GEOFFREY BEENE CANCER RESEARCH CENTER 10 Year Report, 2007–2017
10 YEAR REPORT | 2007–2017 2 COVER IMAGES, CLOCKWISE FROM TOP LEFT: Tumor- and stromal cell-derived cathepsin S expression in primary breast cancer. Shown here is an immunofluorescence image of a human breast cancer specimen stained for the cysteine protease cathepsin S in red, and tumor cells in green. Cathepsin S expression, which is typically associated with immune cells such as macrophages, is expressed in a subset of breast carcinoma cells, and may endow them with the ability to metastasize to the brain The Iacobuzio lab and Kellan Lutz, an ambassador for the Geoffrey Beene Foundation Epifluorescent imaging of transparent casper zebrafish transplanted with the human-derived PC3 prostate cancer cell line exhibits dissemination solely to the spinal column Epifluorescent imaging of transparent casper zebrafish transplanted with the zebrafish- derived ZMEL1 melanoma cell line exhibits widely disseminated tumors to the skin, eyes, muscles, and brain. Image by Isabella Kim of the White lab Ping Chi and lab members Confocal microscopy shows that the nucleolar structure of hematopoietic stem cells is altered with Stag2 loss of function. Image by Aaron Viny of the Levine lab Scott Lowe and lab member
3 GEOFFREY BEENE CANCER RESEARCH CENTER CONTENTS
Welcome ...... 2
Supporting Innovation through the Years . 5. Milestones ...... 6 Highlights of Breakthrough Projects . . . 8 Retreats and Special Conferences . . . 14.
Supporting Novel Research ...... 16 Faculty ...... 18. Graduate Students ...... 19 Q&A with Barry Taylor ...... 19 Financial Statistics ...... 20 Research Grants ...... 21 Publications ...... 38
Shown are intestinal organoids derived from transgenic shRen mice in which renilla luciferase is suppressed by doxycycline . GFP expression (shRen) and immunofluorescence staining with DAPI (blue), phalloidin (yellow), and anti-Ki67 (red) demonstrates that inducible and reversible gene silencing can be tested in long term ex vivo culture where intestinal stem cells form fully differentiated crypt-villus organoid structures . Image by Kevin O’Rourke and Lukas Dow of Scott Lowe’s Lab .
10-YEAR REPORT | 2007–2017 1 WELCOME
As the founder of the Geoffrey Beene Foundation, my primary goal has been to fund new research to discover revolutionary treatment options and diagnostics across all types of cancer . In 2006, my collaboration with Memorial Sloan Kettering President Harold Varmus led to the creation of the Geoffrey Beene Cancer Research Center at MSK, giving us the opportunity to focus on accelerated funding for initial-stage research . The remarkable progress that has been made at the Geoffrey Beene Cancer Research Center since then has been a great accomplishment for everyone involved . You are all to be congratulated on your shared research vision, made possible by your expertise, passion, and dedication to end suffering from all cancers .
Since its creation, the Geoffrey Beene Cancer Research Center has aimed to translate works at the cellular level into revolutionary research approaches to preventing, diagnosing, and treating the disease . It brings together researchers and doctors, primarily from two complementary areas: the Sloan Kettering Institute’s Cancer Biology and Genetics Program and the Memorial Hospital–based Human Oncology and Pathogenesis Program (HOPP) . Cancer Biology and Genetics studies what transforms normal cells into cancerous ones, whereas HOPP pursues insights into the molecular causes of cancer from a clinical oncology perspective .
From 2006 through 2017, the Geoffrey Beene Cancer Research Center has awarded 112 research grants and funded 15 proposals for shared resources . Each grant funds initial- stage research and is renewed for a second year . The executive committee reviews submissions of innovative research proposals every year . This highly competitive review process awards grants to the most compelling and profound ideas proposed by researchers from the MSK community . After completion of the funded project, grant recipients have gone on to develop their novel ideas and apply for further grants from external sources . Since 2006, for every dollar of direct support from the Geoffrey Beene Cancer Research Center, grant awardees have received an additional $1 .55 in follow-up funding from external sources based on the early-stage ideas supported by the center .
In addition to the critical funding of initial-stage research, I directed that Geoffrey Beene fund the establishment of multiple junior and senior faculty chairs at MSK, fund fellowships for graduate students, conduct symposiums and conferences (which have evolved into the joint Geoffrey Beene–Nature conferences, most recently held this March), and hold annual retreats, which have increased collegiality across the MSK campus and led to critical collaborations among its members . The Center supported the Geoffrey Beene Translational Oncology Core, as well as the Microchemistry and Proteomics Core Facility and Genomics Core Facility, both of which aim to significantly augment MSK’s capacity for translational cancer research in genomics .
It has been my honor and privilege to support MSK and its dedicated mission to save lives . I look forward to leading the Geoffrey Beene Foundation’s continued support for new research initiatives and supporting the amazing scientists, doctors, and investigators at MSK .
I am grateful to each of you for your continued dedication and lifesaving work .
Very truly yours,
G . Thompson Hutton CEO and Trustee, Geoffrey Beene Foundation
2 GEOFFREY BEENE CANCER RESEARCH CENTER In the past ten years, the Geoffrey Beene Cancer Research Center (GBCRC) at Memorial Sloan Kettering has become a bedrock of the MSK community . The center has allowed translational research to proceed within an accelerated time frame . The important science done through many collaborative projects has progressed our journey to fight cancer . It has been my privilege to be Chair of the Geoffrey Beene Cancer Research Center since 2011 .
In 2006, the Geoffrey Beene Cancer Research Center was founded by Geoffrey Beene CEO G . Thompson (“Tom”) Hutton through the philanthropy of the Geoffrey Beene Foundation . The mission of the Geoffrey Beene Cancer Research Center is to achieve major advances in controlling cancer and producing better outcomes for people with cancer . The center’s ultimate goal is making cancer a more manageable disease . Tom and the Geoffrey Beene Executive Committee have been wonderful partners in helping us pursue our mission .
I am proud to say that, since its inception, the Geoffrey Beene Cancer Research Center has funded 112 research proposals and 15 shared resource projects, encompassing innovative topics in basic, translational, and clinical cancer research . That is more than $50 million in direct research support! Furthermore, for every $1 in grant funding provided by the Geoffrey Beene Cancer Research Center, MSK has received $1 .55 in subsequent grant awards .
During this same period, more than 31 graduate students have been supported by funds from the Geoffrey Beene Center, and as you will read in this report, many of them have gone on to prestigious positions . The center has also supported junior and senior faculty chairs . Positions like these help Memorial Sloan Kettering attract and retain scientists working on the cutting edge of cancer research .
In addition, the Geoffrey Beene Center provides crucial support to several core facilities, enabling MSK to quickly implement new technologies and capabilities . The first of these efforts, the Geoffrey Beene Core, helped investigators obtain and characterize molecularly annotated human tumor material . This core provided key infrastructure that ultimately helped establish what is now the Marie-Josée and Henry R . Kravis Center for Molecular Oncology, which is the main vehicle for establishing personalized cancer therapy at MSK . We hope to continue supporting such important and necessary efforts at MSK .
Finally, the Geoffrey Beene Center has played a critical role in fostering interactions between doctors and basic scientists both within and outside the institution through the annual Geoffrey Beene Cancer Research Center retreat, meetings, and most recently, the Nature–Geoffrey Beene conferences .
On behalf of the GBCRC Executive Committee and all of MSK, we thank the Geoffrey Beene Foundation for its support . We hope that the next ten years continue to bring major contributions to cancer research, a new generation of research scientists and graduate students, and discoveries that lead us closer to a cure for cancer!
Scott Lowe Chair, Geoffrey Beene Cancer Research Center
10-YEAR REPORT | 2007–2017 3 MISSION The goal of the Geoffrey Beene Cancer Research Center is to provide direct support for revolutionary new cancer research, with the ultimate goal of making cancer a more manageable, and potentially curable, disease .
EXECUTIVE COUNCIL
Scott Lowe David Scheinberg Chair, Geoffrey Beene Cancer Chair, Molecular Pharmacology Research Center and Chemistry Program
Craig Thompson Alexander Rudensky President and CEO, Memorial Chair, Immunology Program Sloan Kettering Cancer Center
David Solit Lisa DeAngelis Member, Human Oncology and Acting Physician in Chief Pathogenesis Program
Joan Massagué Nikola Pavletich Director, Sloan Kettering Chair, Structural Biology Institute Program
Larry Norton G . Thompson Hutton Senior Vice President, Ex Officio Office of the President Trustee of the Geoffrey Beene Foundation President of Geoffrey Beene
Charles Sawyers Chair, Human Oncology and Pathogenesis Program
4 GEOFFREY BEENE CANCER RESEARCH CENTER SUPPORTING INNOVATION THROUGH THE YEARS
10-YEAR REPORT | 2007–2017 5 MILESTONES
2007 2008 2009 2010 2011 2012
An Illumina microarray platform is purchased for The Rock the Genomics Core . Stars of Science campaign launches . A high-throughput screening robotics platform is purchased for the High-Throughput Core .
The Geoffrey Beene Translational Oncology Core Facility opens . Scott Lowe joins MSK and becomes Chair of the Geoffrey Beene Cancer Research Center . Ross Levine and Johanna Joyce are named the inaugural Geoffrey Beene Jr . Chairs . Michael Berger is given funding to develop a rapid, high-throughput clinical sequencing test . The first Geoffrey Beene Cancer It is known today as the Research Center retreat takes MSK-IMPACT™ assay . place in Skytop, Pennsylvania .
The first nine Geoffrey Beene research grants are funded .
6 GEOFFREY BEENE CANCER RESEARCH CENTER 2013 2014 2015 2016 2017
Funding of the Viable Tumor Cell The Center for Precision pilot projects leads Disease Modeling to the development launches with support and funding of the from the National National Institutes Institutes of Health and of Health–funded the Geoffrey Beene Precision Disease Cancer Research Center Modeling Program, led by Scott Lowe and David Solit .
Cancer as an Evolving and Systemic Disease March 12-15, 2016 | New York, NY, USA Program and Abstracts #cesd16 Funds from the Geoffrey Beene Cancer Research Center allow Andrea Ventura to develop a procedure for generating virtually any chromosomal rearrangement in the cells of adult mice, and potentially other model organisms, using a technique called genome editing . Sponsored by the Geoffrey Beene Cancer Research Center
www.nature.com/natureconferences
Presented by:
Nature and Geoffrey Beene present “Cancer as an Evolving and Systemic Disease” at MSK .
10-YEAR REPORT | 2007–2017 7 HIGHLIGHTS OF BREAKTHROUGH PROJECTS
A CRISPR-Based Approach to Generate Chromosomal Rearrangements In Vivo Structural changes to chromosomes are common in human cancers . They often result in unique gene fusion products that might be targeted with treatments . Unfortunately, although it is possible in some cancer- causing mutations, chromosomal changes are difficult to engineer in model organisms . This limits investigations Cancer biologist Andrea Ventura, MD, PhD, Associate Member, of their biology as well as their potential uses in Cancer Biology and Genetics Program treatment .
Thanks to generous funding from the Geoffrey Beene Cancer Research Center, the Andrea Ventura lab at the Sloan Kettering Institute has developed a novel CRISPR-based strategy . Other ongoing investigations in the Ventura lab that are supported by the Geoffrey Beene Cancer Research Center include studies of two forms of pediatric brain cancer . Both are driven by gene fusions involving BRAF to engineer chromosomal The team can now create rearrangement directly in the somatic cells of adult virtually any chromosomal mice . As proof of concept, the lab generated a mouse rearrangement directly in the model of lung cancer driven by the EML4-ALK gene somatic cells of adult mice. fusion . (Maddalo L, Nature, 2014) . It also demonstrated that a different chromosomal deletion, resulting in a gene fusion between BCAN and NTRK1, is a potent driver of glioma . This particular fusion makes cancer more sensitive to the experimental drug entrectinib .
So that more investigators can use this method to study other cancer-associated mutations more easily, the Ventura lab developed improved experimental and computational tools to design and construct the CRISPR-expressing oncogene . These efforts have greatly expanded scientists’ ability to model human cancers in vivo . Tools such as these are leading to the discovery and validation of new targeted therapies . n
8 GEOFFREY BEENE CANCER RESEARCH CENTER High-Throughput Profiling of Genomic Alterations in Clinical Tumor Specimens Before joining Memorial Sloan Kettering, Michael Berger was a staff scientist at the Broad Institute in Cambridge, Massachusetts . There, he led some of the first research projects to use next-generation sequencing (NGS) to map cancer genomes, including melanoma and prostate cancer . Dr . Berger was particularly drawn to the idea that this technology could be used to assist in the diagnosis and treatment of disease . He worked with other scientists and doctors at the nearby Dana-Farber Cancer Institute Geneticist Michael Berger, PhD, Associate Director, Marie-Josée and Foundation Medicine to develop NGS tests that and Henry R . Kravis Center for Molecular Oncology would identify targetable mutations in tumors .
In 2010, Dr . Berger accompanied his wife to MSK Dr . Berger’s initial research grant was used to: when she joined the hematology-oncology fellowship • design a sequencing test for all known genomic program . He was recruited as an Assistant Member of changes related to the diagnosis, prognosis, and the Department of Pathology and saw coming to MSK, treatment of cancer one of the world’s foremost cancer research centers, as an exciting opportunity for him to further the • optimize the test so that it could handle the technologies that he had started at the Broad . One of challenging low-abundance specimens that are his goals was to create a comprehensive NGS-based routinely encountered in patient care tumor-sequencing test for clinical use . • automate and validate the test
Dr . Berger and his colleagues believed that such Today’s cancer research and treatment landscapes a test would enable researchers to identify new are dramatically different because of this and other biomarkers . These genetic mutations could be used genomic advances . The MSK-IMPACT assay has to predict disease outcome or response to targeted enabled MSK doctors to practice precision medicine . therapies . The team envisioned that this test would In precision medicine, doctors use an individual’s become a routine part of cancer care . For the test mutational profile to inform the therapeutic approach, to be useful, however, it would need to be robust yet often a targeted therapy . By including hundreds sensitive enough to work on available patient samples, of cancer-related mutations (currently 468) in a which were often pathological specimens in limited single test, doctors have a high-resolution view of quantities . Dr . Berger and his team of two research what’s happening in a single tumor . What’s more, technicians and a computational postdoctoral fellow each tumor is unique, and two tumors from the began to develop an NGS test that included hundreds same tissue, or even the same patient, may respond of genes . They worked closely with collaborating differently to a given therapy . Doctors and scientists physician-scientists to collect suitable tumor samples have now acquired enough knowledge to make clear from people with cancer . distinctions among certain tumor subtypes and to At a critical time in his research program, Dr . Berger treat them accordingly . Doctors can make informed received a grant from the Geoffrey Beene Cancer choices about whether to offer MSK patients available Research Center to develop new technology that targeted therapies; thousands of patients have been would improve cancer diagnosis and inform cancer matched to related clinical trials . Doctors can also treatment . This funding allowed the Berger lab to match patients to basket trials . These specialized continue its work and, ultimately, to secure additional clinical trials use agents that target a cancer based support for what has become the MSK-IMPACT™ test . on a tumor’s mutations rather than the location in
10-YEAR REPORT | 2007–2017 9 the body . Improved therapies, even for rare cancers, will increase as the data set grows and its resolution increases .
