Omar Abdel-Wahab
HOPP
Project: Understanding aberrant LZTR1 signaling in cancer and cancer predisposition
Project Abstract: This project focuses on understanding the role of the protein LZTR1 in a variety of cancers as well as the role of mutations in the gene coding for LZTR1 in familial forms of cancer. LZTR1 was recently found to regulate the abundance of RAS proteins, which are encoded by some of the most commonly mutated genes across solid and liquid tumors. Understanding how LZTR1 regulates RAS proteins will help us to identify the clinical impact of alterations in this novel pathway in patients and means to improve cancer therapies targeting RAS pathways.

Heeseon An
SKI-Chemical Biology
Project: Harnessing Cancer Metabolism by Modulating the Stability of Metabolic Enzymes
Project Abstract: The mammalian target of rapamycin (mTOR) is a master regulator of cell growth. Research efforts have historically focused on mTOR’s role in transcription, translation, and autophagic degradation of cellular contents, collectively recycling available metabolites in cells. We recently discovered a new regulatory function of mTOR in cancer metabolism: controlling cell proliferation by regulating the stability of critical metabolic enzymes through the ubiquitin-proteasome system (UPS). We hypothesize that the dynamic regulation of these enzymes’ stability may be a new paradigm that cancer cells employ to sustain metabolite production and tumor growth. This project aims to investigate the underlying molecular mechanisms concerning how mTOR communicates with the UPS and controls the stability of the metabolic enzymes.

Jayanta Chaudhuri
SKI-Immunology
Project: Role of G-quadruplexes in B cell function and lymphomagenesis
Project Abstract: B cells are essential components of the immune system owing to their ability to make neutralizing antibodies against a potentially infinite number of pathogens. To achieve this enormous diversity, B cells undergo a series of genomic alteration events termed class switch recombination (CSR) and somatic hypermutation (SHM). Activation-induced cytidine deaminase (AID), a B cell-specific DNA cytidine deaminase carries out this function by deaminating antibody-coding genes. Research in the Chaudhuri lab showed in addition to binding regions that undergo CSR and SHM, AID also associated with regions encoding the MHCII genes. Moreover, AID expression correlates with decreased MHCII expression in both activated B cells and in diffuse large B cell lymphomas. Challenging the paradigm that this activity is merely an “off-target” effect that contributes to B cell lymphomagenesis, this project tests the idea that AID activity beyond the antibody-coding regions contributes to gene regulation in B cells following infection or vaccination. Successful completion of the project will significantly enhance our understanding of several aspects of both B cell immunity and lymphomagenesis.

Ming Li
SKI-Immunology
Project: Macrophage Surveillance of Diet-Conditioned cMyc-Overexpressing Tumors
Project Abstract: Emerging evidence indicates the diet can influence cancer progression. This project will identify how tumor-associated macrophages suppress growth of the diet-conditioned tumor. Pharmacological means to enhance the macrophage-mediated anti-tumor immune response will also be explored. These studies will generate insights into the diet-controlled tumor immune crosstalk and pave the way for the development of macrophage-directed cancer therapies against metabolically active tumors.

Luc Morris
Surgery
Project: Deciphering altered metabolism and immune evasion in FAT1-mutated head and neck cancer
Project Abstract: Head and neck cancer is the 6th leading cause of cancer death worldwide. This study focuses on the 2nd most mutated gene in HNSCC – FAT1 – which has largely unknown function. FAT1is genetically inactivated in close to 30% of HNSCCs, as well as large numbers of lung, esophageal and bladder cancers, but it is unclear how this inactivation promotes cancer cell growth and aggressiveness. This project will investigate how this gene is associated with changes in metabolic function, which may help cancer cells to grow more aggressively and escape immune surveillance.

Paul Romesser
Radiation Oncology
Project: Leveraging Radiation Induced Senescence to Potentiate Anti-Tumor Immunity
Project Abstract: Ionizing radiation is known to induce cellular senescence and activate a secretory program that can result in immune modulation. This project uses both mouse models and patient tissue to test the hypothesis that radiation induced senescence activates systemic antitumor immune surveillance that contributes to both local and distant tumor response and will test novel therapeutic strategies based on this concept.

