Geoffrey Beene Cancer Research Center: Geoffrey Beene Grant Awards

The Geoffrey Beene Cancer Research Center annually funds the top research proposals submitted by Memorial Sloan Kettering faculty members whose research supports the field of human oncology, human cancer pathogenesis, cancer biology, and cancer genetics, which together span the range of research from basic laboratory investigations to translational clinical studies, and from the development of new therapies to their evaluation in clinical trials.

All applications are reviewed by a committee, which consists of the Geoffrey Beene Cancer Research Center Executive Committee and other selected faculty members. Grant recipients may be awarded a second year of support based on the progress made and findings after their first year of funding.

2014

Matthew Hellmann
Department of Medicine
Project: Exome sequencing to identify genetic predictors of response to anti-PD-1 therapy in patients with NSCLCs

Alan Hall
Cell Biology Program
Project: Use of human pancreatic precursor cells to explore the cellular changes associated with the development of pancreatic malignancy

Gregoire Altan-Bonnet
Computational Biology
Project: Single-cell multi-parametric analysis of lymphocyte signaling in health and disease using CyTOF

Ming Li
Immunology Program
Project: Differentiation and Function of Tumor-associated Macrophages

Marilyn Resh
Cell Biology Program
Project: Hedgehog Acyltransferase as a Target in Breast and Lung Cancers

Maurizio Scaltriti
Human Oncology and Pathogenesis Program
Project: Unraveling resistance to PI3K p110 inhibitors in breast cancer

Emily Foley
Cell Biology Program
Project: Non-cell-autonomous rewiring of mitosis by the tumor microenvironment

Andrea Ventura
Cancer Biology Program
Project: A CRISPR- based approach to generate chromosomal rearrangements in vivo

Simon Powell
Molecular Biology Program
Project: BRCA Pathway Defects in Sporadic Breast Cancer

John Petrini
Molecular Biology Program
Project: Dissecting the mechanism of DDR signaling: Mining the Nbs1/Mre11 interface

Kayvan Keshari
Molecular Biology and Pharmacology Program
Project: Non-invasive detection of Glutamate pool metabolism using Hyperpolarized MRI

James Fagin
Human Oncology and Pathogenesis Program
Project: NF2-Hippo in RAS-driven cancers

2013

Omar Abdel-Wahab
Human Oncology and Pathogenesis Program
Project Title: Somatic genetic alterations in the pathogenesis and therapy of histiocytic disorders

Project Abstract: The histiocytic disorders are a collection of diseases characterized by an accumulation of white blood cells called macrophages and/or dendritic cells in various tissues throughout the body. These diseases present with a wide array of clinical manifestations and have a variety of subtypes based on the microscopic appearance of white blood cells. Because of the rarity of each individual subtype of histiocytic disease and their very heterogeneous clinical presentations, the clinical experience and biologic understanding of many of these diseases has been limited. A major breakthrough in the biology and therapy of these disorders came with a recent discovery that 40 to 50 percent of patients with the most common histiocytic disorders have mutations in the oncogene BRAF. Based on this finding, we organized a group of physicians and scientists at Memorial Sloan Kettering committed to identifying the genetic abnormalities underlying the histiocytic disorders and treating these patients as part of monitored clinical trials using approaches targeting these genetic alterations. Thus far we have made great progress in the treatment of BRAF-mutant histiocyte patients with the mutant BRAF inhibitor vemurafenib and found new genetic alterations, which are promising targets for novel therapies for additional histiocytic-disorder patients.

Yu Chen
Human Oncology and Pathogenesis Program
Project: Generation of personalized models of prostate cancer for correlates of disease response and progression

Project Abstract: Cancer cells growing in the laboratory are extensively used to study tumorigenesis and therapy. Prostate cancer cells are uniquely difficult to grow in the laboratory, hampering the ability for researchers to study the mechanisms of disease and drug resistance. Using newly developed methods to grow prostate cancer cells that are directly derived from patient biopsies, we propose to establish a panel of lines from patients entering clinical trials in prostate cancer. We will characterize these lines for genetic mutations and drug sensitivity to study the genetic basis of tumor growth and drug resistance.

