues which the immune cells gather and interpret for their proper function.

The multi-disciplinary team for this program includes 5 pediatric hematologists/oncologists, highly trained chemotherapy nurses, pediatric social workers, a child life specialist, and the support of all of Albany Medical Center's pediatric subspecialists. The Child Cancer program is a member of the prestigious national Children's Oncology Group, whose membership includes such institutions as St. Jude Children's Hospital, Dana-Farber Cancer Institute, and Memorial Sloan-Kettering Cancer Center. The Child Cancer Program follows the same strict protocols and offers the same advanced treatment as all members of this group, and allows regional children to be treated locally. More than 700 children are seen on a yearly basis in this area for a wide range of cancers and blood disorders in children, including: Leukemias, Lymphomas, Brain Tumors, Wilm's Tumors, Neuroblastomas, Rhabdomyosarcomas, Osteosarcomas, Anemia's, and a host of other bleeding disorders (including hemophilia and platelet disorders) and disorders of the white blood cells. The Hyundai Scholar will research current practices, survey parents and patients, physicians, nurses and other staff within and outside of the Children’s Hospital to determine which service delivery areas are seen as strengths and which continue provide opportunities for growth, change, and quality improvement. In their training, medical professionals including physicians, often receive few or no opportunities to practice the skills necessary for communicating effectively with children who are dying and their families. These conversations are life altering and will be moments in time that the recipients of the information will never forget. The research results will be used to focus on quality improvement.

The Center for Survivor Wellness has a strong commitment to performing research to advancing our understanding of survivorship and the late effects of being cured of childhood cancer. The Center participates in projects that are intramural, extramural, and those that accrue data as part of national cooperative group studies. Presently, Dr. Jennifer Levine and her associates are involved in the following projects: o Completed a study and reported scientific results for the use of carotid artery ultrasound to evaluate risk of cardiovascular disease in survivors of Hodgkin’s Lymphoma (HL); manuscript in process; o Initiated a clinical trial evaluating the use of statin medications in Survivors of HL with the Children’s Hospital of Philadelphia as a secondary site. Patient enrollment has begun at both sites;

Hematopoietic stem cell transplant (HSCT) is the only way to cure a number of pediatric diseases such as relapsed leukemia, myelodysplastic syndrome, sickle cell disease, immunodeficiency, and high risk neuroblastoma. Despite its growing use, there is significant morbidity and mortality associated with HSCT due to infection and graft versus host disease. One way of ameliorating some of this morbidity is to better understand the effects of radiation on the bone marrow microenvironment that leads to stem cell engraftment. This is an important area to study so we can make HSCT a safer modality of treatment for children. The project described herein utilizes the Danio rerio model of hematopoiesis. Danio rerio, commonly known as the zebrafish, has been increasingly used as a model of human disease over the last few years because of several beneficial aspects of its biology such as: ease of maintenance in the laboratory, relatively uncomplicated genetic manipulation allowing creation of transgenic lines, and its optical clarity during development from the embryonic stage through the first few weeks of life permitting in vivo microscopic study. Furthermore, many human and mouse genes have homologs in the zebrafish genome allowing experimental results to be translated to mammalian systems including pediatric stem cell transplant. In fact, early mutagenesis experiments showed that disruption of homologous genes in the zebrafish produced pathology very similar to that of human disease [6, 9]. The zebrafish hematopoietic system has been extensively characterized [3], and it is now accepted that this system provides an excellent opportunity to study hematopoietic stem cells (HSC) and stem cell homing capitalizing on the unique advantages that this system offers. Finally, myeloablative hematopoietic stem cell transplantation can be done utilizing unrelated donor zebrafish just as performed in pediatric stem cell transplant [4]. We hypothesize that the myeloablation caused by radiation triggers the upregulation of “signaling factors” critical to stem cell homing.

My current research focuses on the evaluation of novel therapeutic agents for the treatment of childhood cancer. Through collaboration with scientists at OHSU and throughout the country and in conjunction with the Children’s Oncology Group (COG), I am intricately involved in the testing of new anti-cancer drugs in early phase (phase I and phase II) clinical trials. I’ve recently taken over leadership of the Doernbecher Children’s Hospital Developmental Therapeutics Program, and I am in the Principal Investigator at Doernbecher for the COG Phase I Consortium. Doernbecher Children’s Hospital is one of 21 select institutions within COG who make up the Phase I Consortium. The purpose of this group is to collaborate on research studies to evaluate promising new drugs for the treatment of childhood cancer. The support that I have received from Hyundai will allow to advance the Developmental Therapeutics Program at Doernbecher and to make a significant contribution to the clinical testing of novel agents within the COG Phase I Consortium. In particular, I’m currently the Chair of a Phase I study of an exciting new drug that inhibits the Insulin-like Growth Factor-I Receptor in cancer cells. The funding from Hyundai will be directed towards laboratory work to evaluate how the drug works at the cellular level in patients on study who receive the drug. This type of work, done in collaboration with scientists at OHSU, is critical to understanding how the drug works in the body and to making decisions about how to further study the drug and how to combine it with other anti-cancer agents. We will be receiving blood samples for analysis from patients enrolled on this trial at different hospitals around the United States and Canada.