Tuomas Tammela
SKI- Cancer Biology & Genetics
Project: Role of hypoxia in determining cancer cell fate
Project Abstract: Cells in the same tumor can show substantial diversity at the molecular level and in how they respond to therapies. The inability to effectively target all cancer cell subsets within a tumor contributes to treatment failure. The project will identify fundamental drivers of this cell state diversity, which may point to a new generation of targeted therapies that will control the cellular composition of tumors to improve treatment response.

Stephen Long
SKI-Structural Biology Program
Structure, substrate specificity, and inhibition of Hedgehog acyltransferase
Project Abstract: Cells must communicate with one another for embryos and mature organisms to develop properly. Cancers sometimes hijack the signaling mechanisms that underlie these communication networks. A protein known as Hedgehog acts as a key messenger between cells and thereby governs many developmental processes. While this protein is crucial for proper embryonic development, the Hedgehog signaling network is turned off in most adult tissues. The Hedgehog network is reactivated in certain breast, lung and pancreatic cancers and this aberrant signaling can be a driver of cancer progression. The current work is focused on an enzyme that prepares Hedgehog for its signaling roles – this enzyme, Hedgehog acyltransferase, attaches a lipid moiety onto Hedgehog. The attached lipid is necessary for the ability of Hedgehog to act as a messenger between cells. Therefore, inhibition of this enzyme disrupts the Hedgehog signaling network. Preliminary data from other researchers at MSKCC (Marilyn Resh lab) suggests that inhibitors of the enzyme may provide new avenues to combat certain cancers. In this research program, we aim to visualize the enzyme at atomic resolution in order to better understand the mechanisms of how it attaches the lipid onto Hedgehog. The successful completion of the studies will also provide structural and mechanistic context to existing inhibitors of the enzyme and could facilitate the design of improved compounds

Christina Leslie
SKI - Computational and Systems Biology Program
Project: Epigenetic and transcriptional regulation in FOXA1 mutant prostate and breast cancer
Project Abstract: The pioneer transcription factor FOXA1 is well known for its role in embryonic development but is also recurrently mutated in prostate and breast cancer. We recently found that oncogenic FOXA1 mutants acquire aberrant pioneering activity, leading to widespread chromatin accessibility changes associated with non-canonical FOXA1 binding motifs and altering the cistromes of cooperating factors such as hormone receptors. We will take a comprehensive systems biology approach to dissect the epigenetic and transcriptional changes and altered motif grammars induced by mutant FOXA1 alleles, using single cell and transcription factor cistrome analyses in prostate organoid models. Mechanistic themes that emerge from this work will be highly relevant to other cancers driven by perturbed transcription networks.

Simon Powell
Radiation Oncology
Project: Exploiting Replication-associated Single-Strand Gaps for Synthetic Lethality in BRCA2-associated Cancers
Project Abstract: Cancer cells have many strategies to manage replication stress that result in the use of back-up DNA repair mechanisms, whose inhibition offer opportunities for treating cancer cells with synthetic lethal approaches. A genome-wide CRISPR loss-of-function screen for selective cell killing of BRCA2-deficient cells identified the 9-1-1 complex (i.e. RAD9A, HUS1and RAD1) or its binding partner TOPBP1, but not the replication stress signaling kinase ATR. The function of this protein complex is hypothesized to protect single-stranded regions of the genome that are generated after DNA replication, which are predicted to be important when the cancer is homologous recombination deficient.

Morgan Huse
SKI - Immunology Program
Project: Local Reprogramming of the Tumor Microenvironment by Dual-Bivalent T Cell Engaging Bispecific Antibodies
Project Abstract: Bispecific T cell engaging antibodies (BsAbs), which redirect a patient’s own T cells against their tumor, represent an intriguing class of anti-cancer immunotherapeutics. We have recently developed a new type of BsAb architecture that is particularly effective against solid tumors. This project seeks to understand why this reagent works so well, and in doing so identify the key features distinguishing successful from unsuccessful immunotherapy.