Nai-Kong Cheung
Department of Pediatrics
Project: Bispecific antibody to engage T cells for cancer therapy

Project Abstract: T lymphocytes are ferocious killers. They kill serially and while killing, they multiply, setting up killer colonies at the sites where they encounter tumor cells. Unfortunately many tumor cells, including neuroblastoma, are immune to these killer T cells. Bispecific antibodies (BsAb) are engineered to carry the binding sites of two different antibodies – one site is to bind to T cells; the other is to handcuff T cells to the tumors. Now, T cells can do what they are trained to do – be killing machines. With BsAb, tumors can no longer escape the immune system. First, the expression of antigens called HLA on tumors is no longer required. Moreover, nearly all T cells can be recruited, and they no longer need to be prior-educated or “primed” to the tumor. Early studies in leukemia and lymphoma have shown dramatic positive clinical results. In this proposal, a BsAb to retarget T cells to the ganglioside GD2 on human tumors will be developed into a clinical drug, and be made ready for first-in-human clinical trial. Since GD2 is present on many pediatric tumors including neuroblastoma, osteosarcoma, Ewing’s family of tumors, and rhabdomyosarcoma, this drug will be useful for some of these difficult-to-cure childhood cancers. If it is proven safe and effective, this BsAb may have broad application to adult cancers with GD2 present, such as small cell lung cancer, melanoma, and brain tumors.

Ping Chi
Human Oncology and Pathogenesis Program
Project: Clinically targeting ETV1 in advanced gastrointestinal stromal tumor (GIST)

Project Abstract: Gastrointestinal stromal tumor (GIST) is characterized by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Despite the clinical success of imatinib, nearly all advanced GIST patients develop imatinib resistance and eventually die of their disease. We have recently discovered that ETV1 – an ETS family transcription factor and a well-established oncogene involved in recurrent genomic alterations in prostate cancer, Ewing sarcoma, and melanoma – plays a critical role and cooperates with mutant KIT/PDGFRA in GIST pathogenesis. Here, we propose to examine a novel therapeutic strategy that simultaneously targets both the mutant KIT/PDGFRA and ETV1 in preclinical murine GIST models and in a phase Ib/II clinical trial in advanced GIST patients. We will examine the efficacy and imatinib/MEK inhibitor-resistance mechanisms of this dual-targeting strategy and develop predictive therapeutic biomarkers using biospecimens derived from the murine models and the clinical trial. We believe that this strategy, if successful, has the potential to change the landscape of clinical practice in GIST management and has important therapeutic implications in other ETV1-dependent malignancies.

Filippo Giancotti
Cell Biology Program
Project Title: Inactivation of neogenin in castration-resistant prostate cancer

Project Abstract: Once prostate cancer has become refractory to antiandrogen therapy and metastatic, it cannot be effectively cured. The molecular pathways underlying prostate cancer progression to this advanced stage are incompletely understood. We have observed that the cell adhesion receptor neogenin is inactivated in a fraction of hormone-refractory prostate tumors. We propose to elucidate the molecular mechanisms by which loss of neogenin induces prostate cancer progression and metastasis and to examine whether these mechanisms operate in human prostate cancer. The results of these studies may lead to the identification of novel targets for the therapy of AR-independent prostate cancer.

Morgan Huse
Immunology Program
Project: Quantitative approaches for the mechanistic analysis of tumor cell killing by cytotoxic lymphocytes

Project Abstract: Cytotoxic T lymphocytes (CTLs) fight cancer by recognizing and destroying tumor cells. This proposal describes experiments aimed at learning how CTLs carry out this killing process. The information gained from our study will aid in the development of strategies to use CTLs for antitumor immunotherapy.