Many MSK patients are now offered MSK-IMPACT sequencing as part of their care, contributing Altogether, more than 35,000 important data to researchers about the particular patients have been tested genetic changes that drive whether a cancer grows, using MSK-IMPACT since 2014 spreads, or is killed, and how individual cancers respond to treatment . For instance, the MSK-IMPACT data revealed insights that led to the Exceptional Responders Initiative, a unique project that seeks to identify the molecular features that make some people responsive to a therapy when most are not . These differences reveal vulnerable spots in biological pathways that support cancer .
BRAF Inhibitors in the Treatment of Hairy Cell Leukemia
Hairy cell leukemia (HCL) is a rare form of leukemia . It is named for its characteristic hairlike projections on cancer cells . When HCL develops, the bone marrow doesn’t produce normal white and red blood cells . This causes people with HCL to be fatigued, and it increases the likelihood of infection . People with HCL usually develop an enlarged spleen as the HCL cells spread to other organs . This decreases their ability to eat and usually results in weight loss .
Scientists have known about HCL for decades . Recently, it was discovered that nearly every person with HCL carries a genetic mutation in the BRAF gene, called the BRAFV600E mutation . The mutation is also common in other cancers, including melanoma and thyroid cancer . For melanoma, doctors can now prescribe the BRAF inhibitor vemurafenib (Zelboraf®) . The US Food and Drug Administration approved vemurafenib in 2011 to treat people with BRAF-mutant melanoma .
Hematologic oncologist Omar Abdel-Wahab, MD, Assistant With support from the Geoffrey Beene Cancer Member in the Human Oncology and Pathogenesis Program Research Center, Omar Abdel-Wahab found that (HOPP) and an Attending Physician on the Leukemia Service the BRAFV600E mutation drives the development in the Department of Medicine of HCL . Through clinical trials, he and his team also determined that vemurafenib was a very effective treatment for people with HCL who are not responsive to conventional treatments for the disease . The results of this study were published in the New England Journal of Medicine in 2017 . On the basis of these
10 GEOFFREY BEENE CANCER RESEARCH CENTER The Marie-Josée and Henry R . Kravis Center for and clinical outcome data for research . GENIE was Molecular Oncology mediates access to MSK-IMPACT spearheaded by Charles Sawyers, Chair of the Human data, making it available to the entire research Oncology and Pathogenesis Program at MSK . community through their custom web interface cBioPortal . More than 70 papers by MSK investigators Altogether, more than 35,000 patients have been using MSK-IMPACT data have been published in tested using MSK-IMPACT since 2014 . The test now Science, Cell, Nature Medicine, the Journal of the incorporates an option to counsel patients and family American Medical Association, and Cancer Discovery, members who share inherited mutations . In 2017, the among others . MSK is highly committed to sharing US Food and Drug Administration authorized the MSK-IMPACT results with the broader scientific New York State Department of Health to report MSK- community . We are the leading contributor to the IMPACT results to patients and their doctors, the first American Association for Cancer Research Project test of this kind to receive this designation . Support GENIE (Genomics Evidence Neoplasia Information from the Geoffrey Beene Cancer Research Center has Exchange), an open-access, multi-institutional, been instrumental to the success of MSK-IMPACT and international effort to share linked clinical genomics the growth of precision oncology . n
results, the FDA is considering approving vemurafenib identified genetic changes that drive the development for people with HCL that has come back or become of HCL and can cause resistance to vemurafenib in resistant to conventional firstline therapies . people with HCL . They have designed another clinical trial for people with HCL who no longer respond . n Dr . Abdel-Wahab and colleagues continue to study vemurafenib as treatment for HCL . They have
This analysis of the blood of a person with hairy cell leukemia who is undergoing treatment with vemurafenib (Zelboraf®) as part of a clinical trial shows that the percentage of leukemia cells in the bloodstream greatly diminished during therapy . This patient had relapsed following three prior treatments using conventional chemotherapy . CT scans of the abdomen of a person with hairy cell leukemia show an enlarged spleen before treatment (below left), with shrinkage to normal size after treatment with vemurafenib (below right) .
10-YEAR REPORT | 2007–2017 11 Antitumor Assessment Core studies efficiently on-site . Grants from the Geoffrey Beene Cancer Research Center were used to build As part of its commitment to supporting innovative a state-of-the-art GLP-compliant laboratory and approaches to cancer research, the Geoffrey Beene purchase: Cancer Research Center funds the Shared Resource Awards . These awards go toward purchasing shared • histopathology equipment (a tissue processor, an scientific instruments and developing or improving embedder, a microtome, slide-staining and cover- Core facilities . slipping instruments, and a digital microscope)
MSK investigators routinely use cancer models — • clinical pathology equipment (hematology and ranging from cultured cell lines to patient-derived clinical chemistry analyzers) tumor models to genetic mouse models — to test • a preclinical laboratory information system that new drugs or therapeutic approaches . Many MSK can capture, analyze, and assemble drug-testing investigators also develop new drugs for patient data while meeting the FDA’s requirements for care . The Antitumor Assessment Core helps these data integrity researchers conduct early-stage drug investigation assessments, including pharmacokinetic, toxicity and In 2016, the lab transitioned into a fully GLP-compliant efficacy studies . facility capable of conducting up to ten large safety toxicology studies per year . The GLP lab has overseen Since 2014, the Geoffrey the development of 15 products, including new Beene Cancer Research imaging agents, antibodies, and chimeric antigen Center has funded two receptor T cells . Several of the GLP lab’s products are initiatives to enhance the currently being tested in phase I trials . In fact, MSK is Antitumor Assessment one of very few academic institutions in the United Core, led by Facility States with this capability . The GLP facility allows for Head Elisa de Stanchina . the entire development process to occur in-house The first has focused on — a major benefit to the MSK translational research establishing an in-house community . toxicology laboratory that is compliant with Patient-Derived Xenograft Centralized Core Elisa de Stanchina, PhD, Facility Head, Antitumor federal good laboratory During the past decade, PDX models have become Assessment Core practices (GLP), offering an invaluable tool for cancer research . Investigators investigators a cost- and can conduct myriad human cancer studies relating to time-efficient way to conduct animal safety studies . tumor genetics, new biomarker identification, cancer The second initiative has been to develop a centralized spread (metastasis), personalized therapy, and the resource for the creation of patient-derived xenograft development of novel therapies for early, advanced, (PDX) models, thereby coordinating expertise and and drug-resistant tumors, for example, facilitated by resources, and standardizing the workflow for MSK specialized animal models . investigators interested in using these valuable tools . Obtaining the patient samples to develop PDX Good Laboratory Practices–Compliant Laboratory models, however, is a complex and challenging for Safety Toxicology Studies process . It requires a high degree of coordination Before beginning first-in-human clinical trials, the among multiple clinical and research teams . With US Food and Drug Administration requires that funding from the Geoffrey Beene Cancer Research animal safety studies be conducted in accordance Center, the Antitumor Assessment Core streamlined with federal regulations for GLP . Previously, MSK the workflow for developing PDX models, insight investigators would contract with outside vendors that they recently published in the textbook Patient- to do these GLP studies, which is extremely costly . Derived Xenograft Models: Promise, Potential, and Frequently, there are delays or problems in method Practice . Their workflow template can be used for a development, technology transfer, or the initial variety of difficult to treat cancers and cancers with characterization of novel agents . no applicable laboratory model .
So MSK investigators can stay competitive, the At MSK, umbrella Institutional Review Board and Antitumor Assessment Core set out to conduct GLP Animal Care and Use Committee protocols permit the
12 GEOFFREY BEENE CANCER RESEARCH CENTER RSA, PI PI, Clinical Clinical Team, Screens procedure Team, RSA RSA schedules and Confirms need Obtains consent identifies cases of and feasibility of to the appropriate interest sample collection IRB protocol
Surgical/ Clinical RSA RSA Team, Pathology Coordinates Notifies Obtains specimen from sample surgical team, Patient; Assesses retrieval; pathology, and specimens and allocates Notifies team research sta for diagnostics, of any schedule of upcoming banking, PDX changes collection
RSA Research Research Technician Retrieves Technician Monitors mice for sample and Processes and tumor growth; expeditiously implants patient Propagates transports to sample according established PDX research lab to SOP models
Research Research Research Technician, Technician, Technician Research Scientists RSA, others Collects PDX Validate and Annotate PDXs; samples for characterize PDX Update PDX histology, models; Conduct database and genomics and preclinical studies PDX bank banking
The workflow (right) was provided as a template in a recently published book on PDX models (left) .
collection of samples for both xenograft and organoid models from the same patient at different stages of models from a spectrum of patients who have cancer . the disease, allowing doctors to study how tumors Four dedicated research study assistants identify change over time, specifically, the events related to appropriate study participants, gain patients’ consent, cancer spreading or its resistance to specific therapies and collect their samples . Core research technicians then graft the samples into immunocompromised To accompany the library, the Antitumor Assessment mice and grow them via serial transplantation . As a Core has built a sophisticated PDX database, quality-control measure, newly established models are supported in part by the Geoffrey Beene Cancer characterized histologically and genomically to ensure Research Center . This tool allows investigators to that they resemble the original patient sample . directly compare the genomic profiles of primary tumors and matched PDX samples, as well as review Through this system, the core has created a very data over time, such as genomic changes in a certain extensive, meticulously annotated PDX library . It has period or assessing the reasons for drug resistance . overseen the generation of more than 1,000 PDX The database also gives investigators a place to models, including breast, lung, gastric, pancreatic, make meticulous notes about each PDX model, such colon, liver, bladder, ovarian, prostate, brain, and head as a timeline of a patient’s clinical history (such as and neck cancer, along with sarcoma, neuroblastoma, surgeries or treatments) along with the PDX model’s melanoma, myeloma, leukemia, and lymphoma . In all, establishment . This data is stored in a HIPAA- these PDX models represent more than 150 cancers . compliant manner in MSK’s cBioPortal for Cancer Of particular note, the core has generated PDX Genomics . n
10-YEAR REPORT | 2007–2017 13 RETREATS AND SPECIAL CONFERENCES
Each year, the Geoffrey Beene Cancer Research in several blood cancers and are also mutated in Center hosts a retreat for researchers in the Cancer many other cancers, including lung cancer and breast Biology and Genetics Program and the Human cancer . These mutations can actually drive cancer Oncology and Pathogenesis Program . The center has progression . Understanding these changes could also hosted the following special conferences and lead to new treatments that are effective for cancers workshops on current topics in cancer . caused by the mutations .
Joint Conference on Cancer as an Learning more about the role of altered spliceosomes in cancer requires the involvement of RNA Evolving and Systemic Disease biochemists, bioinformaticians, cancer biologists, and This special conference was held at MSK and translational clinical researchers . Recognizing this sponsored by the Geoffrey Beene Cancer need, Harold Varmus of the National Cancer Institute Research Center, Nature, Nature Cell Biology, and and Weill Cornell Medicine, Siddhartha Mukkherjee Nature Reviews Cancer . It brought together 200 of Columbia University, and Omar Abdel-Wahab of researchers with diverse perspectives on cancer’s Memorial Sloan Kettering hosted this one-day meeting dual qualities as both an evolving and systemic at MSK . Investigators from a variety of fields came disease . To develop and grow, cancer negotiates together for deeper collaboration in this new avenue a relationship between the tumor and the body as of cancer research . a whole . Certain genetic changes in a cell may set its course to becoming cancerous, but tumor cells Workshop on the Microbiome and the Immune System continually change in order to survive and spread . This involves complex interactions between tumors Hosted by Miguel-Angel Perales and the local stroma, such as extracellular matrix For this full-day event, more than 40 doctors, data molecules and nontumor cells, as well as tumor- managers, and translational scientists from 20 derived factors at distant locations . institutions convened at MSK to discuss the PREDICT trial . This first-in-class multi-institutional trial combines This conference highlighted recent progress microbiome and immune system monitoring . PREDICT in the field . Researchers discussed how such aims to create the first clinically annotated hematocrit interactions influence immune responses, mobilize biospecimen repository that includes samples cell types that foster tumor growth, and establish for immune monitoring, transcriptomics (such as environments that are hospitable for cancer growth . peripheral blood mononuclear cells and plasma), and Tumor burden has additional adverse effects at microbiome analysis (like stool samples) . Investigators an organismal level, including such conditions will study about 300 people who are undergoing as cachexia and paraneoplastic syndrome . They allogeneic stem cell transplants to look for molecular discussed the challenges in understanding how predictors of outcome, including the rebuilding of the these features of tumor development influence one microbiome and immune system . another and how current knowledge may be used to improve patient care . The trial’s state-of-the-art analyses will be run in centers in the Blood and Marrow Transplantation Think Tank Conference Clinical Trials Network (BMT CTN) . The BMT CTN, Splicing Factors Meeting which is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, has Hosted by Omar Abdel-Wahab approved the PREDICT trial . Great progress has been made in identifying genetic changes in people with cancer . One of the most surprising findings has been the relatively high frequency at which the RNA splicing mutations occur in cancer cells . These so-called “spliceosomal mutations” are among the most common mutations
14 GEOFFREY BEENE CANCER RESEARCH CENTER
IF exhibiting clonal complexity of PanIN formation in murine model of pancreas cancer . Image by Kelly Lafaro in the Leach Lab Dr . Lowe, Chair of the Geoffrey Beene Cancer Research Center (top right), and Dr . Massague, Director of Sloan Kettering Institute (bottom right), are among the Beene-affiliated researchers who have attended our Annual Geoffrey Beene Cancer Research Retreats .
Geoffrey Beene Retreat This two-day retreat, sponsored by the Geoffrey Beene interactions between clinicians and basic science Cancer Research Center, focuses on a wide range of researchers across the institution . In addition to several translational research topics . The retreat is a highly short talks by program members, a world-renowned anticipated annual event that has fostered collaborative guest speaker is invited to the retreat each year .