Andrew Kung
Pediatrics
Project: Optimizing T cell-based immunotherapies for pediatric sarcomas and AML
Project Abstract: Although 80% of all children with cancer are cured, these results have largely achieved through maximal dose intensification of conventional chemotherapeutics in conjunction with aggressive radiotherapy and surgery. More recent advances in targeted therapies and immuno-oncology have had less impact on pediatric cancers by comparison to adult cancers. This multi-project proposal brings together investigators across MSK to develop new immunotherapies for pediatric cancers. The Projects seek to develop next generation engineered T cells for application to osteosarcoma, Ewing sarcoma, and acute myelogenous leukemia in pediatric and young adult patients. By working collaboratively and with open scientific exchange, and supported by 2 state of the art cores, technological advances in each Project will be disseminated across all Projects.

Jae Park
Medicine
Early intervention with IL-1 inhibitor, Anakinra, for prevention and management of CD19 CAR T cell-associated toxicities
Project Abstract: Patients’ own immune cells called T cells can be genetically engineered to express a chimeric antigen receptor (CAR) designed specifically to target cancer cells. These CAR T cells targeting a specific cancer antigen called CD19 have shown to completely eradicate cancer cells that have failed or returned after multiple rounds of chemotherapy, leading to approval by the FDA for treatment of patients with leukemia and lymphoma. However, the CD19 CAR T cell-therapy can cause severe toxicities, some of which have been fatal, restricting its use to a limited clinical setting. Based on the data generated from our previous clinical trials and in the laboratories at MSK, we aim to investigate the efficacy of using a specific cytokine (IL-1) inhibitor called anakinra in preventing CD19 CAR-associated side effects, with an ultimate goal to disseminate this promising therapy to a wider patient population.

Xiaolan Zhao
Molecular Biology
Structure-function illumination of a tumor-suppressing SMC genome maintenance complex
Project Abstract: The SMC complexes enable DNA looping, sister chromatid cohesion, and chromatin topological organization that facilitate a wide range of DNA replication, repair and transcription functions. Of the three conserved eukaryotic SMC complexes, the SMC5/6 complex exhibits the most intricate action mechanisms and dynamic range of impact. We propose to investigate this complex functionally and structurally and illuminate Smc5/6-mediated DNA transactions and tumor suppression mechanisms.

Prasad Jallepalli
Molecular Biology
Understanding and exploiting replication stress in cohesin-mutant tumors
Project Abstract: Cohesin is a ring-shaped complex with multiple roles in chromosome organization and maintenance that is frequently mutated in several types of cancer, including acute myeloid leukemia (AML). In recent work we found that cohesin mutations cause non-cancerous cells to become “addicted” to backup pathways for genome integrity. In this project, we will test if addiction to these backup pathways can be exploited as an Achilles heel for improved treatment of this AML subtype.

Jason Lewis
Radiology
Imaging and therapy of Neuroendocrine Prostate Cancer using DLL3 targeting antibodies
Project Abstract: Androgen receptor (AR) signaling is critical for Prostate cancer (PC) cell survival and therefore represents the major therapeutic target when treating the disease. Though highly effective in early stages, Androgen deprivation therapy (ADT) almost always leads to resistance, which in turn gives way to metastasis, disease aggressiveness, and ultimately death. ADT can produce tumors that bypass a functional requirement for AR signaling via lineage plasticity, predominantly by trans-differentiating into neuroendocrine prostate cancer (NEPC). It is estimated that more than 25% of patients with advanced PC might eventually develop this type of highly aggressive NEPC. Clinically, the disease presents as visceral metastases and demonstrates explosive growth and non-responsiveness to ADT or chemotherapy, and rapidly leads to patient death. With about 3.1 million patients (in 2019) living with the disease and undergoing treatment with different ADT agents, NEPC is poised to impose a significant burden on healthcare. Therefore, identifying and developing novel treatment strategies for patients with NEPC lesions is a critical unmet need. Our central hypothesis is that ADT-resistant NEPC lesions express high levels of delta-like protein 3 (DLL3) that can be targeted using our fully human anti-DLL3 mAbs to develop diagnostic and therapeutic radiopharmaceuticals. The radiotherapeutic targeting of tumors offers a unique and unparalleled avenue for treating NEPC for which currently there are no effective therapeutic options.