Raajit Rampal
Department of Medicine
Project: Combined JAK2/HSP90 inhibition in primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis

Project Abstract: The Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET). Mutations in the JAK2 gene occur in the majority of MPN patients, which has led to efforts to target this mutation with JAK2 inhibitors. The JAK1/2 inhibitor ruxolitinib has been approved for the treatment of MF. While JAK inhibitor therapy relieves symptoms in the majority of MF patients, there is no evidence that these inhibitors can induce remission of the disease. Thus, other agents are needed that can target JAK2. Hsp90 is a protein chaperone that stabilizes JAK2. We previously demonstrated that JAK2 associates with Hsp90, and that inhibition of Hsp90 leads to degradation of JAK2. Our preliminary studies suggest that combined Hsp90/JAK2 inhibition results in more potent JAK2 inhibition. We therefore seek to determine the effect of combined Hsp90 and JAK2 inhibition in preclinical studies and in MPN patients with the goal of improving the outcome of patients with MPNs.

Jonathan Rosenberg
Department of Medicine
Project: TFIIH complex somatic mutations as biomarkers of platinum chemotherapy sensitivity

Project Abstract: While platinum-chemotherapy has been long used in oncology, most patients do not derive dramatic benefits. Newly identified DNA repair gene mutations in urothelial carcinoma appear to be associated with high levels of sensitivity to cisplatin chemotherapy in muscle-invasive urothelial tumors. This project will determine whether these findings predict response to platinum chemotherapy drugs in metastatic urothelial carcinoma and begin to explore whether these or similar mutations in other cancer types predict platinum treatment responses. In addition, laboratory investigations will explore the molecular underpinnings of these findings. The ultimate goal of this project is to determine whether these mutations can be used to predict which tumors will respond to platinum chemotherapy, allowing better selection of patients for chemotherapy treatment.

Neal Rosen
Molecular Pharmacology and Chemistry Program
Project: Functional consequences and therapeutic implications of RAF-dimer signaling in cancer

Project Abstract: Activation of the ERK signaling pathway occurs in at least half of human cancers and is controlled by a protein called RAF. RAF can exist as a single protein (monomer) or a pair of proteins bound together (dimer); in most tumors, activation occurs via dimers. Inhibitors of RAF monomers have been developed that have remarkable clinical activity in melanoma, but no inhibitors of RAF dimers currently exist. We have now identified the first known inhibitor of RAF dimers and found that it inhibits some tumors that are driven by this protein. Our grant is focused on understanding how this compound works, using this information to make better drugs, and developing these drugs as cancer therapeutics.

Joseph Sun
Immunology Program
Project: Investigating the role of transcription factor Zbtb32 in the NK cell response against tumor establishment and metastasis

Project Abstract: Natural killer (NK) cells recognize and destroy transformed host cells in a process termed tumor immunosurveillance. Humans lacking NK cells or NK cell function have severe health complications due to certain cancers and viral infections. The general goals of my research program are to understand the molecular mechanisms behind NK cell responses against cancer and infectious pathogens. Because the transcription factor Zbtb32 is critical for NK cell activation and proliferation, we will investigate the role of Zbtb32 in the generation of a robust immune response against tumor establishment and metastasis. The studies in this proposal will uncover the biological pathways mediated by Zbtb32 and provide a framework for manipulating powerful NK cell responses in the clinic to target cancer.

Wolfgang Weber
Department of Radiology
Project: Theranostics of neuroendocrine tumors with somatostatin antagonists

Project Abstract: The goal of this study is to develop a new therapy for neuroendocrine tumors (a group of tumors that can arise from hormone-producing cells throughout the body). The therapy is based on a novel class of molecules (somatostatin receptor antagonists) that can selectively deliver radiation to these tumors. The study will evaluate how much radiation can be delivered safely in patients and how well tumors respond to this therapy.

2012

Timothy 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 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 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 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 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 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 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 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 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.

