Geoffrey Beene Cancer Research Center: 2009 Geoffrey Beene Grant Awards

The following investigators were awarded Geoffrey Beene Cancer Research Center grants in 2009:

Nai-Kong Cheung

Nai-Kong Cheung, MD, PhD
Department of Pediatrics
Project: Humanized Antibody 8H9 to Target Immunoinhibitory Molecule B7H3 on Solid Tumors

Project Abstract
Few curative treatments exist for cancers metastatic to the brain. Liquid radiation delivered by mouse monoclonal antibody 8H9 has prolonged survival measured in years. The humanized form of 8H9 should make the treatment safer and more effective.

Ronald DeMatteo

Ronald DeMatteo, MD
Vice Chair, Department of Surgery; Head, Division of General Surgical Oncology
Immunology Program, Sloan Kettering Institute
Project: Combined Molecular Therapy and Immunotherapy for Gastrointestinal Stromal Tumor

Project Abstract
Tyrosine kinase inhibitors are a new class of drugs that have already proven to be highly effective in certain types of human cancers. We are using a mouse tumor model to investigate the effects of using tyrosine kinase inhibitors with agents that activate the immune system. The hypothesis is that this combination therapy will be more effective than either treatment alone. The work may ultimately provide the basis for human clinical trials.

Filippo Giancotti

Filippo G. Giancotti, MD, PhD
Cell Biology Program, Sloan Kettering Institute
Project: Suppression of Mammary Tumorigenesis and EMT by the Atypical Rho Protein Rnd1

Project Abstract
We are studying the function of the potential tumor suppressor gene RND1, which appears to be altered in about 20 percent of human breast cancers. We have found that RND1 directs the production of a signaling protein that restrains the cell division cycle and prevents the changes in cell architecture and motility that accompany tumor invasion and metastasis. Inactivation of RND1 leads to the conversion of normal mammary epithelial cells to breast cancer cells and renders already transformed breast cancer cells more invasive and metastatic. We are currently studying the mechanism through which RND1 suppresses cellular signaling, examining if genetic inactivation of RND1 is sufficient to initiate tumorigenesis in the mammary gland of mice, and exploring the genetic mechanisms through which RND1 is inactivated in human breast cancer.

Michael Glickman

Michael Glickman, MD
Infectious Disease Service, Department of Medicine
Immunology Program, Sloan Kettering Institute
Project: BCG Susceptibility of Bladder Cancer Cells: Role of PTEN-AKT Signaling in Pathogen Infection

Project Abstract
Early stage bladder cancer is often treated with BCG, a live bacterium, but its mechanism of action is unknown. This project will investigate the possibility that deficiencies in tumor suppressor pathways within bladder cancer tumor cells render them sensitive to BCG therapy. If successful, this project will identify the mechanism of action of BCG therapy and allow targeting of this therapy to specific patients based on their tumor characteristics.

Alexandra L. Joyner

Alexandra L. Joyner, PhD
Developmental Biology Program, Sloan Kettering Institute
Project: Development of a Novel Technique for Modeling and Characterizing Sporadic Tumors in Mice

Project Abstract
Most cancer arises sporadically due to genetic mutations that occur in one or a few cells within a tissue. Current animal models of cancer, however, do not accurately model sporadic tumor formation. Using sophisticated mouse genetics, we are developing a novel approach to study the natural progression of sporadic tumors and test cancer treatments.

Andrew Lassman

Andrew Lassman, MD
Department of Neurology
Project: Pulsatile Kinase Inhibitor Therapy for Malignant Glioma: Proof of Concept Clinical Trial

Project Abstract
Malignant gliomas are the most common brain cancer in adults and the average survival for patients with the most aggressive type (glioblastoma) is about one year. In many of these tumors, a molecule called Epidermal Growth Factor Receptor (EGFR) signals tumor cells to grow. Thus far, drugs that inhibit EGFR have not been effective for most patients, at least partly because drugs do not adequately reach the tumor when given in the standard manner, a low dose every day. To improve results, we plan a clinical trial that differs from previous studies in two important ways: 1) a different dosing schedule called “pulsatile” dosing with a high dose once per week that blocks EGFR less frequently, but more completely, than standard dosing; 2) selection of patients most likely to benefit because EGFR in their tumors is abnormally active; previous trials treated all patients regardless of whether EGFR were “on” or “off.” We will treat 20 patients in this manner, 10 of whom will also undergo surgery after receiving the EGFR inhibiting drug so that we can determine whether the treatment effectively turns “off” EGFR. Through this design, we hope to change the current paradigm of drug development for gliomas.