Emily Cheng
HOPP
The Impact of BAX/BAK-Dependent Cell Death in Tumor-Immune Crosstalk and Immunotherapy
Project Abstract: Immune checkpoint blockade has revolutionized cancer therapy in recent years, with FDA approvals in multiple cancer types. However, there remains a need to identify additional therapeutic strategies to increase response rates. Here, we will investigate whether activating a specific form of cell death in cancer cells can convert an immunologically “cold” tumor to a “hot” tumor, leading to sensitization of tumors to immune checkpoint blockade.

Joseph Sun
Immunology
Project: Mechanisms underlying IRF8-mediated NK cell responses against AML
Project Abstract: Among the cancer patients treated with stem-cell transplantation at MSKCC, acute myeloid leukemia (AML) is among the cancers most easily targeted by natural killer (NK) cells of the immune system. As their name implies, NK cells can rapidly recognize and eliminate tumors cells using specific cytotoxic mechanisms. The focus of this grant is to understand how the underlying transcriptional program of NK cells can be harnessed to battle cancers such as AML.

Elli Pappaemanouil
CBG
Project: Studying disease progression SF3B1 mutated Myelodysplastic Syndromes
Project Abstract: Mutations in SF3B1 are initiating and disease defining events in Myelodysplastic Syndromes (MDS) and co-mutations with secondary hits define disease progression and transformation to acute and aggressive variants of the disease. With the support of the Geoffrey Beene funding mechansims we are establishing a panel of 18 genetically matched (mutated and wild type) induced pluripotent stem cells (iPSC) lines from three MDS patients with SF3B1 mutations. Integrative genomic approaches that consider molecular profiling, transcriptomic and epigenetic profiling are applied to understand the mechanisms of disease pathogenesis and identify therapeutic vulnerabilities.

John Maciejowski
Molecular Biology
Project: Strategies to leverage the cGAS-STING response to cancer intrinsic genomic instability
Project Abstract: cGAS-STING activation by cytosolic DNA triggers a wide-ranging, anti-viral response that includes the expression of Type I interferons and other immuno-modulatory molecules. We seek to understand how cancer-instrinsic genomic instability engages the cGAS-STING pathway, to identify factors that antagonize the cGAS-STING response to genomic instability, and to determine if cGAS-STING activation can serve as a predictive biomarker for the success of immune checkpoint blockade in the treatment of non-small cell lung cancer.

Alex Kentsis
Molecular Pharmacology
Project: MECHANISMS OF GENOMIC PLASTICITY IN NEUROBLASTOMA DEVELOPMENT
Project Abstract:The origin of oncogenic genomic rearrangements in childhood solid tumors remains poorly understood. In this project supported by the Geoffrey Beene Cancer Research Center, we aim to define the mechanisms of genomic rearrangements mediated by the human DNA transposase PGBD5. These studies are expected to advance our understanding of mutational processes in normal and precancerous tissues, leading to improved therapeutic strategies for patients with refractory solid tumors. 

Omar Abdel-Wahab
HOPP
Project: Understanding the Functional and Therapeutic Implications of Oncogenic Nuclear Export in Cancer
Project Abstract: Proper distribution of proteins between the nucleus and cytoplasm is critical for normal function of cells. We recently identified that mutations impacting the machinery responsible for taking proteins from the nucleus to the cytoplasm in patients with a variety of cancer types, particularly patients with lymphomas. In this grant we aim to understand how genetic changes in the nuclear export machinery cause cancer and how this process can be corrected for improved cancer treatment.

Jayanta Chaudhuri
Immunology
Project: Structure specific nucleases in immunity and genomic integrity
Project Abstract: DNA double strand breaks (DSBs) constitute one of the most genome-destabilizing lesions in a cell.Unrepaired DSBs can lead to cell death or can participate in chromosomal translocations that are hallmarks of many kinds of tumors, including lymphomas. Thus, all organisms have evolved robust pathways to efficiently repair DSBs that are inadvertently generated during replication or through exposure to genotoxic stress suchas ionizing radiation. Yet, despite the associated toxicity, during immunoglobulin heavy chain (Igh) class switch recombination (CSR), DSBs are deliberately introduced into defined regions of Igh through the activity of the DNA deaminase AID (activation induced cytidine deaminase). AID activity however, is not restricted to Igh. AID has the potential to induce genome-wide DSBs in B cells, including at oncogenes and such off-target DSBs are the major lesions behind the ontogeny of a large number of mature B cell lymphomas. The mechanisms that repair such non-Igh DSBs are not fully understood. Here we examine the role of two structure-specific nucleases, Mus81 and Gen1, in homology-dependent repair (HDR) of AID-induced DSBs