Past retreat speakers:
2008 2011 2014 2016
Charles Sherr Jacqueline Lees Frank McCormick Ton Schumacher St . Jude’s Children’s Koch Institute for University of California, Netherlands Cancer Research Hospital Integrative Cancer San Francisco, Institute Research Helen Diller Family 2009 2017 Comprehensive Cancer 2012 David Livingston Center Titia de Lange Dana-Farber Cancer Rockefeller University William Sellers 2015 Institute and Harvard Novartis Institutes for Medical School BioMedical Research Lewis C . Cantley Sandra and Edward 2010 2013 Meyer Cancer Center Louis Staudt Stephen Elledge at Weill Cornell Medical Center for Cancer Harvard Medical School, College Research, National Brigham and Women’s Cancer Institute Hospital
10-YEAR REPORT | 2007–2017 15 SUPPORTING NOVEL RESEARCH
IF exhibiting clonal complexity of PanIN formation in murine model of pancreas cancer . Image by Kelly Lafaro in the Leach Lab
16 GEOFFREY BEENE CANCER RESEARCH CENTER “The integration of complementary expertise via collaboration is a powerful driver of new discoveries, both basic and translational ”.
BARRY TAYLOR Associate Director, Marie-Josée and Henry R . Kravis Center for Molecular Oncology 2008 Geoffrey Beene Graduate Student Fellow
10-YEAR REPORT | 2007–2017 17 FACULTY
Senior Chairs
Scott Lowe Dr . Lowe is Chair of the Cancer Biology and Genetics Program at the Sloan Kettering Institute . He is interested in tumor-suppressor gene networks that control apoptosis and senescence . His laboratory studies how disrupting these networks influences varied features of cancer, such as tumor growth, survival, and metastasis .
David Solit Dr . Solit is a physician-scientist, a member of the Human Oncology and Pathogenesis Program, and director of the Marie-Josée and Henry R . Kravis Center for Molecular Oncology . His laboratory uses genomics and chemical biology approaches to understand functional characteristics of human tumors . This approach can reveal “druggable” alterations that drive cancer development and progression, and informs rational therapeutic strategies focused on molecularly defined subclasses of people with cancer .
Junior Chairs
Johanna Joyce, 2007-2011 Kitai Kim, 2012-2016 Dr . Joyce led a lab investigating Dr . Kim is a stem cell biologist who the molecular mechanisms of studies the epigenetic regulation tumor-host interactions . She joined of DNA methylation in stem and the Ludwig Institute for Cancer cancer cells and the role it plays in Research in Switzerland in 2016 . pluripotency and cancer .
Ross Levine, 2007-2011 Joseph Sun, 2014-2018 Dr . Levine was an inaugural Junior Dr . Sun is an immunologist who Chair . He is a physician-scientist investigates the natural killer cell who focuses on the genetic basis response to infection and cancer . of hematopoietic cancers .
Andrea Ventura, 2008-2012 Alan Ho, 2015-2019 Dr . Ventura is a cancer biologist Dr . Ho is a medical oncologist who who studies noncoding RNAs specializes in the treatment of and their contribution to the head and neck cancers, specifically pathogenesis of human cancer . cancer of the salivary glands and thyroid .
Ping Chi, 2011-2015 Dr . Chi is a physician-scientist who studies the genetic and epigenetic mechanisms of transcriptional regulation by oncogenic factors in solid tumors .
18 GEOFFREY BEENE CANCER RESEARCH CENTER GRADUATE STUDENTS
The Geoffrey Beene Graduate 2007 John Halliday Edward Kastenhuber, Student Fellowship program Neel Shah Hyung Song Nam Ellen Hukkelhoven provides full stipends for up to Currently: Biotech 2013 two years for exemplary graduate Sindy Escobar- Analyst at Perceptive students at the Gerstner Sloan Alvarez Advisors Kelsey Temprine, Currently: Senior Mary Klein, Kinisha Kettering Graduate School of Program Officer 2010 Gala Biomedical Sciences (GSK) at the Doris Duke Daniel Marks, 2015 who are conducting research at Foundation Oakley Olson, Piero Memorial Sloan Kettering research 2008 Sanfillipo Kinisha Gala, Ryan labs . Recipients are selected at Smith, Hannah the end of their first year of study Vaseilena Gocheva 2011 Johnsen based on academic excellence . By Barry Taylor Robert Bowman, 2016 providing support for outstanding Currently: Faculty at Jenny Karo, Gregory GSK students, the Beene MSK Mazo Jacob Boyer, Nicolas Kuhn, Xiayo Li Fellowships are designed to 2009 2012 expand the pool of investigators 2017 trained to pursue research in the Neha Bagwat Emily Casey Currently: Research Medical Anton Dobrin, highly complex, multidisciplinary Currently: Scientist at Prelude Writer at Health Hsuan-An Chen, field of cancer biology . Therapeutics Interactions Caroline Gleason
Q&A WITH How did the Geoffrey Beene and, in particular, may determine fellowship help your graduate sensitivity to anticancer therapy . BARRY TAYLOR studies? The Geoffrey Beene fellowship How did the Geoffrey Beene made me part of a community of fellowship lead to your current GBCRC-supported and GBCRC- success? affiliated scientists who were doing The Geoffrey Beene fellowship like-minded basic and translational was instrumental . It gave me the genome-driven research . My freedom to foster long-lasting graduate studies benefited and productive collaborations greatly from the collaboration with so many MSK investigators and mentorship of so many young that continue to this day . These and senior investigators affiliated collaborations have pushed my with GBCRC . These collaborations science in new directions . They proved pivotal for accelerating my showed me, at the earliest stage graduate studies and broadening of my scientific training and their scientific horizons . career, that the integration of complementary expertise via
Barry Taylor, Associate Director, How would you describe our collaboration is a powerful driver Marie-Josée and Henry R . Kravis research to nonscientists? of new discoveries, both basic and Center for Molecular Oncology; 2008 Our research centers on translational . They showed me Geoffrey Beene Graduate Student understanding how genetic that team science is possible, it is Fellow changes of all sorts, from inherited productive, it is fun, and that has to somatic and from individual carried through to my work today mutations to broader molecular and will typify our approach far into alterations, drive the genesis and the future . progression of human cancers
10-YEAR REPORT | 2007–2017 19 FINANCIAL STATISTICS
2007-2016 Followup Funding Summary Geoffrey Beene Foundation Directed Donations
$20M 2006 $12,000,000 $16M
$12M
$8M 2007 $4M $10,400,300
0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
GBCRC Grant Additional Funding 2008 $6,000,000 Follow-up Funding: The Geoffrey Beene Cancer Research Center 2009 carefully follows the progress of grant recipients in the years after their $6,000,000 support from the center ends . Since the center issues seed funding, many of the proposals it funds generate enough good data to continue 2010 research with other sources of external funding . For most years, the $2,800,000 external income exceeds the amount of seed funding initially provided 2011 $9,200,000
Sources of Additional Funding 2012 $6,000,000 16 2013
12 $6,000,000
2014 8 $6,000,000
4 2015 $6,000,000
0
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2015 $4,955,425 Federal Foundation Industry Internal 2016 $6,000,000
2017 Return on Investment $6,000,000
$1 .55 for every $1 awarded Total: For every $1 the Geoffrey Beene Cancer Research Center invested in an innovative research project, MSK investigators received $1 .55 in other grant funding . $87,355,725
20 GEOFFREY BEENE CANCER RESEARCH CENTER RESEARCH GRANTS
Since 2007, the Geoffrey Beene Cancer Research the Geoffrey Beene Cancer Research Center Executive Center has issued an annual Request for Applications Committee . The invitation to submit a full application within the Memorial Sloan Kettering community, with is extended to 50 percent of the applicants . the goal of supporting innovative research projects Applications are peer-reviewed by members of that may not qualify for other sources of funding . In the Geoffrey Beene Executive Committee, and addition, the center began offering funding for shared investigators throughout MSK . The Geoffrey Beene resource proposals starting in 2008, in an effort to Cancer Research Center has provided more than $40 make expensive resources that can only be justified on million in grant funding and more than $3 million for a shared-use basis available to MSK research labs for shared instrumentation . meritorious projects . Letters of Intent are submitted to
2007 Cancer is complex, and no two patients cells have been injected into mice, and present an identical disease . Because those that have acquired the ability Applying the Glioblastoma of the diversity of molecular alterations, to metastasize to the lung have been Genome Atlas to Glioma-Relevant it is difficult in clinical settings to recovered from this organ . Sequencing Signaling determine the exact combination of the tagged genes has led to the identification of two novel genes that Cameron Brennan, MD of drugs that will result in the best outcome . Our technology offers the play a key role in metastasis . One of The genome of glioblastoma, promise of identifying, patient by the two genes directs cells to make a the most common brain tumor in patient, the subset of proteins that secreted protein, called Coco, which adults, has recently been analyzed become aberrant in every cancer blocks a signaling receptor, called the in unprecedented detail through a cell type/patient tumor tissue . The BMP receptor . We are isolating new national collaborative project: the information gained may be compiled metastasis genes and studying their Cancer Genome Atlas . Early results in creating a molecular map of cell- mechanism of action . We hope that a point to three distinct subclasses of and cancer-specific transformation better understanding of the molecular glioblastoma, which differ in gene pathways . This will ultimately allow processes that drive metastasis will expression and mutations . We are physicians to design a personalized lead to the design of drugs that investigating the activation state of therapy for patients . Such proteomic specifically block this process . signal transduction pathways among these genomically defined subclasses map has obvious advantages over the more common genetic signature maps PTEN Signaling in Cancer: Novel of glioma to identify which might Regulation and Potential Therapy be good candidates for therapeutic because most anticancer agents are inhibition . small molecules that target proteins, Xuejun Jiang, PhD not genes, and many small molecules PTEN is a potent tumor suppressor Genetic Modifications to targeting specific molecular alterations and a master regulator for multiple Enhance the In Vivo Survival are currently in development . Thus, cell-signaling processes . Mounting and Antitumor Activity of Gene- our efforts aim to set the basis for evidence indicates that PTEN itself Modified CD19-Targeted T Cells designing combination therapies with is also under precise regulation, and Renier Brentjens, MD, PhD better efficacy and less toxicity in the such regulation dictates its signaling treatment of patients with cancers and tumor suppressive function . This T cells are immune cells that may be and, moreover, to define the specific project aims to understand regulation genetically altered to recognize a molecular alterations in a particular of PTEN by its ubiquitin ligase NEDD4- patient’s own tumor cells . The goal tumor, facilitating the development of 1, the potential of NEDD4-1 as a cancer of this project is to better design novel molecularly targeted therapies . therapeutic target, and potential novel these genetic modifications such that functions of PTEN in other tumor- these T cells are more likely to fully A Gain-of-Function Genetic related signaling events . eradicate all of the tumor cells when Screen for Human Breast Cancer injected back into the patients . Data Metastasis Genes A Genome-Wide Association for generated from these studies will be Pancreatic Susceptibility Loci used to design better clinical trials Filippo Giancotti, MD, PhD for cancer therapy using genetically We are studying the genetic Robert J . Klein, PhD targeted T cells . instructions that induce cancer cells Although it is known that individuals to become metastatic . We have whose relatives have had pancreatic Chemical and Proteomic Mapping constructed a library of genes from cancer are at a greater risk of of Cancer-Specific Molecular metastatic breast cancer cells, added developing this deadly malignancy, Therapeutic Targets a molecular tag, and introduced them it is not known what particular genes Gabriela Chiosis, MA, PhD into nonmetastatic cells . The recipient are responsible for this increased
10-YEAR REPORT | 2007–2017 21 susceptibility . Here, we have used RNAi Screen to Identify Discovery and Evaluation of individuals from the MSK Familial Suppressors and Modifiers of Novel Adjuvants for Cancer and Pancreatic Cancer Registry to conduct Treatment Response Infectious Disease Vaccines the first stage of a genome-wide Hans Wendel, MD David Gin, PhD association study aimed at identifying common genetic changes responsible Using a process called RNA The clinical success of vaccines against for an inherited susceptibility to interference (RNAi), we can selectively cancer and infectious diseases critically pancreatic cancer . Our ultimate goal inactivate genes in living cells . depends on the identification of novel with this research is to identify genes Moreover, we can use libraries of potent adjuvants, substances that that can be used to predict both who is RNAis to target every gene in the augment a patient’s immune response . at risk of developing pancreatic cancer human genome . This technology now The aims of this collaborative effort and whose action can be targeted for allows us to investigate genes whose will involve the chemical synthesis and treatment of this disease . inactivation contributes to various preclinical evaluation of novel molecular adjuvants from botanical sources, with cancers and may affect therapeutic the goal of discovering new vaccine The Impact of PIK3CA Mutations responses . on the Efficacy of Bevacizumab formulations of increased potency . in Recurrent Hormone Receptor- Positive Breast Cancer 2008 Identification of Rho GTPase Signaling Pathways Involved in Mary Ellen Moynahan, MD Synthetic Lethal Screen for Breast Cancer Cell Proliferation In our work funded by the Geoffrey Viability Genes in MEK Inhibitor– Alan Hall, PhD Beene Cancer Research Center, Treated Thyroid Cancer Cell Lines we identified PIK3CA mutations in with BRAF Mutation Cell division is most obvious during approximately one-third of invasive embryonic development, but although James Fagin, MD breast primary tumors . PIK3CA it is much more restricted in adults, cell mutations are associated with BRAF is the most common oncogene division is nevertheless crucial — for favorable clinicopathologic features: in aggressive forms of thyroid cancer example, in the maintenance of tissues lower tumor grade, hormone-receptor and is believed to be important in and organs through the division of stem positive status, HER2 negativity, older causing the disease . This proposal cells . Whether a cell chooses to enter age at diagnosis, lower tumor stage, aims to identify kinases that may allow the cell cycle is mostly determined by and lymph node negativity . Notably, thyroid cancer cells to remain viable signals in the external environment, and in accordance with these favorable after the function of BRAF is blocked, such as growth factors, growth pathologic predictors, patients with as these could potentially be targeted inhibitors and cell-cell and cell-matrix mutated tumors demonstrate an selectively with small molecule interactions . Inappropriate cell division improvement in overall and breast inhibitors . is a hallmark of cancer, and the aim of cancer–specific survival . The protective this program of work is to identify new role imparted by a PIK3CA mutation Identifying the Biological biochemical pathways that drive the will significantly affect future clinical Consequences of Cdc7 Kinase growth of human breast cancer cells . trial design for PI3K-targeted therapy . Inhibition in Human Cells Use of Array CGH to Improve Characterizing the Mark Frattini, MD, PhD HER2 Testing and Better Identify Cancer Genome in Lung Cdc7 is a protein kinase whose activity Trastuzumab Sensitivity in Breast Adenocarcinomas from Patients is required to begin the process of Cancer with Acquired Resistance to EGFR DNA duplication and is essential for Clifford Hudis, MD Tyrosine Kinase Inhibitors normal passage through the cell cycle . Subtypes of breast cancer that Both Cdc7 and its known substrate, William Pao, MD, PhD responded differently to targeted the minichromosome maintenance Patients whose lung cancers harbor drugs can be identified by examining complex, are overexpressed in the epidermal growth factor receptor their genetic material for certain majority of leukemias, lymphomas, (EGFR) gene mutations have a high changes . One example is the and solid tumors, making Cdc7 kinase likelihood of responding to the tyrosine identification of HER2 (human kinase inhibitors (TKIs) gefitinib activity a potential therapeutic target . epidermal growth factor receptor) (Iressa®) or erlotinib (Tarceva®) . To this end, we have recently identified positive breast cancer by finding extra However, after about one year, these a novel, naturally occurring small copies (amplification) of the gene for patients develop progression of molecule inhibitor of Cdc7 . The goal of HER2 . We are using a newer method disease . In this proposal, we aim to this project is to more precisely define — comparative genomic hybridization, genetically characterize resistant the result of inhibiting Cdc7 kinase or CGH — to examine HER2 (and other tumors in order to develop new activity in cancer cells and to begin to genes of interest) to allow us to more strategies to treat progressive disease look at possible mechanisms through accurately identify patients with HER2 and suppress the development of which cancer cells might become positive breast cancer for treatment acquired resistance . resistant to Cdc7 kinase inhibition . with an anti-HER2 drug .