2011

Michael Berger, PhD
Department of Pathology
Project: High-Throughput Profiling of Genomic Alterations in Clinical Tumor Specimens

Project Abstract
Efforts to understand cancer at the molecular level have revealed genetic biomarkers that reflect the nature and course of disease and, in some cases, predict the likelihood that a patient will benefit from a particular treatment. We plan to develop and apply a robust and cost-effective methodology, empowered by massively parallel “next-generation” sequencing, by which any clinical tumor specimen may be characterized for DNA mutations and copy number changes in all known cancer genes. By systematically deploying this platform across clinically annotated tumors and, ultimately, every cancer patient at Memorial Sloan Kettering, we hope to facilitate individual approaches to cancer treatment through improved diagnostics and the identification of novel biomarkers.

Sarat Chandarlapaty, MD, PhD
Breast Cancer Service, Department of Medicine
Human Oncology and Pathogenesis Program
Molecular Pharmacology and Chemistry Program
Project: Targeting AKT Inhibitor-Induced Feedback Signaling in Breast Cancer

Project Abstract
The PI3K/AKT/mTOR pathway is mutationally activated in the majority of breast cancers. While this pathway is druggable by a variety of compounds, the pathway is subject to multiple forms of negative feedback regulation and these feedback pathways become relieved under conditions of drug inhibition of the pathway. We hypothesize that loss of negative feedback limits the effectiveness of drugs targeting this pathway. We propose to (1) identify the specific mechanisms of feedback regulation of PI3K/AKT/mTOR-pathway-activated breast cancers, (2) determine the consequence of loss of negative feedback on the efficacy of drug therapy, and (3) clinically evaluate combining an AKT inhibitor with an inhibitor of a known oncogenic pathway that is hyperactivated through AKT-inhibitor-mediated loss of feedback.

Eric Holland, MD, PhD
Cancer Biology and Genetics Program
Department of Neurosurgery
Project: Understanding Clonal Evolution and Heterogeneity of the Therapeutic Response by Lineage Tracing in Mouse Models of Glioma

Project Abstract
It is increasingly appreciated that cancer cells within any given tumor differ considerably from each other, and such heterogeneity is likely a major hurdle in cancer therapeutics. Still, little is known about the mechanisms underlying the emergence of tumor cell heterogeneity. Traditionally, all cells within the tumor have been assumed to originate from a common ancestor. However, in addition to bona fide tumor cells, solid tumors also contain numerous cells derived from the normal host microenvironment such as blood vessels and immune cells. In brain tumors, a large number of normal brain cells are trapped within the growing tumor. Our research indicates that such normal cells can become corrupted by the tumor environment and actually become bona fide tumor cells themselves, suggesting that cancer cells within the same tumor may be unrelated to each other and may thus differ considerably in their response to specific therapeutic agents. By developing a new mouse model, we aim to characterize the corruption of such initially normal brain cells within gliomas, a common group of brain tumors, specifically with regard to their contribution to resistance to commonly used anticancer therapeutics and tumor recurrence.

Xuejun Jiang, PhD
Cell Biology Program
Project: Mechanism and Therapeutic Potential of PTEN Regulation upon Hypoxia

Project Abstract
The overall goal of this proposal is to understand the molecular basis underlying the context-specific regulation of PTEN tumor suppressor, and the cancer therapeutic implication of such regulation. Specifically, we will study how the ubiquitin ligase NEDD4-1 regulates PTEN function, AKT activation, cell survival/apoptosis, and tumorigenesis in the context of hypoxia. Success of this study will not only elucidate the molecular mechanisms governing the context-specific regulation of PTEN and novel aspects of hypoxia biology, but will also provide insights into therapeutic targeting of the NEDD4-1-PTEN circuitry in treating specific human cancers.