Michael McDevitt
Radiology
Project: High Energy Alpha Particle Irradiation of Enzalutamide-Treated Prostate Cancer
Project Abstract: Interference with AR is the primary treatment option for late stage and castration-resistant PCa. However, mutations arise and diminish Enzalutamide bioactivity. AR interference affects numerous other pathways: upregulating PSMA expression and decreasing mechanisms of radioresistance. We anticipate that PSMA upregulation in disease will provide a therapeutic benefit enabling us to overcome resistance. We propose to use (i) AR interference, (ii) PSMA upregulation, and (iii) AR-mediated radioresis.

Neal Rosen
Molecular Pharmacology
Project: Studies of the role of ARAF in normal physiology and tumors
Project Abstract: We have discovered that ARAF has a unique, hitherto unrecognized function: it activates RAS by antagonizing NF1 binding to RAS. By this mechanism, ARAF reduces ERK-dependent feedback inhibition of RAS and prolongs the duration of ERK signaling. Our preliminary data suggests that ARAF plays an important role in maintaining pathway output in human tumors driven by RTKs and that its overexpression can cause resistance to pathway inhibitors. We propose now to study in more detail ARAF activation of RAS and its role in tumor biology.

Robert Benezra
CBG
Project: Modeling BRAF-fusion driven pediatric brain tumors in the mouse
Project Abstract: A subset of tumors of the central nervous system that are found in children and adults is driven by a genetic event in which chromosomes are rearranged in cells that initiate these tumors. This rearrangement produces a fusion protein of the BRAF oncogene not found in normal cells that can drive the rapid growth and expansion of cells which harbor this new protein. Chromosome rearrangements are difficult to model in mice but we have devised a protocol using the CRISPR gene editing technique that precisely models one such fusion event and recapitulates in mice the disease seen in humans. In this proposal we will use this mouse model to understand the mechanistic basis of this tumor type and develop novel therapeutic strategies based on rational drug design.

Andrew Intlekofer
HOPP
Project: Deciphering metabolic regulation of anti-tumor immune responses in kidney cancer
Project Abstract: Anti-tumor immunity can be shaped by metabolic features of the tumor microenvironment, including oxygen tension, pH, and nutrient availability. Our preliminary data demonstrate that kidney cancers deregulate production and disposal of a group of hypoxia-associated metabolites, which are capable of suppressing effector T cell function. We will employ metabolomic profiling of primary kidney cancer specimens, in vitro culture systems, and novel genetically engineered mouse models to determine if targeting specific metabolites can enhance anti-tumor T cell responses in kidney cancer

David Scheinberg
Project: Building a Better Kill Switch for Cellular Therapies
Project Abstract: “Engineered T cell therapies, including CAR T cells, have emerged recently as important therapies for cancer. However, recent reports of significant toxicities and even deaths after CAR T cell therapy, strongly call for mechanisms to better control the various T cell therapies. We propose to develop technology to selectively kill the T cells by virtue of an enzyme that converts a safe prodrug into an active killing drug within the cytoplasm of the T cell. Other normal cells will be spared this effect. This is a “kill switch” for the cells.”

Sarat Chandarlapaty
Project: Elucidating ER function in hormone-independent breast cancer
Project Abstract: Over 70% of breast cancers are characterized by their dependence on the hormone estrogen for their growth and survival. Antiestrogens are highly beneficial in most patients with breast cancer, however drug resistance frequently emerges over time. We have found that the estrogen receptor (ER) is still playing a critical role in such cancers despite the absence of estrogen stimulation. In this proposal we will characterize the key partners and targets of such “hormone-independent” ER in order to identify new ways of treating these cancers after hormone-resistance develops or preventing hormone-resistance in the first place.

