The following investigators were awarded Geoffrey Beene Cancer Research Center grants in 2008:
James Fagin, MD
Chief, Endocrinology Service, Department of Medicine
Human Oncology and Pathogenesis Program
Project: Synthetic Lethal Screen for Viability Genes in MEK Inhibitor-Treated Thyroid Cancer Cell Lines with BRAF Mutation
BRAF is the most common oncogene in aggressive forms of thyroid cancer, and is believed to be important in causing the disease. This proposal aims to identify kinases that may allow thyroid cancer cells to remain viable after the function of BRAF is blocked, as these could potentially be targeted selectively with small molecule inhibitors.
Mark Frattini, MD, PhD
Leukemia Service, Department of Medicine
Project: Identifying the Biological Consequences of Cdc7 Kinase Inhibition in Human Cells
Cdc7 is a protein kinase whose activity is required to begin the process of DNA duplication and is essential for normal passage through the cell cycle. Both Cdc7 and its known substrate, the minichromosome maintenance (MCM) complex, are overexpressed in the majority of leukemias, lymphomas, and solid tumors making Cdc7 kinase activity a potential therapeutic target. To this end, we have recently identified a novel naturally occurring small molecule inhibitor of Cdc7. The goal of this project is to more precisely define the result of inhibiting Cdc7 kinase activity in the cancer cell and to begin to look at possible mechanisms through which the cancer cell might become resistant to Cdc7 kinase inhibition.
David Gin, PhD
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute
Project: Discovery and Evaluation of Novel Adjuvants for Cancer and Infectious Disease Vaccines
The clinical success of vaccines against cancer and infectious diseases critically depends on the identification of novel potent adjuvants, substances which augment patient immune response. The aims of this collaborative effort will involve the chemical synthesis and preclinical evaluation of novel molecular adjuvants from botanical sources, with the goal of discovering new vaccine formulations of increased potency.
Alan Hall, PhD
Chair, Cell Biology Program, Sloan-Kettering Institute
Project: Identification of Rho GTPase Signaling Pathways Involved in Breast Cancer Cell Proliferation
Cell division is most obvious during embryonic development, but although it is much more restricted in the adult, cell division is nevertheless crucial, for example in the maintenance of tissues and organs through the division of stem cells. Whether a cell chooses to enter the cell cycle is mostly determined by signals in the external environment, such as growth factors, growth inhibitors and cell-cell and cell-matrix interactions. Inappropriate cell division is a hallmark of cancer and the aim of this program of work is to identify new biochemical pathways that drive the growth of human breast cancer cells.
Clifford Hudis, MD
Chief, Breast Cancer Medicine Service, Department of Medicine
Project: Use of Array CGH to Improve HER2 Testing and Better Identify Trastuzumab Sensitivity in Breast Cancer
Subtypes of breast cancer that responded differently to targeted drugs can be identified by examining their genetic material for certain changes. One example is the identification of HER2 (human epidermal growth factor receptor) positive breast cancer by finding extra copies (“amplification”) of the gene for HER2. We are using a newer method (comparative genomic hybridization or “CGH”) of examining the HER2 (and other genes of interest) to allow us to more accurately identify patients with HER2 positive breast cancer for treatment with anti-HER2 drug.
Tari King, MD
Breast Service, Department of Surgery
Project: A Genetic Analysis of the Invasive Breast Cancer Risk Associated with Lobular Carcinoma In-Situ
Lobular carcinoma in situ (LCIS) is most often an incidental finding in a breast biopsy performed for another reason, yet once a women is diagnosed with LCIS she faces a much higher risk for the subsequent development of invasive breast cancer. Historical data suggests that the lifetime risk of breast cancer is 20 to 25 percent and is conferred equally to both breasts. New research however suggests that all LCIS may not behave in the same way and therefore all LCIS may not confer the same increased risk of breast cancer. The objective of this proposal is to identify different types of LCIS by examining which genes are turned on and off in different LCIS specimens. Our hypothesis is that in some LCIS specimens we will find that the same genes are turned on as in invasive lobular breast cancer (ILC) and therefore these particular LCIS specimens will be the ones that carry the highest risk for ILC.
Douglas Levine, MD
Gynecology Service, Department of Surgery
Project: Integrated MicroRNA Genomics in Endometrial Cancer
Most women with early endometrial cancer will be cured and only 10 to 15 percent of these women are likely to recur. Nonetheless radiation therapy is frequently given after surgery to prevent cancer from coming back. This study aims to use microRNA gene expression profiling and DNA copy number analyses to predict which women are most likely to recur so that post-surgical therapy can be better individualized.
Joseph O'Donoghue, PhD
Department of Medical Physics
Project: Evaluation of Antiangiogenic Therapies by Hypoxia-Imaging Methods
Some recent drugs for cancer treatment work by preventing the development of new blood vessels. Without these new vessels, the cancer is unable to keep growing. It is important that physicians are able to monitor how well these drugs are working, preferably as early as possible after treatment begins. Our project aims to identify new ways in which the effectiveness of such drugs can be measured. The methods involve the use of non-invasive tumor imaging, which would make this process more convenient and less traumatic for patients than other methods currently available.
Milind Rajadhyaksha, PhD
Dermatology Service, Department of Medicine
Project: Line-scanning Confocal Endoscope for Screening Oral Precancers In Vivo
Confocal endoscope technology will be created for noninvasive screening and diagnosis of oral and head-and-neck cancers and to guide surgery of such cancers. The screening, diagnosis and surgical guidance will be directly on the patient, with minimal need for biopsy, minimal pain and minimal expense. The technology may also prove useful for noninvasively detecting other cancers such as in skin, cervix, breast and other tissues.
Marilyn Resh, PhD
Cell Biology Program, Sloan-Kettering Institute
Project: Inhibitors of Hedgehog Palmitoylation to Block Pancreatic Cancer Cell Growth
The Sonic Hegehog (Shh) protein is a key contributor to the growth of pancreatic cancer cells. The goal of the proposed research is to identify and develop drugs that inhibit attachment of the fatty acid palmitate to Shh. Since palmitoylation is required for Shh function, inhibitors that block Shh palmitoylation could be developed into novel chemotherapeutics that will be efficacious in the treatment of pancreatic cancer.