Ross L. Levine

Ross Levine, MD
Leukemia Service, Department of Medicine
Human Oncology and Pathogenesis Program
Project: Identification and Characterization of Inherited Predisposition and Modifier Alleles that Contribute to the Pathogenesis of Myeloproliferative Neoplasms

Project Abstract
The goal of our project is to identify novel inherited dna changes which predispose individuals to develop chronic leukemias. The long term goal of our efforts is to improve our understanding of the genetic basis of leukemias to better use existing treatments and develop new therapies.

Jason S. Lewis

Jason S. Lewis, PhD
Chief, Radiochemistry Service, Department of Radiology
Project: Zirconium-89 Labeled Antibodies for ImmunoPET Guided Radioimmunotherapy

Project Abstract
This proposal will focus on the use of trastuzumab (Herceptin), a monoclonal antibody (mAb) which targets the HER2/neu growth factor receptor; a member of the epithelial growth factor receptor (EGFR) family. The central hypothesis is that 89Zr-radiolabeled Herceptin can be used for quantitative PET imaging of breast tumors, improved early detection, staging, monitoring of immunotherapy with Herceptin, and the development of new radioimmunoPET guided radioimmunotherapeutic agents specific for breast cancer. By the end of this project we anticipate that we will have translated 89Zr-DFO-Herceptin to the clinic for quantitative PET imaging of HER2/neu positive breast cancers in patients.

Yueming Li

Yueming Li, PhD
Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute
Project: Role of Notch/y-secretase Pathway in the Proliferation and Survival of Breast Cancer Cells

Project Abstract
Notch signaling may play a causative role in breast cancer. Overall objectives of this proposal are to investigate the function of Notch/gamma-secretase signaling in breast cancer cells and to develop a target-based therapy that is not available today.

Dimitar B. Nikolov

Dimitar B. Nikolov, PhD
Structural Biology Program, Sloan Kettering Institute
Project: Novel Anti-Cancer Compounds Targeting the Tie2/Angiopoietin Interactions and Signaling

Project Abstract
The Tie2 receptor and its angiopoietin ligands regulate developmental and tumor-induced blood vessel formation. The potential to inhibit tumor formation and growth by blocking tumor-induced blood vessel formation has shown great promise in many cancer types. Our preliminary results indicate that small molecules could disrupt the Tie2/angiopoietin interactions, and we propose to identify such compounds and start developing them into effective anti-tumor therapies.

Michael Overholtzer

Michael Overholtzer, PhD
Cell Biology Program, Sloan Kettering Institute
Project: Examining the Role of Entosis in Human Cancers

Project Abstract
Cancers arise when individual cells evade homeostatic mechanisms that control their growth. By investigating how tumors arise from normal cells in the lab, we discovered a new cellular mechanism called entosis, which eliminates cells by causing cell death. Evidence of entosis has been seen for decades by pathologists in human cancers, because it results in the formation of “cell-in-cell” structures, where whole cells are engulfed inside of others. Characterization of this process will shed light on a novel aspect of how some cancers arise and also on a new cell death program than can kill tumor cells.

David Solit

David B. Solit, MD
Genitourinary Oncology Service, Department of Medicine
Human Oncology and Pathogenesis Program
Project: The Memorial Sloan Kettering Cancer Center Colorectal Cancer Oncogenome Project: Somatic and Germline Predictors of Recurrence and Response to Therapy

Project Abstract
Cancers arise when individual cells evade homeostatic mechanisms that control their growth. By investigating how tumors arise from normal cells in the lab, we discovered a new cellular mechanism called entosis, which eliminates cells by causing cell death. Evidence of entosis has been seen for decades by pathologists in human cancers, because it results in the formation of “cell-in-cell” structures, where whole cells are engulfed inside of others. Characterization of this process will shed light on a novel aspect of how some cancers arise and also on a new cell death program than can kill tumor cells.

Andrea Ventura

Andrea Ventura, MD, PhD
Cancer Biology and Genetics Program, Sloan Kettering Institute
Project: Investigating the Functions of Oncogenic MicroRNAs in Mammals

Project Abstract
Using a combination of mouse genetics, bioinformatic and biochemistry, we are investigating the role of Oncomir-1 (also known as miR-17~92) in the pathogenesis of human cancers. Our preliminary results indicate that this cluster of miRNAs is essential for the survival of lymphoma cells and we are currently identifying the molecular mechanisms underlying its oncogenic properties. These studies extend our basic knowledge of the role of miRNAs in tumorigenesis and may pave the way for an entirely novel approach for the targeted treatment of human cancers.