Geoffrey Beene Cancer Research Center: 2010 Geoffrey Beene Grant Awards

The following investigators were awarded Geoffrey Beene Cancer Research Center grants in 2010:

Boris C. Bastian

Boris C. Bastian, MD, PhD
Chair, Department of Pathology
Human Oncology and Pathogenesis Program
Project: A Comprehensive Genomic Approach to Identify Cancer Genes in Uveal Melanoma

Project Abstract
Uveal melanoma is an aggressive form of melanoma with unique genetic characteristic, which involve frequent mutations in GNAQ or GNA11 and deletions of chromosome 3. In this project we are performing a systematic genetic and functional analysis to identify the tumor suppressor(s) on chromosome 3, with the goal to improve the understanding of the pathogenesis of this dreadful disease and to find better methods for diagnosis, prognosis, and treatment.

Filippo G. Giancotti

Filippo G. Giancotti, MD, PhD
Cell Biology Program
Sloan Kettering Institute
Project: Early Development of Small Molecule Inhibitors of the E3 Ubiquitin Ligase CRL4DCAF1

Project Abstract
We have recently provided evidence that the FERM domain protein Merlin, encoded by the neurofibromatosis type II gene (NF2), suppresses tumorigenesis by translocating to the nucleus to inhibit the E3 ubiquitin ligase CRL4DCAF1 (Li et al. Cell. 140:477-490, 2010b). These results indicate that inhibitors targeting CRL4DCAF1 will display therapeutic efficacy in NF2 and mesothelioma cases driven by NF2 mutations. We propose to identify and to begin to optimize compounds able to inhibit CRL4DCAF1.

Jason T. HuseJason T. Huse, MD, PhD
Department of Pathology

Human Oncology and Pathogenesis Program
Project: A Comprehensive Genomic and Epigenomic Analysis of the Impact of First-Line Therapy in the Molecular Evolution of Malignant Glioma

Project Abstract
Malignant gliomas are routinely treated with radiation and chemotherapy, but invariably recur in a state refractory to conventional treatment regimens. The biological mechanisms underlying this resistance, especially with regard to the impact of cytotoxic therapy at the molecular level, remain largely unknown. We intend to comprehensively characterize the effects of first-line glioma treatment on the development of therapeutic resistance in malignant glioma using an integrated, global genomics/epigenomics approach.

Ingo K. Mellinghoff

Ingo K. Mellinghoff, MD
Department of Neurology
Human Oncology and Pathogenesis Program
Project: Identification of Aberrant Signal Transduction Pathways in Primary CNS Lymphoma

Project Abstract
Primary CNS Lymphoma (PCNSL) is an aggressive primary human brain tumor. There remains a paucity of knowledge regarding the molecular events driving this disease. Our project will molecularly characterize a clinically well annotated set of PCNSL samples with the goal to derive new insights into its pathogenesis and to identify new treatment opportunities for its most aggressive subtype(s).

Vincent A. Miller

Vincent A. Miller, MD
Thoracic Oncology Service
Department of Medicine
Project: Characterization of the Molecular Heterogeneity of EGFR Mutant Lung Adenocarcinoma: Baseline and Post-Treatment Tumor Analysis

Project Abstract
Lung cancers with mutations in the epidermal growth factor receptor (EGFR) are a unique subset of adenocarcinomas of the lung that are unusually vulnerable to targeted therapy with tyrosine kinase inhibitors (TKIs) such as erlotinib. Despite an unparalleled 14-month-median progression-free survival, patients treated with erlotinib exhibit significant differences in benefit, with some gaining years of disease control and others progressing after several months. Response rate is similarly variable. These observations suggest that there are underlying differences among EGFR mutant lung adenocarcinomas. The goal of this study is to more uniformly characterize the biologic heterogeneity of this disease through assessment of intra- and inter-tumoral changes in key genes linked prospectively to outcome from patient samples taken before and immediately after treatment with erlotinib. This understanding is fundamental to the improvement of current therapies and generation of new ones.

Stephen D. Nimer

Stephen D. Nimer, MD
Leukemia Service
Department of Medicine
Molecular Pharmacology and Chemistry Program
Sloan Kettering Institute
Project: Establishment of a Unique Mouse Model for Plasma Cell Malignancies

Project Abstract
We have generated a novel mouse model that allows us to study the development and progression of human plasma cell disorders, including multiple myeloma and plasma cell leukemia. We will use these mice to gain insights into the mechanisms by which these diseases arise, the genetic abnormalities and changes in gene expression that drive their growth, and the precise defects in their growth regulation. This information will be incorporated into new therapeutic approaches, which we will evaluate using the mice. The results of these studies will be used to procure future NCI or NIH funding.

Kenneth Offit

Kenneth Offit, MD
Chief, Clinical Genetics Service, and Lymphoma Service
Department of Medicine
Cancer Biology and Genetics Program
Sloan Kettering Institute
Project: Exome Sequencing of Familial Lymphoproliferative Syndrome

Project Abstract
This project will seek to uncover mechanisms of genetic susceptibility in families affected by multiple cases of lymphoid malignancies. The approach taken will be to utilize next-generation massively parallel sequencing to discover within coding segments of the genome rare events that can explain increased risk for developing lymphoid cancers. We will sequence the exome from one affected individual in each series of families affected by lymphoproliferative malignancies, and identify rare events not seen in reference genomes.

John H. J. Petrini

John H. J. Petrini, PhD
Molecular Biology Program
Sloan Kettering Institute
Project: DNA Replication Stress and the Sumoylation of RPA

Project Abstract
DNA replication stress, which is caused by DNA lesions or metabolic states that impair the process DNA replication, causes chromosome alterations. Defects in pathways that respond to DNA replication stress have been definitively linked to the development of cancer. Using human, mouse, and yeast cells, we are analyzing the response to replication stress. Ultimately, the information obtained will illuminate molecular mechanisms of tumor suppression.

Howard I. Scher

Howard I. Scher, MD
Chief, Genitourinary Oncology Service
Department of Medicine
Project: Molecular Profiling in Circulating Tumor Cells in Patients with Metastatic Prostate Cancer: Development of Predictive Biomarkers for Targeted Treatment

Project Abstract
The experience to date with androgen-receptor-signaling-directed approaches for castration-resistant prostate cancer shows dramatic and durable responses in some patients, an intermediate response in others, and a distinct cohort that is intrinsically resistant to therapy. Our program seeks to establish robust assays for genes associated with intrinsic and acquired resistance in circulating tumor cells isolated from patients enrolled on trials of AR-signaling-targeted agents in clinical development at Memorial Sloan Kettering. Our long-term objective is to generate data to qualify predictive biomarkers of sensitivity in CTC to guide treatment selection.

Hans-Guido Wendel

Hans-Guido Wendel, MD
Cancer Biology and Genetics Program
Sloan Kettering Institute
Projects: Oncogenic MicroRNAs in Acute Lymphatic Leukemia

Project Abstract
Cytogenetic and recent genomic studies from the Downing lab and others have produced great insight into the genetics of acute lymphatic leukemia (ALL). However, the contribution of microRNAs (miRNAs) to the molecular pathogenesis of ALL has not been explored systematically. This proposal focuses on oncogenic miRNAs in ALL, and we expect to gain insight into the contribution of miRNAs to the pathogenesis and clinical course of ALL.