James Fagin
Project: SWI/SNF disruptions in advanced thyroid tumors: Identification of epigenome-guided
Project Abstract: This project will explore how disruptions of individual components of the SWI/SNF chromatin remodeling complex, which are frequently mutated in advanced forms of thyroid cancer, lead to tumor progression and loss of differentiated properties in mouse models of the disease. The goal is to identify novel therapeutic vulnerabilities arising as a result of these changes.

Kitai Kim
Project: Novel embryonic tumor suppression mechanism by NEPN via direct sequestering of growth-promoting ligands and indirect T cell activation in the tumor microenvironment
Project Abstract: Expressing multiple tumor-causing genes in adult cells can induce tumor formation. During early-stage embryo development, multiple tumor-causing genes are highly expressed in embryonic cells to support rapid growth of various tissues and organs, but early-stage embryos rarely develop tumors. We hypothesized that the early embryo microenvironment contains anti-tumor factors and proposed to identify these embryonic anti-tumor factors. Understanding their mechanisms may lead to the development of novel cancer therapies.

Dinshaw Patel
Project: Structure-based Mechanistic Insights into CRISPR-Cas Pathways Impacting on Cancer Biology
Project Abstract: Bacteria and archaea have developed RNA-guided adaptive defense systems to protect themselves against phage and viral invaders. These discoveries made initially in prokaryotes have been rapidly extended to eukaryotes, given that CRISPR-Cas represents a simple, flexible and cost-effective way to precisely edit and manipulate the mammalian genome. Specifically, the nuclease Cas can be reprogrammed with synthetic RNAs to generate site-specific double-strand DNA breaks in mammalian cells. This powerful approach allows engineering in either precise changes to correct genetic defects, or chromosomal rearrangements that contribute to tumorigenesis, as well as develop genetically engineered mouse models of human cancer. These represent powerful tools for monitoring tumor initiation and progression and identification of drivers of cancer metastasis.

Jorge Reis-Filho
Project: Reconstructing the Evolutionary History of BRCA1-associated Breast Cancer
Project Abstract: Inherited mutations in the BRCA1 gene are known to confer an increased risk of breast cancer. The mutations acquired during life (i.e. somatic mutations) that are required for the development of BRCA1-associated breast cancer have yet to be fully characterized. It is currently unclear if complete loss of function of BRCA1 is the initial step in the development of BRCA1-associated breast cancers or if other somatic mutations precede the complete inactivation of BRCA1. We will combine the analysis of clinical samples, single-cell sequencing techniques and laboratory models of BRCA1-associated breast cancer to define the somatic mutations required for tumor development in the context of inherited BRCA1 mutations and to determine if the order of such alterations influences the evolution of the tumor and its sensitivity to specific treatments.

Stewart Shuman
Project: tRNA splicing enzymes as therapeutic target for fungal infections in the cancer setting
Project Abstract: Invasive fungal infections, especially Aspergillosis and Candidiasis, are a major cause of morbidity and mortality in cancer patients with prolonged neutropenia following chemotherapy or hematopoietic stem cell transplantation. The development of more effective treatments for these infections hinges on defining new targets for antifungal drug discovery and implementing screening to identify inhibitors. The goal of this project is to advance the case for two fungal tRNA splicing enzymes, Trl1 and Tpt1, as antifungal targets, by determining the atomic structures of the Aspergillus and Candida enzymes and their interactions with substrates, cofactors, and reaction intermediates.

Andrea Ventura
Project: A novel approach for the identification of microRNA targets in vivo

Alex Kentsis
Project: Mechanisms of PGBD5 transposase-induced transformation of rhabdoid tumors

Elli Papaemmanouil
Project: Therapy related myeloid neoplasms: Characterization of mutation order and clonal dynamics in response to therapy during disease transformation

Gopa Iyer
Project: Biologic and Clinical Characterization of ERCC2 mutations in Urothelial Carcinoma
Project Abstract: Cisplatin-based chemotherapy followed by removal of the bladder is the current standard of care treatment for patients with muscle-invasive bladder cancer. Mutations of ERCC2 have been identified as predicting for exquisite sensitivity to cisplatin in bladder cancer. This proposal seeks to characterize the biology of ERCC2 alterations in bladder cancer and also to initiate a clinical trial of chemotherapy without removal of the bladder in patients with ERCC2 mutant muscle-invasive bladder cancer.