22 GEOFFREY BEENE CANCER RESEARCH CENTER A Genetic Analysis of the Invasive can be measured . The methods involve require images for their research Breast Cancer Risk Associated the use of noninvasive tumor imaging, projects . The System for Research with Lobular Carcinoma In Situ which would make this process more Image Management, Storage, and convenient and less traumatic for Processing will be referred to as Tari King, MD patients than other methods currently Research PACS (picture archiving and Lobular carcinoma in situ (LCIS) is available . communication system), analogous to most often an incidental finding in a the clinical PACS currently in operation breast biopsy performed for another Line-Scanning Confocal at MSK . reason, yet once a women is diagnosed Endoscope for Screening Oral with LCIS, she faces a much higher Precancers In Vivo Capillary LC-MS/MS System risk for the subsequent development Milind Rajadhyaksha, PhD for High-Complexity, High- of invasive breast cancer . Historical Sensitivity, Quantitative Confocal endoscope technology will be data suggests that the lifetime risk of Proteomics breast cancer is 20 to 25 percent and created for noninvasive screening and is conferred equally to both breasts . diagnosis of oral and head and neck Paul Tempst, PhD New research, however, suggests that cancers and to guide surgery of such A THERMO ‘LTQ Orbitrap XL’ all LCIS may not behave in the same cancers . The screening, diagnosis, and electrospray linear ion trap hybrid FT way, and therefore, all LCIS may not surgical guidance will be directly on the tandem mass spectrometer, coupled confer the same increased risk of patient, with minimal need for biopsy, online to an Eksigent ‘NanoLC’ capillary breast cancer . The objective of this minimal pain, and minimal expense . multidimensional high-performance proposal is to identify different types The technology may also prove useful liquid chromatography separation of LCIS by examining which genes are for noninvasively detecting other system with autosampler . The combined turned on and off in different LCIS cancers, such as in the skin, cervix, system, commonly known as cLC-MS/ specimens . Our hypothesis is that in breasts, and other tissues . MS, can identify up to 1,000 proteins some LCIS specimens, we will find that per analysis, at accuracies of less than Inhibitors of Hedgehog the same genes are turned on as in two parts per million, and will be used Palmitoylation to Block invasive lobular breast cancer (ILC), to characterize very complex protein Pancreatic Cancer Cell Growth and therefore these particular LCIS mixtures, including relative quantitative specimens will be the ones that carry Marilyn Resh, PhD comparisons of two or three different the highest risk for ILC . The Sonic Hegehog (Shh) protein is samples in a single analysis . a key contributor to the growth of Integrated MicroRNA Genomics in pancreatic cancer cells . The goal of 2009 Endometrial Cancer the proposed research is to identify Douglas Levine, MD and develop drugs that inhibit the Humanized Antibody 8H9 Most women with early endometrial attachment of the fatty acid palmitate to Target Immunoinhibitory cancer will be cured, and only 10 to to Shh . Since palmitoylation is required Molecule B7H3 on Solid Tumors for Shh function, inhibitors that block 15 percent of these women are likely Nai-Kong Cheung, MD, PhD to have a recurrence . Nonetheless Shh palmitoylation could be developed radiation therapy is frequently given into novel chemotherapeutics that Few curative treatments exist for after surgery to prevent cancer from will be efficacious in the treatment of cancers metastatic to the brain . coming back . This study aims to use pancreatic cancer . Liquid radiation delivered by mouse microRNA gene expression profiling monoclonal antibody 8H9 has SHARED RESOURCES AWARDS and DNA copy number analyses to prolonged survival measured in years . The humanized form of 8H9 should predict which women are most likely to Expansion of the Functional recur so that postsurgical therapy can make the treatment safer and more Genomics Platform at the High- effective . be better individualized . Throughput Screening Core Facility Evaluation of Antiangiogenic Combined Molecular Therapy Therapies by Hypoxia-Imaging Hakim Djaballah, PhD and Immunotherapy for Methods TRC lentiviral particle-based shRNA Gastrointestinal Stromal Tumor Joseph O’Donoghue, PhD libraries for both human and mouse Ronald DeMatteo, MD species, covering 15,000 genes, as well Some recent drugs for cancer treatment Tyrosine kinase inhibitors are a new as bacterial stocks harboring shRNA work by preventing the development of class of drugs that have already proven plasmids . new blood vessels . Without these new to be highly effective in certain types of human cancers . We are using a vessels, the cancer is unable to keep System for Research Image mouse tumor model to investigate growing . It is important that physicians Management, Storage, and the effects of using tyrosine kinase are able to monitor how well these Processing drugs are working, preferably as early inhibitors with agents that activate the as possible after treatment begins . Our Peter Kijewski, PhD immune system . The hypothesis is that project aims to identify new ways in The equipment will be a core facility this combination therapy will be more which the effectiveness of such drugs to be used by MSK investigators who effective than either treatment alone .
10-YEAR REPORT | 2007–2017 23 The work may ultimately provide the mouse genetics, we are developing a Zirconium-89 Labeled Antibodies basis for human clinical trials . novel approach to study the natural for ImmunoPET-Guided progression of sporadic tumors and Radioimmunotherapy Suppression of Mammary test cancer treatments . Tumorigenesis and EMT by the Jason S . Lewis, PhD Atypical Rho Protein RND1 Pulsatile Kinase Inhibitor Therapy This proposal will focus on the use Filippo G . Giancotti, MD, PhD for Malignant Glioma: Proof of of trastuzumab (Herceptin®), a Concept Clinical Trial We are studying the function of the monoclonal antibody that targets the potential tumor suppressor gene Andrew Lassman, MD HER2/neu growth factor receptor, RND1, which appears to be altered in Malignant gliomas are the most a member of the epithelial growth about 20 percent of human breast common brain cancer in adults, and the factor receptor (EGFR) family . The cancers . We have found that RND1 average survival for patients with the central hypothesis is that 89Zr- directs the production of a signaling most aggressive type (glioblastoma) radiolabeled trastuzumab can be used protein that restrains the cell division is about one year . In many of these for quantitative PET imaging of breast cycle and prevents the changes in tumors, a molecule called epidermal tumors, improved early detection, cell architecture and motility that growth factor receptor (EGFR) signals staging, monitoring of immunotherapy accompany tumor invasion and tumor cells to grow . Thus far, drugs that with trastuzumab, and the metastasis . Inactivation of RND1 leads inhibit EGFR have not been effective development of new radioimmunoPET- to the conversion of normal mammary for most patients, at least partly guided radioimmunotherapeutic epithelial cells to breast cancer cells because drugs do not adequately agents specific for breast cancer . By and renders already transformed reach the tumor when given in the the end of this project, we anticipate breast cancer cells more invasive and standard manner, a low dose every that we will have translated 89Zr- metastatic . We are currently studying day . To improve results, we plan a DFO-trastuzumab to the clinic for the mechanism through which clinical trial that differs from previous quantitative PET imaging of HER2/ RND1 suppresses cellular signaling, studies in two important ways . First, it examining if genetic inactivation has a different dosing schedule, called neu-positive breast cancers in patients . of RND1 is sufficient to initiate “pulsatile” dosing, with a high dose Role of Notch/ -Secretase tumorigenesis in the mammary glands once per week that blocks EGFR less γ of mice and exploring the genetic frequently, but more completely, than Pathway in the Proliferation and mechanisms through which RND1 is standard dosing . Second, the selection Survival of Breast Cancer Cells inactivated in human breast cancer . of patients will be made based on Yueming Li, PhD those who are most likely to benefit BCG Susceptibility of Bladder Notch signaling may play a causative because EGFR is abnormally active in Cancer Cells: Role of PTEN-AKT role in breast cancer . The overall their tumors; previous trials treated all Signaling in Pathogen Infection objectives of this proposal are to patients regardless of whether EGFR Michael Glickman, MD was “on” or “off ”. We will treat 20 investigate the function of Notch/ gamma-secretase signaling in breast Early-stage bladder cancer is often patients in this manner, 10 of whom will cancer cells and to develop a target- treated with BCG, a live bacterium, also undergo surgery after receiving but its mechanism of action is the EGFR-inhibiting drug so that we based therapy that is not available unknown . This project will investigate can determine whether the treatment today . the possibility that deficiencies in effectively turns off EGFR . Through this tumor suppressor pathways within design, we hope to change the current Novel Anticancer Compounds bladder cancer tumor cells render paradigm of drug development for Targeting the Tie2/Angiopoietin them sensitive to BCG therapy . If gliomas . Interactions and Signaling successful, this project will identify the Dimitar B . Nikolov, PhD mechanism of action of BCG therapy Identification and The Tie2 receptor and its angiopoietin and allow targeting of this therapy to Characterization of Inherited ligands regulate developmental specific patients based on their tumor Predisposition and Modifier characteristics . Alleles That Contribute and tumor-induced blood vessel to the Pathogenesis of formation . The potential to inhibit Development of a Novel Technique Myeloproliferative Neoplasms tumor formation and growth by for Modeling and Characterizing Ross Levine, MD blocking tumor-induced blood vessel Sporadic Tumors in Mice formation has shown great promise in The goal of our project is to identify many cancer types . Our preliminary Alexandra L . Joyner, PhD novel inherited DNA changes that Most cancer arises sporadically due predispose individuals to develop results indicate that small molecules to genetic mutations that occur in one chronic leukemias . The long-term could disrupt the Tie2/angiopoietin or a few cells within a tissue . Current goal of our efforts is to improve our interactions, and we propose to animal models of cancer, however, understanding of the genetic basis identify such compounds and start do not accurately model sporadic of leukemias to better use existing developing them into effective tumor formation . Using sophisticated treatments and develop new therapies . antitumor therapies .
24 GEOFFREY BEENE CANCER RESEARCH CENTER Examining the Role of Entosis in extend our basic knowledge of the Early Development of Small Human Cancers role of miRNAs in tumorigenesis and Molecule Inhibitors of the E3 may pave the way for an entirely novel Michael Overholtzer, PhD Ubiquitin Ligase CRL4DCAF1 approach for the targeted treatment of Cancers arise when individual cells human cancers . Filippo G . Giancotti, MD, PhD evade homeostatic mechanisms that We have recently provided evidence control their growth . By investigating SHARED RESOURCES AWARDS that the FERM domain protein Merlin, how tumors arise from normal cells in encoded by the neurofibromatosis the lab, we discovered a new cellular LC/MS/MS Instrument for Use in mechanism, called entosis, which Translational Research and Drug type II gene (NF2), suppresses eliminates cells by causing cell death . Discovery and Development tumorigenesis by translocating to the For decades, pathologists have seen Research at MSK nucleus to inhibit the E3 ubiquitin ligase evidence of entosis in human cancers CRL4DCAF1 . These results indicate Gabriela Chiosis, MA, PhD because it results in the formation of that inhibitors targeting CRL4DCAF1 The requested instrument will “cell-in-cell” structures, where whole will display therapeutic efficacy in NF2 provide investigators with the new cells are engulfed inside of others . and mesothelioma cases driven by NF2 capability of conducting rapid, Characterization of this process will mutations . We propose to identify and shed light on a novel aspect of how routine, and comprehensive drug to begin to optimize compounds able some cancers arise and also on a new metabolism and pharmacokinetics and to inhibit CRL4DCAF1 . cell death program than can kill tumor absorption, distribution, metabolism, cells . and excretion/tox analyses of hit A Comprehensive Genomic and compounds and lead candidates, with The MSK Colorectal Cancer the goal of facilitating and accelerating Epigenomic Analysis of the Oncogenome Project: Somatic the translation of novel therapies from Impact of First-Line Therapy and Germline Predictors of bench to bedside . in the Molecular Evolution of Recurrence and Response to Malignant Glioma Therapy Human Tissue Procurement Jason T . Huse, MD, PhD David B . Solit, MD Service and Tissue Bank, Clinical Database for Hematologic Malignant gliomas are routinely treated The goal of this proposal is to identify Oncology Division with radiation and chemotherapy, genetic mutation “signatures” that but they invariably recur in a state could be used by physicians and Marcel van den Brink, MD, PhD refractory to conventional treatment patients to determine whether or not To develop in collaboration with the regimens . The biological mechanisms a patient is at high risk of recurrence Human Tissue Procurement Service underlying this resistance, especially after surgery (prognostic markers), and Tissue Bank Core Facility at MSK, with regard to the impact of cytotoxic and whether or not a patient is likely a Human Tissue Procurement Service or unlikely to benefit from treatment and Tissue Bank for the Division therapy at the molecular level, with a particular chemotherapy agent of Hematologic Oncology at MSK remain largely unknown . We intend (predictive markers) . We will use (HemTPS/TB) . To develop a point- to comprehensively characterize the these genetic signatures to guide the of-entry clinical database for the effects of first-line glioma treatment selection of both standard currently Hematologic Oncology Division at MSK . on the development of therapeutic available therapies and patients for resistance in malignant glioma using treatment with experimental agents 2010 an integrated, global genomics/ that are designed to target specific epigenomics approach . driver mutations when present in the A Comprehensive Genomic tumor . Approach to Identify Cancer Identification of Aberrant Signal Investigating the Functions Genes in Uveal Melanoma Transduction Pathways in Primary of Oncogenic MicroRNAs in Boris C . Bastian, MD, PhD CNS Lymphoma Mammals Uveal melanoma is an aggressive form Ingo K . Mellinghoff, MD Andrea Ventura, MD, PhD of melanoma, with unique genetic Primary CNS Lymphoma (PCNSL) is Using a combination of mouse characteristics that involve frequent an aggressive primary human brain mutations in GNAQ or GNA11 and genetics, bioinformatics, and tumor . There remains a paucity of deletions of chromosome 3 . In this biochemistry, we are investigating knowledge regarding the molecular the role of Oncomir-1 (also known as project, we are performing a systematic events driving this disease . Our project miR-17~92) in the pathogenesis of genetic and functional analysis to will molecularly characterize a clinically human cancers . Our preliminary results identify the tumor suppressors on well-annotated set of PCNSL samples, indicate that this cluster of miRNAs is chromosome 3, with the goal of essential for the survival of lymphoma improving the understanding of the with the goal of deriving new insights cells, and we are currently identifying pathogenesis of this dreadful disease into its pathogenesis and identifying the molecular mechanisms underlying and finding better methods for new treatment opportunities for its its oncogenic properties . These studies diagnosis, prognosis, and treatment . most aggressive subtypes .