Moritz Kircher, MD, PhD
Department of Radiology
Project: Combined Pre- and Intraoperative Brain Tumor Imaging Using a Novel Dual-Modality Raman-MRI Nanoparticle Probe

Project Abstract
Malignant brain tumors remain a therapeutic challenge, in part because of the difficulty of visualizing the tumor borders during surgical resection. Our project seeks to validate a new molecular approach to brain tumor imaging based on a dual-modality MRI/SERS (surface-enhanced Raman spectroscopy) nanoparticle, allowing combined preoperative staging and intraoperative high-resolution imaging using a single contrast agent. This will include biodistribution and cytotoxicity studies and assessment of the accuracy of tumor delineation by MRI and Raman imaging in transgenic mouse models.   

Robert Klein, PhD
Cancer Biology and Genetics Program
Project: Transcriptional Regulatory SNPs as a Mechanism for Prostate Cancer Risk Loci

Project Abstract
While genome-wide-association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with risk of prostate cancer and other diseases, little is known about the biological mechanism by which these SNPs operate.  Here, we will test the hypothesis that the functional allele(s) at many prostate cancer risk loci alter a functional transcription factor binding site, thereby resulting in misregulation of nearby gene(s) that influence the carcinogenesis process. This research will give new insight into the biology of prostate cancer by identifying both a general mechanism underlying prostate cancer risk SNPs and specific genes that may mediate this altered risk.

Jason Lewis, PhD
Vice Chair for Research, Department of Radiology
Chief, Radiochemistry Service
Molecular Pharmacology and Chemistry Program
Project: Development of 89Zr-5A10 for the Measurement of AR Signaling in Advanced Prostate Cancer with Positron Emission Tomography

Project Abstract
We propose to evaluate 89Zr-5A10 as a pharmacodynamic and predictive biomarker for two important classes of therapies for CRPC (antiandrogens and PI3K inhibitors) and to conduct a phase 0 study with a humanized version of 5A10 in rodents and men with CRPC. This translational project represents one of the first systematic efforts to develop a biomarker for the evaluation of AR signaling in patients with CRPC, and the findings from this proposal have the potential to substantially impact the customization of individual patient care, as well as influence the design and execution of future clinical trials.

Paul Paik, MD
Thoracic Oncology Service, Department of Medicine
Project: Squamous Cell Carcinoma of the Lung Mutation Analysis Program (SQC-MAP)

Project Abstract
Patients with squamous cell carcinomas of the lung (SQCLC) comprise 20 percent of all non-small cell lung cancers diagnosed in the United States annually, amounting to nearly 40,000 patients per year. Unfortunately, no targeted therapies have been identified for these patients, this despite the success of drugs that target the mutant epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in a third of lung adenocarcinoma (ADCL) cases. Exciting new work has identified putative driver oncogenic events in upwards of 50 to 60 percent of SQCLC patients. The complex nature of these mutations, which have almost no overlap with those found in ADCL, necessitates the creation of a new molecular profiling infrastructure. SQ-MAP will fulfill this role, prospectively validating these molecular aberrations in a cohort of 100 SQCLC patients at Memorial Sloan Kettering while simultaneously serving as the platform by which patients will be paired to emerging clinical trials of new targeted therapies.   

Simon Powell, MD, PhD
Chair, Department of Radiation Oncology
Molecular Biology Program
Project: Genomic Determinants of Radiosensitivity

Project Abstract
The project aims to understand the genetic factors that underlie the individual differences in sensitivity to ionizing radiation. We have developed a high-throughput assay of DNA damage and repair using flow cytometry for lymphoblastoid cell lines. By studying the 1000 Genomes Project cell lines, where whole genome sequencing data are available, we can study genetic locus association markers for radiation sensitivity as well as candidate mutations and polymorphisms in known radiation response genes. The ultimate goal is to develop a radiogenomics profile for predicting sensitivity or resistance to radiation that will help in planning radiation therapy.

