Geoffrey Beene Cancer Research Center: 2012 Geoffrey Beene Grant Awards

The following investigators were awarded Geoffrey Beene Cancer Research grants in 2012:

Timothy ChanTimothy Chan
Human Oncology and Pathogenesis Program
Project: The Mutational Landscapes underlying Tumor Aggressiveness in Adenoid Cystic Carcinoma     

Project Abstract: Adenoid cystic carcinoma (ACC) is a deadly malignancy about which very little is known. Our study will define the mutational landscape underlying this cancer and define the changes that drive tumor aggressiveness. We will make use of several rigorous genome-wide strategies to elucidate the genetic changes in ACC. Our work will identify new biomarkers for disease progression and potential novel targets for therapy.

James HsiehJames Hsieh
Human Oncology and Pathogenesis Program
Project: Genetic Basis of mTOR Treatment Response and Its Implication in Kidney Cancer

Project Abstract: This translational Beene grant focuses on understanding the molecular underpinnings of treatment response/resistance to mTOR inhibitors (targeted drugs that have approved by the US Food and Drug Administration for treating kidney cancers). To achieve this outstanding goal, we employ a state-of-the-art integrated genomic, structural, biochemical, and mouse genetic approach. Results are expected to help better predict response/resistance of renal cancers to targeted anticancer agents, with an ultimate goal of personalizing cancer therapies.

Alexander JoynerAlexander Joyner
Developmental Biology Program
Project: Role of Reciprocal Epithelial-Stromal Signaling Elicited by Hedgehog-GLI Signaling in Prostate Cancer

Project Abstract: Most research on prostate cancer (PCa), the second leading cause of cancer-related deaths in American men, has concentrated on the signaling pathways active in tumor cells; however there is growing evidence that cancer-associated fibroblasts (CAFs) have profound effects on tumor growth, with normal stroma reducing tumor burden and CAFs augmenting tumor growth. The hypothesis we will test using mouse models is that a hedgehog protein secreted by PCa stimulates expansion of CAFs that in turn secrete factors that enhance tumor progression. Since small molecule hedgehog pathway inhibitors have been effective in the clinic and mouse cancer models, the results of our studies should be applicable to translational studies.

Mithat GönenMithat Gönen
Department of Epidemiology and Biostatistics
Project: Integrated Genetic Profiling to Predict Response to Therapy in Acute Myeloid Leukemia

Project Abstract: Although induction chemotherapy, consolidation, and allogeneic stem cell transplantation offer the possibility of cure to patients with acute myeloid leukemia (AML), the variable outcome of patients with AML has limited the optimal use of antileukemic therapies. Most recently, randomized trials have established high-dose daunorubicin as the current standard of care for patients 18 to 60 years of age with newly diagnosed acute myeloid leukemia (AML); however it was not clear from these studies whether there were specific patient subsets that derive benefit from more-intensive therapies. Previously we used data from a trial of younger adults with AML to demonstrate mutational analysis can identify which patients benefit from dose-intensive daunorubicin induction chemotherapy and which patients do not derive benefit from the more intensive regimen. We now aim to expand our knowledge of genomic predictors of response or resistance to therapy through a study of elderly patients enrolled in multi-center randomized trials. The results will help us to refine our prognostic signature of overall outcome in AML, identify mutations that predict response to therapy, and determine patient subsets based on mutational analysis that benefit from more-intensive therapies including dose-intense chemotherapy and allogeneic hematopoietic stem cell transplantation.

Christopher ParkChristopher Park
Human Oncology and Pathogenesis Program
Project: Targeting CD99 in Leukemic Stem Cells in Acute Myeloid Leukemia

Project Abstract: We have shown that leukemic stem cells in acute myeloid leukemia (AML) express the cell surface protein CD99. Because AML stem cells can be selectively targeted by antibodies that recognize CD99, we will investigate whether such an antibody can be utilized clinically as a novel AML therapy. We will also determine the function of CD99 in AML stem cells, which are the cells that must be eliminated in order to effect cures for this difficult-to-treat disease.

Jae ParkJae Park
Leukemia Service, Department of Medicine
Project: A Phase II Study of the BRAF Inhibitor Vemurafenib in Patients with Relapsed or Refractory Hairy Cell Leukemia

Project Abstract: A recent exome sequencing study of hairy cell leukemia (HCL) has identified that the BRAF V600E mutation is present in nearly 100 percent of primary HCL samples while absent in other B cell lymphoid malignancies. The exclusive presence of the BRAF V600E mutation in HCL implicates its role in pathogenesis and provides a rational therapeutic target. Therefore, we propose to study the clinical efficacy of the BRAF inhibitor vemurafenib in patients with relapsed or refractory HCL. Our project will also systematically characterize mutation profiles of HCL and investigate the potential mechanisms of resistance to BRAF inhibition. The ultimate goal of the project is to provide a better understanding of the implication of the BRAF mutation and develop the first molecularly targeted therapy in patients with HCL.

John PetriniJohn Petrini
Molecular Biology Program
Project: Oxidative DNA Damage and Oncogenesis: A New Function for the Ku Heterodimer          

Project Abstract: This study will examine the interplay between oxidative DNA damage and the process of DNA synthesis. Previously the protein called Ku has been shown to regulate DNA repair. We have discovered a new function for Ku, which is that during this process it helps to suppress the potential of oxidative DNA damage to cause cancer. We are examining the importance of this process and the role of Ku in preventing breast cancer.

Viviane TabarViviane Tabar
Department of Neurosurgery
Project: Human ES Cells as Candidates for Modeling Glioma    

Project Abstract: Human pluripotent stem cells represent highly promising novel tools for modeling human disease. Our lab has expertise in inducing the differentiation of human pluripotent stem cells into neural precursors. Here we propose to use these cells for the purpose of modeling human glioma. Mutations uncovered in genomic studies of human brain tumors will be introduced into human neural precursors in an effort to uncover oncogenic pathways required for the initiation of brain tumors from specific cells of origin. We hope to demonstrate that human pluripotent stem cells can serve as a platform for modeling gliomas and potentially other cancers in human cells.

Hans-Guido WendelHans-Guido Wendel
Cancer Biology and Genetics Program
Project: New Therapeutic Opportunities in Follicular Lymphoma

Project Abstract: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL), with 18,300 new cases diagnosed per year in the United States. FL is not curable by chemotherapy and is characterized by continuous relapses and disease progression. Genetically, FLs are characterized by the t(14;18) that deregulates Bcl2, and additional genetic events are required for lymphoma development and progression. The identity of oncogenic drivers in FL is not established. FL is clearly a significant health concern; however this cancer has been somewhat neglected scientifically. We have developed a new murine model of FL and established reagents and collaborations that put us in a unique position to conduct the proposed studies.