10-YEAR REPORT | 2007–2017 25 Characterization of the Molecular Exome Sequencing of Familial predictive biomarkers of sensitivity in Heterogeneity of EGFR Mutant Lymphoproliferative Syndrome CTCs to guide treatment selection . Lung Adenocarcinoma: Baseline Kenneth Offit, MD and Post-Treatment Tumor Oncogenic MicroRNAs in Acute This project will seek to uncover the Lymphatic Leukemia Analysis mechanisms of genetic susceptibility in Hans-Guido Wendel, MD Vincent A . Miller, MD families affected by multiple cases of Cytogenetic and recent genomic Lung cancers with mutations in the lymphoid malignancies . The approach studies from the Downing lab and epidermal growth factor receptor taken will be to utilize next-generation others have produced great insight (EGFR) are a unique subset of massively parallel sequencing to into the genetics of acute lymphatic discover within coding segments adenocarcinomas of the lung that leukemia (ALL) . However, the of the genome rare events that can are unusually vulnerable to targeted contribution of microRNAs (miRNAs) explain an increased risk for developing therapy with tyrosine kinase inhibitors, to the molecular pathogenesis of ALL lymphoid cancers . We will sequence such as erlotinib (Tarceva®) . Despite has not been explored systematically . the exome from one affected individual an unparalleled 14-month median This proposal focuses on oncogenic in each series of families affected by progression-free survival, patients miRNAs in ALL, and we expect to gain lymphoproliferative malignancies treated with erlotinib exhibit insight into the contribution of miRNAs and identify rare events not seen in significant differences in benefit, to the pathogenesis and clinical course reference genomes . with some gaining years of disease of ALL . control and others progressing after DNA Replication Stress and the SHARED RESOURCES AWARD several months . Response rate is Sumoylation of RPA similarly variable . These observations John H . J . Petrini, PhD High-Throughput suggest that there are underlying Immunohistochemistry differences among EGFR mutant lung DNA replication stress, which is adenocarcinomas . The goal of this caused by DNA lesions or metabolic Jason T . Huse, MD, PhD study is to more uniformly characterize states that impair the process of DNA We have recently acquired a state- the biologic heterogeneity of this replication, causes chromosome of-the-art immunostainer that will disease through the assessment of alterations . Defects in pathways considerably improve our ability to intra- and intertumoral changes in key that respond to DNA replication detect proteins of interest directly on genes linked prospectively to outcome stress have been definitively linked tissue slides obtained from patient from patient samples taken before to the development of cancer . Using tumors . The device can hold 30 slides and immediately after treatment human, mouse, and yeast cells, we are at any one time, is fully automated, and with erlotinib . This understanding is analyzing the response to replication can complete staining runs in six hours . stress . Ultimately, the information fundamental to the improvement of Our lab, along with Ingo Mellinghoff’s obtained will illuminate the molecular and Timothy Chan’s labs, are already current therapies and the generation of mechanisms of tumor suppression . using it extensively . new ones . Molecular Profiling in Circulating Establishment of a Unique 2011 Tumor Cells in Patients with Mouse Model for Plasma Cell Metastatic Prostate Cancer: Malignancies High-Throughput Profiling of Development of Predictive Genomic Alterations in Clinical Stephen D . Nimer, MD Biomarkers for Targeted Tumor Specimens We have generated a novel mouse Treatment Michael Berger, PhD model that allows us to study the Howard I . Scher, MD development and progression of Efforts to understand cancer at the The experience to date with molecular level have revealed genetic human plasma cell disorders, including androgen-receptor-signaling-directed biomarkers that reflect the nature and multiple myeloma and plasma cell approaches for castration-resistant course of disease and, in some cases, leukemia . We will use these mice to prostate cancer shows dramatic and predict the likelihood that a patient will gain insights into the mechanisms by durable responses in some patients, an benefit from a particular treatment . which these diseases arise, the genetic intermediate response in others, and We plan to develop and apply a robust abnormalities and changes in gene a distinct cohort that is intrinsically and cost-effective methodology, expression that drive their growth, resistant to therapy . Our program empowered by massively parallel and the precise defects in their growth seeks to establish robust assays for next-generation sequencing, by which regulation . This information will be genes associated with intrinsic and any clinical tumor specimen may be incorporated into new therapeutic acquired resistance in circulating tumor characterized for DNA mutations and approaches, which we will evaluate cells (CTCs) isolated from patients copy number changes in all known using the mice . The results of these enrolled in trials of androgen-receptor- cancer genes . By systematically studies will be used to procure future signaling-targeted agents in clinical deploying this platform across clinically National Cancer Institute or National development at MSK . Our long-term annotated tumors and, ultimately, Institutes of Health funding . objective is to generate data to qualify every patient at MSK, we hope to
26 GEOFFREY BEENE CANCER RESEARCH CENTER facilitate individual approaches to themselves, suggesting that cancer Transcriptional Regulatory SNPs cancer treatment through improved cells within the same tumor may be as a Mechanism for Prostate diagnostics and the identification of unrelated to one another and may thus Cancer Risk Loci novel biomarkers . differ considerably in their response Robert Klein, PhD to specific therapeutic agents . By Targeting AKT Inhibitor-Induced developing a new mouse model, we While genome-wide-association Feedback Signaling in Breast aim to characterize the corruption of studies have identified numerous Cancer such initially normal brain cells within single nucleotide polymorphisms (SNPs) associated with the risk of Sarat Chandarlapaty, MD, PhD gliomas, a common group of brain prostate cancer and other diseases, tumors, specifically with regard to their The PI3K/AKT/mTOR pathway little is known about the biological contribution to resistance to commonly is mutationally activated in the mechanism by which these SNPs used anticancer therapeutics and majority of breast cancers . While this operate . Here, we will test the tumor recurrence . pathway is druggable by a variety of hypothesis that the functional alleles compounds, the pathway is subject to Mechanism and Therapeutic at many prostate cancer risk loci multiple forms of negative feedback Potential of PTEN Regulation alter a functional transcription factor regulation, and these feedback upon Hypoxia binding site, thereby resulting in the pathways become relieved under misregulation of nearby genes that conditions of drug inhibition of the Xuejun Jiang, PhD influence the carcinogenesis process . pathway . We hypothesize that the The overall goal of this proposal is This research will give new insights loss of negative feedback limits the to understand the molecular basis into the biology of prostate cancer by effectiveness of drugs targeting this underlying the context-specific identifying both a general mechanism pathway . We propose to identify the regulation of the PTEN tumor underlying prostate cancer risk SNPs specific mechanisms of the feedback suppressor and the cancer therapeutic and specific genes that may mediate regulation of PI3K/AKT/mTOR- implications of such regulation . this altered risk . pathway-activated breast cancers, to Specifically, we will study how the determine the consequences of the loss ubiquitin ligase NEDD4-1 regulates Development of 89Zr-5A10 for of negative feedback on the efficacy of PTEN function, AKT activation, cell the Measurement of AR Signaling drug therapy, and to clinically evaluate survival/apoptosis, and tumorigenesis in Advanced Prostate Cancer with combining an AKT inhibitor with an in the context of hypoxia . The success Positron Emission Tomography inhibitor of a known oncogenic pathway of this study will not only elucidate the Jason Lewis, PhD that is hyperactivated through AKT- molecular mechanisms governing the We propose to evaluate 89Zr-5A10 as inhibitor-mediated loss of feedback . context-specific regulation of PTEN a pharmacodynamic and predictive and novel aspects of hypoxia biology biomarker for two important Understanding Clonal Evolution but will also provide insights into the classes of therapies for castration- and the Heterogeneity of the therapeutic targeting of the NEDD4- resistant prostate cancer (CRPC) Therapeutic Response by Lineage 1-PTEN circuitry in treating specific — antiandrogens and PI3K inhibitors Tracing in Mouse Models of human cancers . — and to conduct a phase 0 study Glioma with a humanized version of 5A10 in Combined Pre- and Intraoperative Eric Holland, MD, PhD rodents and men with CRPC . This Brain Tumor Imaging Using a translational project represents one of It is increasingly appreciated that Novel Dual-Modality Raman-MRI the first systematic efforts to develop cancer cells within any given tumor Nanoparticle Probe differ considerably from one another, a biomarker for the evaluation of AR and such heterogeneity is likely a major Moritz Kircher, MD, PhD signaling in patients with CRPC, and hurdle in cancer therapeutics . Still, Malignant brain tumors remain a the findings from this proposal have little is known about the mechanisms therapeutic challenge, in part because the potential to substantially impact underlying the emergence of tumor of the difficulty of visualizing the tumor the customization of individual patient cell heterogeneity . Traditionally, all borders during surgical resection . care, as well as influence the design cells within a tumor were assumed to Our project seeks to validate a new and execution of future clinical trials . . originate from a common ancestor . molecular approach to brain tumor Squamous Cell Carcinoma of the However, in addition to bona fide imaging based on a dual-modality Lung Mutation Analysis Program tumor cells, solid tumors also contain MRI/SERS (surface-enhanced Raman (SQC-MAP) numerous cells derived from the normal spectroscopy) nanoparticle, allowing host microenvironment, such as blood combined preoperative staging and Paul Paik, MD vessels and immune cells . In brain intraoperative high-resolution imaging Patients with squamous cell tumors, a large number of normal brain using a single contrast agent . This will carcinomas of the lung (SQCLC) cells are trapped within the growing include biodistribution and cytotoxicity comprise 20 percent of all non-small tumor . Our research indicates that such studies and an assessment of the cell lung cancers diagnosed in the normal cells can become corrupted accuracy of tumor delineation by MRI United States annually, amounting by the tumor environment and and Raman imaging in transgenic to nearly 40,000 patients per year . actually become bona fide tumor cells mouse models . Unfortunately, no targeted therapies
10-YEAR REPORT | 2007–2017 27 have been identified for these host disease (GVHD), which is an 2012 patients, this despite the success inflammatory process primarily of drugs that target the mutant involving the intestine, liver, and The Mutational Landscapes epidermal growth factor receptor skin . Neovascularization has been Underlying Tumor Aggressiveness and anaplastic lymphoma kinase implicated in both tumor growth in Adenoid Cystic Carcinoma in a third of lung adenocarcinoma and inflammation, suggesting that Timothy Chan, MD, PhD (ADCL) cases . Exciting new work has neovascularization could be an Adenoid cystic carcinoma (ACC) is a identified putative driver oncogenic attractive therapeutic target in deadly malignancy about which very events in upward of 50 to 60 percent patients with malignancies who are little is known . Our study will define the of SQCLC patients . The complex undergoing HSCT . Based upon our mutational landscape underlying this nature of these mutations, which promising preclinical studies, we cancer and define the changes that have almost no overlap with those hypothesize that the therapeutic drive tumor aggressiveness . We will found in ADCL, necessitates the targeting of neovascularization in allo- make use of several rigorous genome- creation of a new molecular profiling HSCT recipients can simultaneously wide strategies to elucidate the genetic infrastructure . SQC-MAP will fulfill this ameliorate GVHD and inhibit post- changes in ACC . Our work will identify role, prospectively validating these transplant malignant relapse, resulting new biomarkers for disease progression molecular aberrations in a cohort of in improved overall survival in allo- and potential novel targets for therapy . 100 SQCLC patients at MSK while HSCT recipients . simultaneously serving as the platform Genetic Basis of mTOR Treatment by which patients will be paired to Investigating the miR-34 Family Response and Its Implication in emerging clinical trials of new targeted of Tumor Suppressor MicroRNAs Kidney Cancer therapies . Andrea Ventura, MD, PhD James Hsieh, MD, PhD Genomic Determinants of Over the past decade, microRNAs This translational Beene grant focuses Radiosensitivity (miRNAs) have emerged as key on understanding the molecular Simon Powell, MD, PhD modulators of gene expression in underpinnings of treatment response metazoan and plants . Deregulated and resistance to mTOR inhibitors The project aims to understand the expression of miRNAs is a common (targeted drugs that have approved by genetic factors that underlie the feature of human cancers, and the US Food and Drug Administration individual differences in sensitivity a number of miRNAs have been for treating kidney cancers) . To achieve to ionizing radiation . We have proposed to act as oncogenes or this outstanding goal, we employ a developed a high-throughput assay tumor suppressors . We will investigate state-of-the-art integrated genomic, of DNA damage and repair using flow structural, biochemical, and mouse cytometry for lymphoblastoid cell a recently described family of p53- regulated miRNAs whose members genetic approach . Results are expected lines . By studying the 1000 Genomes to help better predict the response and have been proposed to act as tumor Project cell lines, where whole- resistance of renal cancers to targeted suppressors in a variety of human genome sequencing data are available, anticancer agents, with an ultimate cancers . By combining in vivo studies we can study genetic locus association goal of personalizing cancer therapies . markers for radiation sensitivity as in the mouse and high-throughput well as candidate mutations and approaches, we will determine the Role of Reciprocal Epithelial- polymorphisms in known radiation physiologic functions of the various Stromal Signaling Elicited by response genes . The ultimate goal is members of this family of miRNAs, Hedgehog-GLI Signaling in to develop a radiogenomics profile their potential activity as tumor Prostate Cancer for predicting sensitivity or resistance suppressors, and their mechanism of Alexandra Joyner, PhD to radiation that will help in planning action . radiation therapy . Most research on prostate cancer SHARED RESOURCES AWARD (PCa), the second leading cause of Endothelial Precursor Cells cancer-related deaths in American in Allogeneic Bone Marrow Raman Microscope for Label-Free men, has concentrated on the signaling Transplantation during Graft- Tissue Characterization and High- pathways active in tumor cells; versus-Host Disease and Graft- Sensitivity Detection of Raman however, there is growing evidence versus-Tumor Activity Contrast Agents that cancer-associated fibroblasts (CAFs) have profound effects on tumor Marcel van den Brink, MD, PhD Moritz Kircher, MD, PhD growth, with normal stroma reducing Allogeneic hematopoietic stem cell The instrument purchased with this tumor burden and CAFs augmenting transplantation (allo-HSCT) is an grant is a Renishaw InVia Raman tumor growth . The hypothesis we important therapy with curative microscope with Streamline upgrade . will test using mouse models is that potential for a variety of malignant It allows for the rapid acquisition of a hedgehog protein secreted by PCa and nonmalignant diseases . The Raman spectra and Raman imaging stimulates expansion of CAFs that, major obstacles to a more favorable maps of materials, cells, and tissue in turn, secrete factors that enhance therapeutic outcome are tumor sections, as well as of small animals tumor progression . Since small relapse and acute graft-versus- in vivo . molecule hedgehog pathway inhibitors