Approximately 1 in 800 liveborn infants have Down syndrome (DS), or constitutional trisomy of chromosome 21. Children with DS have a 20-fold increased risk of developing leukemia compared to normal children resulting in a 1% lifetime risk of leukemia for any child with Down syndrome. Approximately 10% of newborns with DS develop a preleukemic syndrome, transient myeloproliferative disorder (TMD), which typically self-resolves but can be life-threatening. 20-30% of infants with TMD will develop acute myeloid leukemia (AML), most before age 4 years. As a result, approximately 10% of children currently enrolled in cooperative group trials for AML have Down syndrome. While their leukemia risk is high, children with DS-AML have markedly better outcomes than children with AML without DS. In cooperative group trials, 5-year event-free survival for DS-AML patients is 80% compared to 50% for non-DS AML patients. , , , Despite this overall favorable outcome, 10% of children with DS-AML will relapse and die of leukemia while another 10% die of treatment-related toxicity. To date, the only risk factor identified that predicts leukemia relapse is age > 4 years. , Clinically, there is great interest in improving risk stratification for children with DS-AML. Identification of factors which predict poor outcome would allow treatment intensification for this subgroup and treatment reduction for the majority of DS-AML patients with good prognosis who are at risk of treatment-related toxicity. While investigators have recently discovered the role of mutations in the GATA-1 transcription factor in both TMD and DS-AML, the additional genetic alterations underlying the development of DS-AML remain unknown. One particular region of interest is the long arm of chromosome 1 (1q); amplification of 1q occurs in 10-30% of DS-AML cases, but is generally not found in TMD or DS-ALL (Figure 1). , , In Pediatric Oncology Group study 9421, 13% (6 of 47 patients) had 1q amplifications (O’Brien, unpublished data). In the largest reported series of 189 patients with DS-AML the most frequent partial imbalance was duplication of 1q which occurred in 16% of DS-AML cases compared to 2% of an unselected non-DS AML control group.

The improvements in the survival rate of children diagnosed with acute myelogenous leukemia (AML) seen over the past decades have been the result of these children being treated on large national studies. Moderate advances achieved in each study added together have led to the large gains towards successfully treating this disease. However, despite these improvements, chemotherapy for AML remains imperfect. All of the children are prescribed the same doses of chemotherapy, yet the outcomes for each child can be very different. Some children are cured of their disease, while other die from relapsed disease or die of side effects from the treatment. Those children cured received the right amount of therapy for them; for the other children, the same dose of chemotherapy did not work. The reason for the different response to the same dose of chemotherapy must be found in the children themselves, specifically in our genes which determine how our bodies respond to drugs. Our goal in the laboratory is to figure out which genes are important to how our bodies respond to chemotherapy so that we can test children ahead of time and figure out exactly the right dose of these powerful drugs for each child. We plan to test genes important to drug processing and tolerance to find variations that change response. Our long term goal is to be able to individualize the amount of therapy for each child based on their genetic make up.

Therapeutic strategies in pediatric oncology today are increasingly using “risk-based” therapy that seeks to deliver effective anti-neoplastic therapy with reduced toxicity to the patient. While the number of survivors has grown, untoward health outcomes known as ‘late effects’ are often recognized in survivors of cancer therapy. Some of these issues affect the developing child while others may not surface until adulthood. Research focused on long-term survivors of childhood cancer has allowed us to anticipate certain organ-specific complications, including learning impairment, abnormal growth and development, gonadal and reproductive abnormalities, and the development of secondary malignancies. Although research to identify chemotherapy regimens that minimize late effects without compromising survival rates is ongoing, interventions that identify and manage late effects continue to be important components of the treatment of childhood cancer survivors. Cancer survivorship research requires a systematic approach to identify and characterize the late complications of childhood cancer. Whether the focus of a specific research study is a physical, psychosocial, or care-delivery issue, the overall objective of this field of research is to improve medical outcomes and enhance quality of life in cancer survivors. Although cancer survivorship research is collaborative in nature, the research questions often arise from smaller descriptive studies conducted at a single institution.

Studies indicate that as many as two-thirds of childhood cancer survivors are likely to experience at least one “late effect” (adverse side outcome) as a result of cancer and/or treatment. The Lombardi Cancer Survivorship Clinic is devoted to serving the special needs of survivorship patients from the time they are off treatment for two years through late adulthood. Over the past three years, the number of patients in the Survivorship Clinic’s database has increased to more than 250, including patients from other institutions in the DC-Virginia metro area. The clinic’s methodology for treatment has been streamlined and includes meetings with 1) a social worker, who addresses post traumatic stress resulting from cancer treatment as well as issues surrounding employment and schooling; 2) an art therapist who provides an opportunity to participate in a psychosocial research protocol as well as evaluation and recommendations on issues related to adjustment and trauma associated with the cancer treatment; 3) a nurse practitioner, who takes the patient’s history and performs the physical exam; and 4) a physician, who discusses the specific issues of survivorship. Dr. Shad’s staff, which also includes a nutritionist and a psychologist, provides assistance in coordinating other services and departments throughout Georgetown University Medical Center. Yearly check-ups require input and support not only from Lombardi staff, but also from other specialists including cardiologists, nutritionists, endocrinologists, and others. The nurse practitioner plays a critical role in the care of children who come to the late effects clinic. Without this position, it could not open its doors. In addition, follow up letters are sent to the patients’ primary care physicians to ensure a continuum of care.