Ingo Mellinghoff
Project: In-situ analysis of glioma core signaling pathways and their response to therapy

Jayanta Chaudhuri
Project: Nucleosome remodeling in DNA damage response

Minkui Luo
Project: Define Molecular Network of DOT1L-driven Leukemia via Noncanonical Methylation

Stephen Long
Project: Structure, Function, and Inhibition of the Ras Methyltransferase ICMT

Tobias Hohl
Project: Endogenous fungi and the development of graft versus host disease
Project Abstract: Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with hematologic malignancies, though this treatment modality is limited by graft versus host disease. Tissue-specific inflammation and alloreactive T cell responses underlie GvH pathogenesis. In this proposal, we examine the hypothesis that the composition and diversity of intestinal fungi can regulate intestinal inflammation and GvH during human and murine allo-HCT and that pharmacologic intervention can improve GvH outcomes.

Ross Levine
Human Oncology and Pathogenesis Program
Project: Role of the Cohesin Complex in Leukemic Transformation 

Joao Xavier
Computational Biology
Project: Dissecting the role of cancer metabolism on the tumor microenvironment

Project Abstract: Although metabolic alterations and interactions with stromal cells are both considered hallmarks of cancer, cancer metabolism and the tumor microenvironment remain separate areas of research. This project investigates the intricate link between cancer metabolism and microenvironment. We combine computational models with experiments to determine how the extracellular metabolites produced by cancer cells alter the phenotypes of tumor-associated macrophages, which then impact tumor development, progression, and metastasis.

Guido Wendel
Cancer Biology & Genetics Program
Project: Targeting the oncogenic eIF4A RNA helicase in cancer 

Maria Jasin
Developmental Biology
Project:  Modulators of BRCA1 and BRCA2 function 

Mary Goll
Developmental Biology
Project: Identifying suppressors of Tet mutation in development and disease

Danwei Huangfu
Developmental Biology
Project: Modeling pancreatic ductal adenocarcinoma through gene editing in human embryonic stem cells

Project Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, largely because of delayed diagnosis. We propose modeling pancreatic cancer using human embryonic stem cells (hESCs) based on our ability to perform sophisticated genetics in hESCs and to generate pancreatic cells from hESCs through directed differentiation. We will model early pre-invasive lesions known as PanINs to better understand the cancer “cell(s)-of-origin,” and to further study the genetic regulators of the transition from early PanIN to PDAC.

Michael Kharas
Molecular Pharmacology and Chemistry
Project: Uncovering the role of Syncrip in myeloid leukemia stem cells

Xuejun Jiang
Cell Biology
Project: Ferroptotic Cell Death, Mechanisms and Role in Cancer

Robert Benezra
Cancer Biology & Genetics Program
Project: The Role of Aneuploidy In Tumor Development

Project Abstract: Whole chromosome losses have been known to be a hallmark of tumor aggressiveness for over a century, but whether they are a cause or consequence of tumor proliferation and spread is still poorly understood. We have devised a genetic strategy to induce the loss of individual chromosomes and have found that in both mouse and human cells, the loss of four individual chromosomes in each case leads to reduced fitness in cell culture but dramatically enhanced ability to form tumors in mice. With the help of the Beene Foundation, we will now try to understand the molecular mechanisms underlying this enhanced tumorigenic potential, with the ultimate goal of identifying novel targets for therapeutic intervention.

Meng Fu Bryan Tsou
Cell Biology
Project: Mitotic Stress Response and Cancer 

Project Abstract: Drugs that target cell division have been widely used for cancer chemotherapy, but the underlying mechanism is not clear. We have developed novel reagents and approaches to fully understand how cells sense and respond to cellular dysfunction or stresses that occur specifically during cell division.

Ping Chi
Human Oncology and Pathogenesis Program
Project: Molecular characterization and novel therapeutics in malignant peripheral nerve sheath tumor (MPNST)

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

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.

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.

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

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 CRL4^DCAF1

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 CRL4^DCAF1 (Li et al. Cell. 140:477-490, 2010b). These results indicate that inhibitors targeting CRL4^DCAF1 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 CRL4^DCAF1.

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.

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.

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.

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.