28 GEOFFREY BEENE CANCER RESEARCH CENTER have been effective in the clinic and function of CD99 in AML stem cells, using these cells for the purpose of mouse cancer models, the results of which are the cells that must be modeling human glioma . Mutations our studies should be applicable to eliminated in order to effect cures for uncovered in genomic studies of translational studies . this difficult-to-treat disease . human brain tumors will be introduced into human neural precursors in an Integrated Genetic Profiling to A Phase II Study of the BRAF effort to uncover the oncogenic Predict Response to Therapy in Inhibitor Vemurafenib in Patients pathways required for the initiation Acute Myeloid Leukemia with Relapsed or Refractory Hairy of brain tumors from specific cells of Mithat Gönen, PhD Cell Leukemia origin . We hope to demonstrate that human pluripotent stem cells can serve Although induction chemotherapy, Jae Park, MD as a platform for modeling gliomas consolidation, and allogeneic stem cell A recent exome sequencing study of and potentially other cancers in human transplantation offer the possibility of hairy cell leukemia (HCL) has identified cells . a cure to patients with acute myeloid that the BRAF V600E mutation is present in nearly 100 percent of leukemia (AML), the variable outcome New Therapeutic Opportunities in primary HCL samples while absent in of patients with AML has limited the Follicular Lymphoma optimal use of antileukemic therapies . other B cell lymphoid malignancies . The Most recently, randomized trials have exclusive presence of the BRAF V600E Hans-Guido Wendel, MD established high-dose daunorubicin mutation in HCL implicates its role in Follicular lymphoma (FL) is the (Cerubidine®) as the current standard of pathogenesis and provides a rational most common form of indolent care for patients 18 to 60 years of age therapeutic target . Therefore, we non-Hodgkin lymphoma (NHL), with newly diagnosed AML; however, propose to study the clinical efficacy with 18,300 new cases diagnosed it was not clear from these studies of the BRAF inhibitor vemurafenib per year in the United States . FL whether there were specific patient (Zelboraf®) in patients with relapsed is not curable by chemotherapy subsets that derived benefit from or refractory HCL . Our project will and is characterized by continuous more-intensive therapies . Previously, also systematically characterize relapses and disease progression . we used data from a trial of younger the mutation profiles of HCL and Genetically, FLs are characterized adults with AML to demonstrate that investigate the potential mechanisms by the t(14;18) that deregulates Bcl2, mutational analysis can identify which of resistance to BRAF inhibition . and additional genetic events are patients benefit from dose-intensive The ultimate goal of the project is to required for lymphoma development daunorubicin induction chemotherapy provide a better understanding of the and progression . The identity of and which patients do not derive implication of the BRAF mutation and the oncogenic drivers in FL is not benefit from the more intensive develop the first molecularly targeted established . FL is clearly a significant regimen . We now aim to expand our therapy in patients with HCL . health concern; however this cancer knowledge of the genomic predictors has been somewhat neglected Oxidative DNA Damage and of response or resistance to therapy scientifically . We have developed a new Oncogenesis: A New Function for through a study of elderly patients murine model of FL and established the Ku Heterodimer enrolled in multicenter randomized reagents and collaborations that put trials . The results will help us refine John Petrini, PhD us in a unique position to conduct the our prognostic signature of the overall This study will examine the interplay proposed studies . outcome in AML, identify mutations between oxidative DNA damage that predict response to therapy, and the process of DNA synthesis . Somatic Genetic Alterations in and based on mutational analysis, Previously, the protein called Ku the Pathogenesis and Therapy of determine the patient subsets that has been shown to regulate DNA Histiocytic Disorders benefit from more-intensive therapies, repair . We have discovered a new Omar Abdel-Wahab, MD including dose-intense chemotherapy function for Ku, which is that during The histiocytic disorders are a and allogeneic hematopoietic stem cell this process, it helps suppress the collection of diseases characterized by transplantation . potential of oxidative DNA damage to an accumulation of white blood cells cause cancer . We are examining the called macrophages or dendritic cells Targeting CD99 in Leukemic Stem importance of this process and the role in various tissues throughout the body . Cells in Acute Myeloid Leukemia of Ku in preventing breast cancer . These diseases present with a wide Christopher Park, MD, PhD array of clinical manifestations and Human ES Cells as Candidates for We have shown that leukemic stem have a variety of subtypes based on Modeling Glioma cells in acute myeloid leukemia (AML) the microscopic appearance of white express the cell surface protein CD99 . Viviane Tabar, MD blood cells . Because of the rarity of Because AML stem cells can be Human pluripotent stem cells represent each individual subtype of histiocytic selectively targeted by antibodies that highly promising novel tools for disease and their very heterogeneous recognize CD99, we will investigate modeling human disease . Our lab has clinical presentations, the clinical whether such an antibody can be expertise in inducing the differentiation experience and biologic understanding utilized clinically as a novel AML of human pluripotent stem cells into of many of these diseases has been therapy . We will also determine the neural precursors . Here, we propose limited . A major breakthrough in the
10-YEAR REPORT | 2007–2017 29 biology and therapy of these disorders 2013 useful for some of these difficult-to- came with a recent discovery that cure childhood cancers . If it is proven 40 to 50 percent of patients with the Generation of Personalized safe and effective, this BsAb may have most common histiocytic disorders Models of Prostate Cancer for broad application to adult cancers with have mutations in the oncogene BRAF . Correlates of Disease Response GD2 present, such as small cell lung Based on this finding, we organized a and Progression cancer, melanoma, and brain tumors . group of physicians and scientists at Yu Chen, MD, PhD Clinically Targeting ETV1 in MSK who are committed to identifying Cancer cells growing in the laboratory Advanced Gastrointestinal the genetic abnormalities underlying are extensively used to study Stromal Tumor (GIST) histiocytic disorders and treating these tumorigenesis and therapy . Prostate Ping Chi, MD, PhD patients as part of monitored clinical cancer cells are uniquely difficult to trials using approaches targeting these grow in the laboratory, hampering Gastrointestinal stromal tumor genetic alterations . Thus far we have the ability of researchers to study (GIST) is characterized by activating made great progress in the treatment the mechanisms of disease and drug mutations in the KIT or PDGFRA of BRAF-mutant histiocyte patients resistance . Using newly developed receptor tyrosine kinases . Despite the with the mutant BRAF inhibitor methods to grow prostate cancer cells clinical success of imatinib (Gleevec®), vemurafenib (Zelboraf®) and found that are directly derived from patient nearly all advanced GIST patients develop imatinib resistance and new genetic alterations, which are biopsies, we propose establishing a eventually die of their disease . We promising targets for novel therapies panel of lines from patients entering have recently discovered that ETV1 — for additional histiocytic disorder clinical trials in prostate cancer . We an ETS family transcription factor and patients . will characterize these lines for genetic mutations and drug sensitivity to study a well-established oncogene involved in recurrent genomic alterations in SHARED RESOURCES AWARD the genetic basis of tumor growth and drug resistance . prostate cancer, Ewing sarcoma, and Beckman Coulter SPRIworks HT melanoma – plays a critical role and Fragment Library System Bispecific Antibody to Engage T cooperates with mutant KIT/PDGFRA Cells for Cancer Therapy in GIST pathogenesis . Here, we Adriana Heguy, PhD Nai-Kong Cheung, MD, PhD propose examining a novel therapeutic Next-generation deep sequencing of strategy that simultaneously targets T lymphocytes are ferocious killers . human tumors is revolutionizing the both the mutant KIT/PDGFRA and They kill serially, and while killing, they cancer genomics field by facilitating ETV1 in preclinical murine GIST models multiply, setting up killer colonies the correlation of genomics data with and in a phase Ib/II clinical trial in at the sites where they encounter clinical data, which aims to inform advanced GIST patients . We will tumor cells . Unfortunately, many examine the efficacy and imatinib/MEK diagnosis and risk stratification, and tumor cells, including neuroblastoma, inhibitor resistance mechanisms of this ultimately result in individualized are immune to these killer T cells . dual-targeting strategy and develop treatment . Regardless of the platform Bispecific antibodies (BsAb) are predictive therapeutic biomarkers used, libraries of template genomic engineered to carry the binding sites using biospecimens derived from DNA, cDNA, or amplicons have to be of two different antibodies — one site the murine models and the clinical prepared prior to sequencing . The is to bind to T cells; the other is to trial . We believe that this strategy, if manual preparation and quality control handcuff T cells to the tumors . Now T successful, has the potential to change of libraries is labor intensive and is cells can do what they are trained to the landscape of clinical practice in the main bottleneck in the efficient do: be killing machines . With BsAb, GIST management and has important tumors can no longer escape the production of sequence data . The therapeutic implications in other ETV1- immune system . First, the expression use of automation will reduce the dependent malignancies . time burden for technicians, eliminate of antigens called HLA on tumors is no human error, and increase the volume longer required . Moreover, nearly all Inactivation of Neogenin in T cells can be recruited, and they no and efficiency of library construction . Castration-Resistant Prostate longer need to be prior educated, or We have received a Shared Equipment Cancer “primed,” to the tumor . Early studies in Grant to purchase the Beckman leukemia and lymphoma have shown Filippo Giancotti, MD, PhD Coulter SPRIworks HT Fragment dramatic positive clinical results . In this Once prostate cancer has become Library System . This instrument comes proposal, a BsAb to retarget T cells to refractory to antiandrogen therapy with a validated suite of methods for the ganglioside GD2 on human tumors and metastatic, it cannot be the various library construction steps, will be developed into a clinical drug effectively cured . The molecular and its software is flexible, permitting, and be made ready for first-in-human pathways underlying prostate cancer for example, the creation of new clinical trial . Since GD2 is present on progression to this advanced stage methods for target enrichment . The many pediatric tumors — including are incompletely understood . We purchase of this equipment will benefit neuroblastoma, osteosarcoma, have observed that the cell adhesion many departments and investigators the Ewing family of tumors, and receptor neogenin is inactivated in across MSK . rhabdomyosarcoma — this drug will be a fraction of hormone-refractory
30 GEOFFREY BEENE CANCER RESEARCH CENTER prostate tumors . We propose to preclinical studies and in MPN patients, Investigating the Role of elucidate the molecular mechanisms with the goal of improving the Transcription Factor Zbtb32 in by which loss of neogenin induces outcome of patients with MPNs . the NK Cell Response against prostate cancer progression and Tumor Establishment and metastasis, and to examine whether TFIIH Complex Somatic Mutations Metastasis these mechanisms operate in human as Biomarkers of Platinum Joseph Sun, PhD prostate cancer . The results of these Chemotherapy Sensitivity Natural killer (NK) cells recognize studies may lead to the identification Jonathan Rosenberg, MD of novel targets for the therapy of AR- and destroy transformed host While platinum-chemotherapy has independent prostate cancer . cells in a process termed tumor been long used in oncology, most immunosurveillance . Humans lacking Quantitative Approaches for patients do not derive dramatic NK cells or NK cell function have the Mechanistic Analysis of benefits . Newly identified DNA severe health complications due to Tumor Cell Killing by Cytotoxic repair gene mutations in urothelial certain cancers and viral infections . Lymphocytes carcinoma appear to be associated The general goals of my research with high levels of sensitivity to program are to understand the Morgan Huse, PhD cisplatin chemotherapy in muscle- molecular mechanisms behind NK Cytotoxic T lymphocytes (CTLs) fight invasive urothelial tumors . This cell responses against cancer and cancer by recognizing and destroying project will determine whether infectious pathogens . Because the tumor cells . This proposal describes these findings predict response to transcription factor Zbtb32 is critical experiments aimed at learning how platinum chemotherapy drugs in for NK cell activation and proliferation, CTLs carry out this killing process . metastatic urothelial carcinoma and we will investigate the role of Zbtb32 The information gained from our begin to explore whether these or in the generation of a robust immune study will aid in the development of similar mutations in other cancer response against tumor establishment strategies to use CTLs for antitumor types predict platinum treatment and metastasis . The studies in this immunotherapy . proposal will uncover the biological responses . In addition, laboratory pathways mediated by Zbtb32 and investigations will explore the Combined JAK2/HSP90 provide a framework for manipulating molecular underpinnings of these Inhibition in Primary powerful NK cell responses in the clinic findings . The ultimate goal of this Myelofibrosis, Postessential to target cancer . Thrombocythemia Myelofibrosis, project is to determine whether these and Postpolycythemia Vera mutations can be used to predict Theranostics of Neuroendocrine Myelofibrosis which tumors will respond to platinum Tumors with Somatostatin chemotherapy, allowing better Raajit Rampal, MD, PhD Antagonists selection of patients for chemotherapy Wolfgang Weber, MD The Philadelphia chromosome (Ph)- treatment . negative myeloproliferative neoplasms The goal of this study is to develop (MPNs) include myelofibrosis (MF), Functional Consequences and a new therapy for neuroendocrine polycythemia vera (PV), and essential Therapeutic Implications of RAF- tumors (a group of tumors that can thrombocythemia (ET) . Mutations in dimer Signaling in Cancer arise from hormone-producing cells the JAK2 gene occur in the majority throughout the body) . The therapy is Neal Rosen, MD, PhD of MPN patients, which has led to based on a novel class of molecules efforts to target this mutation with Activation of the ERK signaling (somatostatin receptor antagonists) JAK2 inhibitors . The JAK1/2 inhibitor pathway occurs in at least half of that can selectively deliver radiation to ruxolitinib (Jakafi®) has been approved human cancers and is controlled by these tumors . The study will evaluate for the treatment of MF . While JAK a protein called RAF . RAF can exist how much radiation can be delivered inhibitor therapy relieves symptoms as a single protein (monomer) or safely in patients and how well tumors in the majority of MF patients, there a pair of proteins bound together respond to this therapy . is no evidence that these inhibitors (dimer); in most tumors, activation can induce remission of the disease . occurs via dimers . Inhibitors of RAF SHARED RESOURCES AWARDS Thus, other agents are needed that monomers have been developed that Antitumor Assessment Core can target JAK2 . Hsp90 is a protein have remarkable clinical activity in chaperone that stabilizes JAK2 . melanoma, but no inhibitors of RAF Elisa DeStanchina, PhD We previously demonstrated that dimers currently exist . We have now To initiate first-in-human clinical trials, JAK2 associates with Hsp90, and identified the first known inhibitor of the US Food and Drug Administration that inhibition of Hsp90 leads to RAF dimers and found that it inhibits requires that animal safety studies degradation of JAK2 . Our preliminary some tumors that are driven by this be conducted in accordance with studies suggest that combined Hsp90/ protein . Our grant is focused on federal regulations for good laboratory JAK2 inhibition results in more potent understanding how this compound practices (GLP) . In the past five JAK2 inhibition . We therefore seek works, using this information to make years alone, MSK investigators have to determine the effect of combined better drugs, and developing these developed more than 20 investigational Hsp90 and JAK2 inhibition in drugs as cancer therapeutics . new drugs (INDs), including biologics,