Brain tumors are the most common type of solid cancer in children. Brain tumors are also the leading cause of cancer-related deaths in children. Approximately 2,500-3,000 children develop a brain tumor each year in the United States, making this cancer a significant health problem in children. Of the brain tumors in children, one type called “glioma” is the most common. Very little is known about how normal brain cells can become cancerous gliomas, which often have a dismal outcome in children. Better knowledge of how these tumors form and grow is needed in order to develop new therapies to improve survival. My research is focused on examining how genes that are important in the normal development of a child’s brain are “hijacked” to cause glioma brain tumors. One gene named Nuclear Factor I (NFI) was recently found to play an important role in regulating normal brain cells as they mature and form the brain. This prompted me to examine a possible role for NFI in glioma formation and growth. Indeed, I find that NFI can dramatically promote uncontrolled growth of glioma cells both in the test tube and in mice. My work will further investigate how NFI increases growth of glioma cells, which may point to strategies for therapy that improve outcome in patients with gliomas.

T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer that accounts for 15% of pediatric ALL cases. The NOTCH signaling pathway plays a critical role in the pathogenesis of 60% of T-ALLs harboring activating mutations in the NOTCH1 gene. NOTCH1 receptor is a transmembrane protein which, following ligand binding, undergoes proteolytic cleavage first by ADAM metalloproteases (ADAM10 and ADAM17) and then by the secretase complex. This latter cleavage releases the intracellular domains of NOTCH1 (ICN1) from the membrane, allowing them to enter the nucleus where they form a DNA binding complex with the CSL protein and activate the expression of target genes. Prototypical NOTCH1 mutations induce ligand independent activation of the receptor (HD mutations) or increased ICN1 levels due to impaired degradation (PEST mutations). NOTCH1 activation plays a central role in the pathogenesis of T-ALL; however, 40% of T-cell lymphoblastic tumors lack prototypical mutations in the NOTCH1. Based on the fundamental role of the NOTCH1 pathway in promoting growth proliferation and survival of immature T-cells, we postulate that aberrant activation of NOTCH signaling may be a universal mechanism of T-cell transformation. Thus, our central hypothesis is that aberrant NOTCH signaling is activated in the majority of T-ALL tumors either by the prototypical mutations in the NOTCH1 receptor or by as yet unidentified alternative mechanisms in tumors devoid of these genetic lesions. The objective of this project is to identify and characterize novel mechanisms responsible for aberrant NOTCH signaling in T-ALL to ultimately develop effective, highly specific therapies based on molecularly targeted anti-leukemic agents.

In recent years, great progress has been made in the treatment and cure of childhood cancer. This has largely been due to advancements made in research of pediatric malignancies and associated illnesses. Financial support from charitable organizations has helped make much of this research possible. Hematopoetic stem cell and bone marrow transplant play an important role in the treatment of malignant and severe systemic diseases in children. It is an essential part of the first line treatment in many of these diseases and remains the standard of care for many relapsed and resistant cancers. Graft versus host disease (GVHD) is a severe complication seen in patients undergoing bone marrow transplant. Much of the treatment aimed at preventing GVHD leads to significant complications and death during and shortly following transplant. A specific type of white blood cell, known as the T-cell seems to be largely responsible for GVHD. Elimination of these cells from the transplanted bone marrow has been shown to decrease the risk of developing this adverse complication. Unfortunately, without these cells, the recovering bone marrow is unable to fight many of the common infections that afflict the pediatric bone marrow transplant patient, leading to an increased risk of complications and death from infection. Recent advances in determining which specific types of T-cells are involved in GVHD have been very promising, although further advances are needed. Animal models of human disease have been used for many years to better understand the mechanisms behind these processes. This has led to significant advances in pediatric medicine, specifically relating to pediatric cancer. Several animal models have been investigated in trying to better study GVHD in the pediatric transplant patient, but due to lack of similarities between humans and the animals studied up to this point, a clear understanding of these mechanisms is still needed. Researchers from the Aflac Cancer Center and Blood Disorders Service of Children’s Healthcare of Atlanta have been working with colleagues from the Emory Transplant Center to better study the involvement of T-cells in severe graft versus host disease. Currently at our center, the first primate, or monkey model to study the GVHD process is underway, with the goal of reducing GVHD prevalence and severity. Due to the genetic similarities between humans and primates, this model will give a better representation of human GVHD, and ultimately lead to increased survival for patients undergoing necessary bone marrow transplants.