The AACR Career Development Award for Pediatric Cancer Research is open to junior faculty in their first full-time faculty appointment. Proposed research projects may be in any discipline of basic, clinical, translational or epidemiological research with direct applicability and relevance to pediatric cancer.
2010 GRANTEES
Mari H. Dallas, M.D.Assistant Member, St. Jude Children's Research Hospital, Memphis, TN
Dendritic Cell Facilitate Thymic Reconstitution After Transplantation
"Hematopoietic cell transplantation (HCT) is a potential curative treatment for certain hematologic and solid malignancies. However, delayed immune reconstitution following HCT results in prolonged susceptibility to infection and is a major cause of morbidity and mortality. The rate of immune reconstitution is directly correlated with the number of hematopoietic stem cells (HSC) infused and is particularly delayed in patients undergoing umbilical cord blood transplantation (UCBT) secondary to the limited numbers of HSC. Thus, methods to increase the number of umbilical cord blood (UCB) HSC have the potential to accelerate immune reconstitution after UCBT. My previous research in the Bernstein Laboratory at the Fred Hutchinson Cancer Research Center involved ex vivo expansion of hematopoietic progenitors with a Notch ligand, Delta1, a known regulator of cell fate determination. I demonstrated that culture of murine hematopoietic progenitors in the presence of Delta1 results in a multi-log increase in the number of precursors that accelerate T cell reconstitution when infused into a mouse model. Furthermore, I showed that culture of human UCB progenitors with Delta1 increases the number of progenitors that rapidly engraft in the thymus and accelerate T cell recovery in a mouse model. Preliminary data suggest that addition of Delta1-cultured HSC facilitated the thymic engraftment of non-cultured HSC cells. Moreover, significant thymic engraftment of dendritic cells derived from Delta1 cultured cells correlated with rapid immune recovery. Based on these findings, I hypothesize that dendritic cell precursors play a pivotal role in enhancing immune reconstitution after HCT. I plan to determine the role of dendritic cell in facilitating thymic recovery after HCT, investigate the efficacy of various dendritic cell precursors to facilitate T cell reconstitution and to determine the optimal culture condition to generate thymic repopulating dendritic cell progenitors from UCB cells. Because human thymopoiesis in a mouse thymus is inefficient and the MHC restriction and tolerance of human T cells that are selected in mouse thymus is unknown, I will test my hypothesis using a human thymus xenograft mouse model (huNOD/SCID). As a new faculty member at St. Jude Children’s Research Hospital, the AACR Career Development grant will support my research and allow me to continue my investigation."
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Christopher A. French, M.D.Assistant Professor, Brigham and Women's Hospital, Inc., Boston, MA
Targeting the Tumor Epigenome in NUT Midline Carcinoma
"NUT midline carcinoma (NMC) is a lethal cancer of midline organs, such as the upper airways and thymus, which afflicts children and adults, most often in their second decade of life. There is presently no cure for NMC and the average survival is less than one year. NMC is named for and defined by a DNA mutation of the NUT gene. In all NMCs, NUT is fused to another gene, most commonly a gene named BRD4, forming the BRD4-NUT fusion oncogene. Described by our group in 2004, NMC is a newly defined disease, and awareness within the medical community is only just now growing. As a result, its frequency in the population, though likely rare, is not known.
"A unique feature of NMC is the mechanism by which the fusion cancer protein, BRD4-NUT, causes the cancer to grow. Normally, tissue that makes up our organs forms by the differentiation of rapidly dividing “progenitor cells” into non-proliferative, mature cells which perform the functions of the working organ. If the progenitor cells did not differentiate, they would continue to grow and eventually form a tumor. We have recently shown that BRD4-NUT works by blocking the ability of progenitor cells to differentiate into mature tissue. This results in the uncontrolled growth of progenitor cells which are arrested in a state of perpetual proliferation.
"A recent discovery in our lab was that the arrest of maturation in NMC cells is due to a general shutdown of the expression of genes required for maturation. It turns out that BRD4-NUT represses their expression by binding to a limited number of locations within the cell’s DNA, called foci. At those foci, it traps proteins required for gene expression. The end result is that genes which cause maturation that require those proteins for expression are left bare, are not expressed, and thus maturation cannot proceed. Remarkably, we have found that the proteins required for gene expression can be freed from BRD4-NUT foci with the use of a new class of small molecule inhibitor drugs called HDACi, resulting in the rapid maturation and arrested growth of NMC cells. Thus far, we have had the opportunity to treat a 10 year-old boy with NMC using an HDACi drug. The patient’s tumor immediately stopped growing but, unfortunately, he could not tolerate the medication, and it grew back. The findings thus far identify the first targeted therapy of a cancer with an HDACi drug.
"The question which has emerged from these studies, and which is the focus of this grant application, is how, at a molecular level, do HDACi drugs reverse the cancerous effects of BRD4-NUT? Ultimately, the goal of this project is to better understand how HDACi interferes with BRD4-NUT so that improved, more specific therapy, and ultimately a cure for NUT midline carcinoma will be possible."
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Dan Ruan, Ph.D.Instructor, Stanford University, Stanford, CA
Image Gently for Pediatric Image Guided Radiotherapy: A Systematic Study
"The proposed study aims to ensure tumor coverage and minimize normal tissue exposure by optimally utilizing gentle image guidance in pediatric radiotherapy. We will adopt the state-of-the-art intensity modulated radiotherapy (IMRT) for high-resolution modulated delivery, develop economical image guidance protocols for online geometry monitoring, and investigate an adaptive mechanism to align the treatment beams with the instantaneous geometry. I thank Dr. Paul Keall for his guidance, and research support from NIH/NCI, Varian Medical Systems, and AAPM Research initiative."
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Narendra Wajapeyee, Ph.D.Assistant Professor, Yale University, New Haven, CT
Understanding the Mechanism of BCR-ABL-Mediated Transformation
"Leukemia is the most common form of childhood cancer which starts in blood-forming cells. Each year, over 3,500 children are diagnosed with leukemia. Like many other human cancers, leukemia arises due to changes in genes. One such change is fusion between chromosome 9 and 22, which results in a leukemia causing BCR-ABL fusion protein. BCR-ABL is believed to participate with other cancer-associated changes that lead to childhood leukemia such as ALL and CML. Here in this proposal, I propose to identify secondary genetic changes that co-occur with BCR-ABL fusion protein and are required for leukemia to form. I will use both cell culture systems and a mouse model of BCR-ABL-induced leukemia to study the human leukemia-like disease caused by BCR-ABL fusion protein. These experiments will possibly identify genes that cooperate with BCR-ABL to cause leukemia. Identification and characterization of these genetic changes that co-occur with BCR-ABL will lead to development of alternative therapies for treatment of BCR-ABL-driven leukemia and also provide insight into drug resistance towards BCR-ABL kinase inhibitors such as Imatinib. In the long run, these results will allow us to prevent treatment failures in childhood leukemia and also provide new tools for early diagnosis.
"The generous support from the AACR Career Development Award for Pediatric Cancer Research will allow me to perform the above-mentioned experiments. This research was initiated under the outstanding mentorship of Michael R. Green at University of Massachusetts Medical School, Worcester, during my postdoctoral fellowship."
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