Marcel van den Brink, MD, PhD
Head, Division of Hematologic Oncology
Immunology Program
Project: Endothelial Precursor Cells in Allogeneic Bone Marrow Transplantation during Graft-versus-Host Disease and Graft-versus-Tumor Activity

Project Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapy with curative potential for a variety of malignant and non-malignant diseases. The major obstacles to a more favorable therapeutic outcome are tumor relapse and acute graft-versus-host disease (GVHD), which is an inflammatory process primarily involving the intestine, liver, and skin. Neovascularization has been implicated in both tumor growth and inflammation suggesting that neovascularization could be an attractive therapeutic target in patients with malignancies undergoing HSCT. Based upon our promising preclinical studies we hypothesize that therapeutic targeting of neovascularization in allo-HSCT recipients can simultaneously ameliorate GVHD and inhibit post-transplant malignant relapse resulting in improved overall survival in allo-HSCT recipients.

Andrea Ventura, MD, PhD
Cancer Biology and Genetics Program
Project:  Investigating the miR-34 Family of Tumor Suppressor MicroRNAs

Project Abstract
Over the past decade, microRNAs (miRNAs) have emerged as key modulators of gene expression in metazoan and plants. Deregulated expression of miRNAs is a common feature of human cancers, and a number of miRNAs have been proposed to act as oncogenes or tumor suppressors. We will investigate a recently described family of p53-regulated miRNAs whose members have been proposed to act as tumor suppressors in a variety of human cancers. By combining in vivo studies in the mouse and high-throughput approaches we will determine the physiologic functions of the various members of this family of miRNAs, their potential activity as tumor suppressors, and their mechanism of action

2010

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, 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. 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, 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, 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, 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, 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, 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, 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, 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.

2009

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, 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 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, 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, 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, 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 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, 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, 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, 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, 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 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, 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.

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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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

Project Abstract
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.

2007

Cameron Brennan, MD
Department of Neurosurgery
Project: Applying the Glioblastoma Genome Atlas to Glioma-relevant Signaling

Project Abstract
The genome of glioblastoma, the most common brain tumor in adults, has recently been analyzed in unprecedented detail through the national collaborative project: The Cancer Genome Atlas. Early results point to three distinct subclasses of glioblastoma which differ in gene expression and mutations. We are investigating the activation state of signal transduction pathways among these genomically-defined subclasses of glioma to identify which might be good candidates for therapeutic inhibition.

Renier Brentjens, MD, PhD
Leukemia Service and Hematology Laboratory Service, Department of Medicine
Project: Genetic Modifications to Enhance the In Vivo Survival and Anti-tumor Activity of Gene-Modified CD 19-Targeted T Cells

Project Abstract
T cells are immune cells which may be genetically altered to recognize a patient's own tumor cells. The go of this project is to better design these genetic modifications such that these T cells are more likely to fully eradicate all the tumor cells when injected back into the patients. Data generated from these studies will be used to design better clinical trials for cancer therapy using genetically targeted T cells.

Gabriela Chiosis, MA, PhD
Breast Cancer Medicine Service, Department of Medicine
Molecular Pharmacy and Chemistry Program, Sloan Kettering Institute
Project: Chemical/Proteomic Mapping of Cancer-Specific Molecular Therapeutic Targets

Project Abstract
Cancer is complex and no two patients present an identical disease. Because of the diversity of molecular alterations, it is difficult in clinical settings to determine the exact combination of drugs that will result in a best outcome. Our technology offers the promise of identifying, patient-by-patient, the subset of proteins that become aberrant in every cancer cell type/patient tumor tissue. The information gained may be compiled in creating a molecular map of cell- and cancer-specific transformation pathways. This will ultimately allow the physician to design a personalized therapy for patients. Such proteomic map has obvious advantages over the more common genetic signature maps because most anti-cancer agents are small molecules that target proteins not genes, and many small molecules targeting specific molecular alterations are currently in development. Thus, our efforts aim to set the basis for designing combination therapies with better efficacy and less toxicity in the treatment of patients with cancers, and moreover, to define the specific molecular alterations in a particular tumor, facilitating the development of novel molecularly targeted therapies.