10-YEAR REPORT | 2007–2017 31 radiopharmaceuticals, and small 2014 supportive environment, including the molecule drugs, which have been immune system . In this program, we cleared by the FDA for clinical trials Exome Sequencing to Identify will study how a new type of tumor- at MSK The Antitumor Assessment Genetic Predictors of Response to infiltrating immune cell is induced and Facility conducted IND-enabling Anti-PD-1 Therapy in Patients with coerced to promote tumor growth . Our safety studies for more than half of NSCLCs goal of this research is to target these these studies in a GLP-like manner . Matthew Hellmann, MD cells for novel cancer immunotherapy . However, similar future studies will Immunotherapies, medicines that Single-Cell Multiparametric have to be conducted under strict stimulate the body’s immune system to Analysis of Lymphocyte Signaling GLP conditions . Currently, no facility better recognize and attack cancers, in Health and Disease Using exists for conducting GLP-compliant have recently shown great promise CyTOF studies at MSK; therefore, the only as a new treatment for patients Gregoire Altan-Bonnet, PhD option available for investigators with lung cancers . We hypothesize developing novel agents is to contract that the degree and type of genetic B cell lymphoma is the result of GLP safety studies to an outside change (called mutations) in lung abnormal proliferation and apoptosis, cancer is important for predicting vendor (CRO) . Drug development as well as in the in vivo maintenance and understanding which patients of a neoplastic clone within the efforts with CROs are extremely costly, are most likely to benefit from peripheral B cell compartment . A frequently delayed, and often suffer immunotherapies . Using state-of-the- key driver mechanism for oncogenic difficulties in method development, art genetic sequencing technology transformation in lymphoma is the technology transfer, and the initial and new computational methods dysregulation of the B cell receptor- characterization of novel agents . Thus, developed by our team at MSK, we mediated signaling machinery and its to maintain a competitive translational will study tumors from patients with synergy with other pathways (e .g ., Bcl- research program, MSK needs to lung cancer to examine how mutations 2 and antiapoptosis) . The Altan-Bonnet develop internal resources to conduct in cancers can be used to predict and Wendell labs are collaborating GLP studies in a more cost- and time- response to immunotherapies . We to characterize quantitatively such effective way . The proposed resource believe this work can lead to direct dysregulation by developing genetic will enable investigators to conduct benefits to patients, by being able to mouse models of B cell lymphoma, identify which patients are most likely GLP-compliant animal safety studies and probing their signal transduction to benefit from immunotherapies, on-site at MSK, thereby streamlining using single-cell phosphor profiling and can lead to the development preclinical development and reducing with mass cytometry and mathematical of better and more personalized costs . modeling . immunotherapies in the future . Hedgehog Acyltransferase as a Computational Biology Use of Human Pancreatic Target in Breast and Lung Cancers Gunnar Ratsch, PhD Precursor Cells to Explore the Cellular Changes Associated with Marilyn Resh, PhD The rapid increase in speed and the Development of Pancreatic decrease in cost of DNA sequencing The project focuses on cancer Malignancy pathways driven by hedgehog have started a revolution in genomics . acyltransferase (Hhat) . Hhat attaches While data generation is now quick Alan Hall, PhD an essential fatty acid onto a and cost-effective, data transfer Pancreatic cancer is the fourth most hedgehog, a protein that is aberrantly and storage issues currently prevent common cause of cancer death in the expressed in human cancers . The Resh the effective use of many new data- United States . Mutations in K-Ras are lab has developed Hhat inhibitors and sequencing resources . At present, known to be present in 90 percent of these cancers, and yet it has proven aims to use these drugs as tools to researchers may lose precious extremely difficult to target this block the growth of breast and lung time, bandwidth, and disk space by oncogene and treat the disease . We cancer tumors . downloading and storing large-scale propose to generate pancreatic cells Unraveling Resistance to PI3K and commonly utilized data resources . from human embryonic stem cells and The establishment of a one petabyte explore the effects of introducing the p110 Inhibitors in Breast Cancer (1,000,000 gigabytes) local data K-Ras oncogene on their behavior in Mauri Scaltriti, PhD storage server will solve these issues culture . We hope to uncover a new Activating mutations of the PI3K for many MSK investigators across understanding in the development of pathway are present in up to 40 departments by providing fast and this devastating disease . percent of breast cancer . Many of convenient access to insight-enabling these tumors respond to specific PI3K Differentiation and Function of data . The resources we have targeted inhibitors, but the emergence of drug Tumor-Associated Macrophages include the Cancer Genome Atlas, resistance inevitably occurs . In this ENCODE, the 1000 Genomes Project, Ming Li, PhD proposal, we aim to investigate the the Human Microbiome Project, and Tumors are complex tissues that mechanisms of resistance to these others . progress through the exploitation of a agents in patients with breast cancer .
32 GEOFFREY BEENE CANCER RESEARCH CENTER Non-Cell-Autonomous Rewiring landscape assays (genomic scars) gene transcription in other RAS-driven of Mitosis by the Tumor have been developed by both Myriad tumor lineages to determine the role Microenvironment Genetics and other academic groups of upstream effectors of the Hippo to provide a readout of homologous pathway on thyroid and pancreatic Emily Foley, PhD recombinational repair . Chromosomal RAS-induced tumorigenesis in vivo, Cancer cells proliferate in the midst breaks and chromatid breaks are and to test whether pharmacological of a complex environment composed responsible for the initiation of these interference with the YAP-TEAD of numerous other cell types . These landscape changes, which can arise transcriptional complex will attenuate neighbors have influential roles in from HR deficiency, but these changes the phenotype . cancer development and metastasis, can also occur from other sources of and are expected to play a role in how genomic instability SHARED RESOURCES AWARDS chemotherapeutic drugs kill cancer cells . The goal of this proposal is to Dissecting the Mechanism of DDR Automated High-Throughput DNA identify how a tumor cell’s environment Signaling: Mining the Nbs1/Mre11 Extraction Facility Dedicated to impacts the response to anticancer Interface Research Studies drugs, like paclitaxel (Abraxane®, John Petrini, PhD Rajmohan Murali, MBBS, MD, FRCPA Onxol®), which are commonly used in Dr . Murali would like to establish an chemotherapy . With the support of the Geoffrey Beene Cancer Research Center, we automated, research-dedicated DNA extraction facility that will be operated A CRISPR-Based Approach will use state-of-the-art genetic tools by the Pathology Core . The facility will to Generate Chromosomal to understand the mechanism by be shared by all investigators at MSK Rearrangements In Vivo which cells sound the alarm when chromosomes are damaged . This alarm whose projects require DNA extraction Andrea Ventura, MD, PhD sets in motion an array of processes from tissue and blood . Automation The main goal of this research that help cells survive and repair will be crucial to support the high- proposal is to develop a novel damage to chromosomes . The detailed bandwidth and volume demands of strategy to engineer chromosomal information we gather in this effort next-generation assays . rearrangements in vivo using somatic will ultimately allow us design tools A Validated Laboratory genome editing . The underlying idea to disable the alarm in cancer cells, Information System for Integrated is that by inducing two simultaneous making them more vulnerable to DNA Management of Preclinical double-stranded breaks at specific damaging therapies, such as radiation Projects chromosomal locations, it should be and chemotherapy . possible to engineer a wide array Elisa DeStanchina, PhD of chromosomal rearrangements, Noninvasive Detection of The resource requested in this including inversions, deletions, and Glutamate Pool Metabolism Using application is a validated preclinical reciprocal translocations . Hyperpolarized MRI laboratory information system, which Kayvan Keshari, PhD consists of computers, network servers, NF2-Hippo in RAS-Driven cancers Metabolic reprogramming can be software licenses, and crucially, a James Fagin, MD observed in the change in substrate US Food and Drug Administration– The goals of this project are to uptake and utilization of cancer compliant validation package for test whether the Merlin-Hippo axis cells . Glutamine and the subsequent GLP studies . The system will capture, promotes transformation in part glutamate that is metabolized in the analyze, and link drug-testing data through the activation of mutant Ras cell can provide a source of both from multiple instruments and gene transcription in other RAS-driven carbon and nitrogen for proliferating locations, improving collaboration and tumor lineages to determine the role cells to meet their growing needs . streamlining interdisciplinary studies of upstream effectors of the Hippo Until recently, it was difficult to at all levels of research and preclinical pathway on thyroid and pancreatic noninvasively image these changes in development within the center . RAS-induced tumorigenesis in vivo, cancer cell metabolism as well as the and to test whether pharmacological flux through different pathways . To 2015 interference with the YAP-TEAD address this, we propose developing transcriptional complex will attenuate molecules using hyperpolarized MRI to Role of the Cohesin Complex in the phenotype . interrogate these pathways and extend Leukemic Transformation them to a better understanding of Ross Levine, MD BRCA Pathway Defects in tumor metabolism in vivo . SporadicBreast Cancer Programmed cell death plays NF2-Hippo in RAS-Driven cancers important roles in normal biology, Simon Powell, MD, PhD and its deregulation impacts various The major goal of this project is to James Fagin, MD human diseases, including cancer . define the nature of homologous The goals of this project are to Recent progress has established that recombination (HR) deficiency in test whether the Merlin-Hippo axis in addition to apoptosis (which is the breast cancers, and potentially in other promotes transformation in part best-established mode of programmed cancer types in the future . Genomic through the activation of mutant Ras cell death), there are also other forms of
10-YEAR REPORT | 2007–2017 33 programmed cell death . Ferroptosis is a many tumor suppressors, including with myeloid leukemia . Overall, newly emerged programmed necrosis the breast and ovarian susceptibility these studies will provide evidence process that is implicated in various genes BRCA1 and BRCA2, are DNA that SYNCRIP is required for human biological and pathological conditions . repair genes . Our aim in this grant is leukemia and uncover mechanisms The overall goal of this proposal is to investigate potential modulators of of leukemogenesis, providing a novel to investigate the mechanisms of BRCA2 function that may be important therapeutic strategy in leukemia . ferroptosis and its potential involvement for tumor suppression . in cancer and cancer treatment, which Ferroptotic Cell Death, are poorly understood currently . Identifying Suppressors of Tet Mechanisms and Role in Cancer Mutation in Development and Xuegun Jiang, PhD Dissecting the Role of Cancer Disease Programmed cell death plays Metabolism on the Tumor Mary Goll, PhD important roles in normal biology, Microenvironment The ten-eleven translocation protein and its deregulation impacts various Joao Xavier, PhD TET2 is one of the most commonly human diseases, including cancer . Although metabolic alterations mutated genes in myeloid leukemias . Recent progress has established and interactions with stromal cells Mechanistically, TET proteins are that in addition to apoptosis (which are both considered hallmarks of important for removing methyl groups is the best-established mode of cancer, cancer metabolism and the from DNA . Mutation of TET enzymes programmed cell death), there are tumor microenvironment remain can lead to aberrant accumulation also other forms of programmed cell separate areas of research . This of DNA methylation, which can death . Ferroptosis is a newly emerged project investigates the intricate link interfere with normal gene expression programmed necrosis process that is between cancer metabolism and and promote abnormal cell states . implicated in various biological and microenvironment . We combine The goal of this project is to use the pathological conditions . The overall computational models with hematopoietic system of the zebrafish goal of this proposal is to investigate experiments to determine how the embryo as a model system to identify the mechanisms of ferroptosis and its extracellular metabolites produced chemical and genetic alterations that potential involvement in cancer and by cancer cells alter the phenotypes promote normal gene expression in cancer treatment, which are poorly of tumor-associated macrophages, cells that are compromised for TET understood currently . which then impact tumor development, activity . The Role of Aneuploidy in Tumor progression, and metastasis . Modeling Pancreatic Ductal Development Targeting the Oncogenic eIF4A Adenocarcinoma through Gene Robert Benezra, PhD RNAhelicase in Cancer Editing in Human Embryonic Stem Whole chromosome losses have been Hans Guido Wendel, MD Cells known to be a hallmark of tumor We discovered that an RNA unwinding Danwei Huangfu, PhD aggressiveness for over a century, enzyme called eIF4A is a new and Pancreatic ductal adenocarcinoma but whether they are a cause or exciting drug target in leukemia and (PDAC) is one of the most deadly consequence of tumor proliferation potentially other cancers . The natural cancers, largely because of delayed and spread is still poorly understood . product silvestrol is a selective inhibitor diagnosis . We propose modeling We have devised a genetic strategy of eIF4A . However, the compound pancreatic cancer using human to induce the loss of individual is purified from the Aglaia silvestris embryonic stem cells (hESCs) based chromosomes and have found that, plant in Malaysia in small quantities on our ability to perform sophisticated in both mouse and human cells, the and is not suitable as a clinical drug . genetics in hESCs and to generate loss of four individual chromosomes in Together with MSK chemist Derek Tan, pancreatic cells from hESCs through each case leads to reduced fitness in we will develop synthetic analogues of directed differentiation . We will model cell culture but dramatically enhanced silvestrol and ensure that they retain early preinvasive lesions, known as ability to form tumors in mice . With the the anticancer activity and specificity PanINs, to better understand the help of the Beene Foundation, we will of silvestrol . The goal is to develop cancer cells of origin and to further now try to understand the molecular compounds that can lead to new study the genetic regulators of the mechanisms underlying this enhanced clinical drugs against this exciting transition from early PanINs to PDAC . tumorigenic potential, with the ultimate target . goal of identifying novel targets for Uncovering the Role of SYNCRIP therapeutic intervention . Modulators of BRCA1 and BRCA2 in Myeloid Leukemia Stem Cells Function Michael Kharas, PhD Mitotic Stress Response and Cancer Maria Jasin, PhD Our proposal will utilize novel mouse By providing a mechanism for cells to models to understand the role of Meng Fu Bryan Tsou, PhD acquire mutations in tumor-relevant SYNCRIP in normal and malignant Drugs that target cell division genes, ongoing genomic instability hematopoietic cells . Our second aim have been widely used for cancer promotes tumor initiation, progression, will dissect how SYNCRIP modulates chemotherapy, but the underlying and metastasis . Not surprisingly then, critical transcription factors associated mechanism is not clear . We have