Filippo Giancotti, MD, PhD
Cell Biology Program, Sloan Kettering Institute
Project: A Gain-of-Function Genetic Screen for Human Breast Cancer Metastasis Genes

Project Abstract
We are studying the genetic instructions that induce cancer cells to become metastatic. We have constructed a library of genes from metastatic breast cancer cells, added a molecular tag, and introduced them into non-metastatic cells. The recipient cells have been injected into mice and those that have acquired the ability to metastasize to the lung have been recovered from this organ. Sequencing of the tagged genes has led to the identification of 2 novel genes that play a key role in metastasis. One of the two genes directs cells to make a secreted protein, called Coco, which blocks a signaling receptor, called BMP-receptor. We are isolating new metastasis genes and studying their mechanism of action. We hope that a better understanding of the molecular processes that drive metastasis will lead to the design of drugs that specifically block this process.

Xuejun Jiang, PhD
Cell Biology Program, Sloan Kettering Institute
Project: PTEN Signaling in Cancer: Novel Regulation and Potential Therapy

Project Abstract
PTEN is a potent tumor suppressor and a master regulator for multiple cell signaling processes. Mounting evidence indicates that PTEN itself is also under precise regulation, and such regulation dictates its signaling and tumor suppressive function. This project aims to understand regulation of PTEN by its ubiquitin ligase NEDD4-1, the potential of NEDD4-1 as a cancer therapeutic target, and potential novel functions of PTEN in other tumor-related signaling events.

Robert J. Klein, PhD
Cancer Biology and Genetics Program, Sloan Kettering Institute
Project: A Genome-wide Association for Pancreatic Susceptibility Loci

Project Abstract
Although it is known that individuals whose relatives have had pancreatic cancer are at greater risk of developing this deadly malignancy, it is not known what particular genes are responsible for this increased susceptibility. Here, we have used individuals from the Memorial Sloan Kettering Familial Pancreatic Cancer Registry to conduct the first stage of a genome-wide association study aimed at identifying common genetic changes responsible for an inherited susceptibility to pancreatic cancer. Our ultimate goal with this research is to identify genes that can be used both to predict who is at risk of developing pancreatic cancer and whose action can be targeted for treatment of this disease.

Mary Ellen Moynahan, MD
Breast Cancer Medicine Service, Department of Medicine
Project: The Impact of PIK3CA Mutations on the Efficacy of Bevacizumab in Recurrent Hormone-Receptor-Positive Breast Cancer

Project Abstract
In our work funded by the Geoffrey Beene Cancer Research Center, we identified PIK3CA mutations in approximately 1/3rd of invasive breast primary tumors. PIK3CA mutations are associated with favorable clinicopathologic features: lower tumor grade, hormone receptor positive status, HER2 negativity, older age at diagnosis, lower tumor stage, and lymph node negativity. Notably, and in accordance with these favorable pathologic predictors, patients with mutated tumors demonstrate an improvement in overall and breast cancer-specific survival. The protective role imparted by a PIK3CA mutation will significantly affect future clinical trial design for PI3K-targeted therapy.

William Pao, MD, PhD
Project: Characterizing the Cancer Genome in Lung Adenocarcinomas from Patients with Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

Project Abstract
Patients whose lung cancers harbor epidermal growth factor receptor (EGFR) gene mutations have a high likelihood of responding to the tyrosine kinase inhibitors (TKIs), Iressa or Tarceva. However, after about one year, these patients develop progression of disease. In this proposal, we aim to genetically characterize resistant tumors, in order to develop new strategies to treat progressive disease and suppress the development of acquired resistance.

Hans Wendel, MD
Cancer Biology and Genetics Program, Sloan Kettering Institute
Project: RNAi Screen to Identify Suppressors and Modifiers of Treatment Response

Project Abstract
Using a process called RNA interference (RNAi) we can selectively inactivate genes in living cells. Moreover, we can use libraries of RNAis to target every gene in the human genome. This technology now allows us to investigate genes whose inactivation contributes to various cancers and may affect therapeutic responses.