34 GEOFFREY BEENE CANCER RESEARCH CENTER developed novel reagents and Mechanisms of PGBD5 in DDR are poorly understood . We approaches to fully understand how Transposase-Induced have recently identified the ATPase cells sense and respond to cellular Transformation of Rhabdoid CHD4 as a novel effector of CSR . In dysfunction or stresses that occur Tumors this proposal, we will assess the role specifically during cell division . of CHD4 in recruiting AID to DNA and Alex Kentsis, MD, PhD determine its function in DNA repair in Molecular Characterization and Specific aim 1: Define molecular B cells . Novel Therapeutics in Malignant mechanisms of PGBD5-induced DNA Peripheral Nerve Sheath Tumor transposition and cell transformation Biologic and Clinical (MPNST) using functional genomics and Characterization of ERCC2 epigenomics . Mutation of regulatory Ping Chi, MD, PhD Mutations in Urothelial Carcinoma DNA elements and dysregulation of Gopakumar Iyer, MD Malignant peripheral nerve sheath gene expression are inherently linked tumors (MPNSTs) arising from the to chromatin accessibility . Here, Cisplatin-based chemotherapy cellular component of the peripheral using inducible alleles of PGBD5 and followed by the removal of the nerves represent a group of highly functional genomic approaches, we bladder is the current standard of care aggressive soft tissue sarcomas will determine the targeting and DNA treatment for patients with muscle- with limited treatment options . They repair mechanisms that are required invasive bladder cancer . Mutations can occur in the setting of type I for PGBD5-induced transformation and of ERCC2 have been identified as neurofibromatosis (NF1-associated), establish its regulatory mechanism predicting for exquisite sensitivity sporadically, or in association with to cisplatin in bladder cancer . This prior radiotherapy (RT-associated) . Therapy-Related Myeloid proposal seeks to characterize the Using comprehensive genomic Neoplasms: Characterization biology of ERCC2 alterations in approaches, we and others have of Mutation Order and Clonal bladder cancer and also to initiate a recently discovered that the majority Dynamics in Response to Therapy clinical trial of chemotherapy without of MPNSTs have an inactivation of during Disease Transformation the removal of the bladder in patients three tumor suppressor pathways, Elli Papaemmanuil, PhD with ERCC2-mutant muscle-invasive including NF1, CDKN2A (INK4A/ bladder cancer . Aim 1: To study the molecular ARF), and polycomb repressive mechanisms leading to the complex 2 (PRC2) . Here, we In Situ Analysis of Glioma Core development of therapy-related propose to use multidisciplinary and Signaling Pathways and Their leukemia whilst on therapy for integrative approaches to dissect Response to Therapy neuroblastoma in children . Aim 2: To the transcriptional dysregulation Ingo Mellinghoff, MD evaluate the utility of gene-based mediated by PRC2 pathway loss in molecular profiling in the clinical The overarching goal of our project MPNST pathogenesis, to examine the setting to support early diagnosis of is to develop an approach to quantify influence of PRC2 loss on the tumor therapy-related disease in patients intratumoral heterogeneity and spatial microenvironment, and to explore the treated for neuroblastoma . tumor/microenvironment interactions therapeutic vulnerability of PRC2 loss at the single-cell level . This question in MPNSTs, with the goal of clinical Nucleosome Remodeling in DNA is particularly relevant to high-grade translation of novel therapeutic Damage Response glioma, which is histopathologically developments for this difficult disease . Jayanta Chaudhuri, PhD heterogenous (glioblastoma “multiforme”) and remains one of the DNA double-strand breaks (DSBs) 2016 most treatment-refractory human constitute one of the most toxic cellular cancers . Genomic studies in bulk tumor lesions, with a single unrepaired DSB A Novel Approach for the samples have identified core signaling potentiating cell death or tumor- Identification of MicroRNA pathways in glioma, but their functional initiating chromosomal translocations . Targets In Vivo and spatial relationship is unknown . Yet in B cells undergoing class Andrea Ventura, MD, PhD switch recombination (CSR), DSBs Define Molecular Network of The goal of this proposal is to are deliberately introduced into the DOT1L-Driven Leukemia via overcome these limitations by immunoglobulin heavy chain locus Noncanonical Methylation developing a novel system for the by the DNA deaminase activation- unbiased identification of miRNA/ induced cytidine deaminase . An Minkui Luo, PhD mRNA interactions in a cell and efficient DNA damage response DOT1L is the sole protein tissue-specific manner in vivo . The pathway rapidly senses and repairs the methyltransferase that methylates new method we propose developing DSBs to complete CSR and preserve histone H3 lysine 79 (H3K79) . Strongly (Halo enhanced Ago2 pulldown) takes genomic integrity . While many of supported by our preliminary data, we advantage of the recently developed the DNA repair pathways operating hypothesize that DOTL1-dependent Halo-Tag, a modified bacterial during CSR have been elucidated, the H4K5 methylation facilitates haloalkane dehalogenase designed to role of nucleosomes in sheltering the transcription via two nonexclusive covalently bind a substrate that is not genome from DNA damage and the mechanisms . The overall impact of normally present in mammalian cells . requirement of nucleosome remodeling the proposal lies in the expectation of
10-YEAR REPORT | 2007–2017 35 uncovering the molecular mechanism lncRNA DINO directly binds to the p53 of cells and complex tissues . Most of DOT1L-deriven leukemia, the protein in both human and mouse cells notably, two modalities are at the exploration of novel antileukemia through a mechanism that remains to cutting-edge of this revolution and strategies, and the ability to overcome be elucidated, promoting p53 protein are highly sought after . One is super- emerging resistance of DOT1L stability . This effectively increases resolution microscopy, which allows inhibitors via combination therapy . the cellular pool of the p53 protein imaging of molecular dynamics in live and promotes p53 recruitment to cells and tissues at sub-diffraction Structure, Function, and Inhibition regulatory elements genome-wide . limited resolution . The other is light- of the Ras Methyltransferase ICMT While these data point to an important sheet microscopy, which is particularly Stephen Long, PhD role for DINO in the p53 pathway, powerful for imaging developing DINO’s role in tumor suppression and tissues at subcellular resolution over an The enzyme isoprenylcysteine carboxyl the molecular mechanism by which extended period due to its high speed methyltransferase (ICMT) methylates DINO regulates p53 remain to be and low phototoxicity . the carboxyl-terminus of Ras and identified . other CAAX proteins that have an 2017 isoprenoid (farnesyl or geranylgeranyl) Endogenous Fungi and the lipid attached . Methylation increases Development of Graft-Versus- Elucidating ER Function in the hydrophobicity of modified Host Disease proteins and is important for their Hormone-Independent Breast Tobias Hohl, MD, PhD targeting to the plasma membrane and Cancer subsequent control of cell proliferation Allogeneic hematopoietic cell Sarat Chandarlapaty, MD, PhD and differentiation . For this and other transplantation (HCT) is a potentially More than 70 percent of breast cancers reasons, ICMT has gained attention curative therapy for patients with are characterized by their dependence as a potential cancer target . The hematologic malignancies, though on the hormone estrogen for their aims of these studies are to study the this treatment modality is limited growth and survival . Antiestrogens molecular mechanisms of ICMT with by graft-versus-host (GvH) disease . are highly beneficial in most patients regard to substrate access, substrate Tissue-specific inflammation and with breast cancer, however, drug specificity, and catalysis, and to alloreactive T cell responses underlie resistance frequently emerges over discover ways to inhibit the enzyme . GvH pathogenesis . In this proposal, time . We have found that the estrogen Strong preliminary data, including we examine the hypothesis that receptor (ER) is still playing a critical an X-ray structure of ICMT that is in the composition and diversity of role in such cancers despite the progress and our development of intestinal fungi can regulate intestinal absence of estrogen stimulation . In this antibodylike inhibitors, support the inflammation and GvH during proposal, we will characterize the key objectives of the proposal . Completion human and murine allo-HCT and partners and targets of such hormone- of the aims would allow more-thorough that pharmacologic intervention can independent ER in order to identify evaluation of ICMT as a cancer target . improve GvH outcomes . new ways of treating these cancers Because relatively little is known about after hormone resistance develops or SHARED RESOURCES AWARDS enzymes that catalyze reactions within to prevent hormone resistance in the lipid membranes, the mechanistic Cancer Genomic Profiling for first place . principles that we discover are likely to Precision Medicine apply to other membrane enzymes . Structure-Based Mechanistic Zhirong Bao, PhD Insights into CRISPR-Cas Investigating the roles of a long We propose to acquire the RainDance Pathways Impacting on Cancer noncoding RNA that regulates p53 RainDrop System Sense and Source Biology Adam Schmitt, MD instruments for the Center for Dinshaw Patel, PhD Molecular Oncology to facilitate the The Schmitt lab has discovered a Bacteria and archaea have developed development of plasma DNA-profiling new, evolutionarily conserved long RNA-guided adaptive defense systems assays that can be readily transferred noncoding RNA (lncRNA) named to protect themselves against phage to the DMP laboratory for clinical DINO . It is required for the p53 and viral invaders . These discoveries implementation as well as the further response to DNA damage in humans made initially in prokaryotes have development of single-cell genomic and mice . DINO-depleted human been rapidly extended to eukaryotes, profiling methodologies for research . and mouse cells have impaired p53- given that CRISPR-Cas represents a dependent gene regulation following High-Resolution Living Imaging simple, flexible, and cost-effective way DNA damage and cellular defects to Study Cell-Cell Interactions to precisely edit and manipulate the in DNA damage–induced cell-cycle and Complex Tissue Formation mammalian genome . Specifically, the arrest, apoptosis, and senescence . nuclease Cas can be reprogrammed Furthermore, Dino-/- mice are resistant Zhirong Bao, PhD with synthetic RNAs to generate site- to lethal total-body irradiation similar With recent breakthroughs in specific double-strand DNA breaks to p53-deficient animals, illustrating fluorescence microscopy, high- in mammalian cells . This powerful the important functional role of Dino resolution live imaging has become approach allows engineering in to the p53 pathway . Surprisingly, a powerful driving force in the study either precise changes to correct
36 GEOFFREY BEENE CANCER RESEARCH CENTER genetic defects or chromosomal organs, but early-stage embryos rarely acquired during life (i .e ., somatic rearrangements that contribute to develop tumors . We hypothesize that mutations) that are required for the tumorigenesis, as well as develop the early embryo microenvironment development of BRCA1-associated genetically engineered mouse models contains antitumor factors and breast cancer have yet to be fully of human cancer . These represent propose identifying these embryonic characterized . It is currently unclear if powerful tools for monitoring tumor antitumor factors . Understanding complete loss of function of BRCA1 is initiation and progression and the their mechanisms may lead to the the initial step in the development of identification of drivers of cancer development of novel cancer therapies . BRCA1-associated breast cancers or if metastasis . other somatic mutations precede the tRNA Splicing Enzymes as a complete inactivation of BRCA1 . We SWI/SNF disruptions in Advanced Therapeutic Target for Fungal Thyroid Tumors: Identification of Infections in the Cancer Setting will combine the analysis of clinical samples, single-cell sequencing Epigenome-Guided Stewart Shuman, MD, PhD techniques, and laboratory models of James Fagin, MD Invasive fungal infections, especially BRCA1-associated breast cancer to This project will explore how Aspergillosis and Candidiasis, are define the somatic mutations required disruptions of individual components a major cause of morbidity and for tumor development in the context of the SWI/SNF chromatin remodeling mortality in people with cancer with of inherited BRCA1 mutations and complex, which are frequently prolonged neutropenia following to determine if the order of such mutated in advanced forms of thyroid chemotherapy or hematopoietic stem alterations influences the evolution of cancer, lead to tumor progression cell transplantation . The development the tumor and its sensitivity to specific and loss of differentiated properties of more effective treatments for these treatments . in mouse models of the disease . The infections hinges on defining new goal is to identify novel therapeutic targets for antifungal drug discovery SHARED RESOURCES AWARD vulnerabilities arising as a result of and implementing screening to identify these changes . inhibitors . The goal of this project is ITC as a Shared Instrument to advance the case for two fungal Minkui Luo, PhD Novel Embryonic Tumor tRNA-splicing enzymes, Trl1 and Tpt1, Suppression Mechanism by as antifungal targets by determining The characterization of interactions NEPN via Direct Sequestering of the atomic structures of the Aspergillus between ligands and macromolecules Growth-Promoting Ligands and and Candida enzymes and their has become a daily routine for many Indirect T Cell Activation in the interactions with substrates, cofactors, research laboratories at MSK . One Tumor Microenvironment and reaction intermediates . specialized instrument with general Kitai Kim, PhD applicability to quantify ligand- Reconstructing the Evolutionary Expressing multiple tumor-causing macromolecule interactions is History of BRCA1-Associated isothermal titration calorimetry (ITC) . genes in adult cells can induce tumor Breast Cancer formation . During early-stage embryo ITC meets the broad needs of MSK development, multiple tumor- Jorge Reis-Filho, MD, PhD laboratories for cancer research . The causing genes are highly expressed Inherited mutations in the BRCA1 gene award allows purchasing a top-end ITC in embryonic cells to support the are known to confer an increased as a shared instrument among more rapid growth of various tissues and risk of breast cancer . The mutations than 20 laboratories .
10-YEAR REPORT | 2007–2017 37 PUBLICATIONS Sorted by year grant was given; publication date may differ.
2007 Carboxyl Terminus of PTEN in lines . J Clin Endocrinol Metab . 2008 Antagonizing NEDD4-1-Mediated Jun;93(6):2194-201 . Renier Brentjens, MD, PhD PTEN Ubiquitination and Degradation . Biochem J. 2008 Sep 1;414(2):221-9. Schweppe RE, Klapper JP, Karch C, Brentjens RJ, Santos E, Nikhamin Pugazhenthi U, Benezra M, Knauf Y, Yeh R, Matsushita M, La Perle K, Wang X, Jiang X . Post-translational JA, Fagin JA, Marlow LA, Copland Quintas-Cardama A, Larson S, Sadelain Regulation of PTEN . Oncogene. 2008 JA, Smallridge RC, Haugen BR . M . Successful Eradication of Systemic Sep 18;27(41):5454-63 . Deoxyribonucleic acid profiling Acute Lymphoblastic Leukemia analysis of 40 human thyroid cancer Xenografts by Genetically Targeted T Robert J . Klein, PhD cell lines reveals cross-contamination cells . Clin Can Res. 2007 Sep 15;13(18): Gold B, et . al Genome-wide association resulting in cell line redundancy and 5426-35 . study provides evidence for a breast misidentification . J Clin Endocrinol Metab . 2008 Nov;93(11):4331-41 . Stephan MT, Ponomarev V, Brentjens cancer risk locus at 6q22 .33 . Proc RJ, Chang AH, Dobrenkov KV, Natl Acad Sci U S A. 2008 Mar Heller G, Sadelain M . T cell encoded 18;105(11):4340-5 2009 CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent William Pao, MD, PhD Ronald DeMatteo, MD tumor rejection . Nat Med. 2007 Dec Yang CH, Yu CJ, Shih JY, Chang YC, Balachandran VP, Cavnar MJ, Zeng 13;(12): 1440-9 . Hu FC, Tsai MC, Chen KY, Lin ZZ, S, Bamboat ZM, Ocuin LM, Obaid H, Huang CJ, Shun CT, Huang CL, Bean Sorenson EC, Popow R, Ariyan C, Rossi Quintas-Cardama A, Yeh RK, Hollyman J, Cheng AL, Pao W, Yang PC . Five F, Besmer P, Guo T, Antonescu CR, D, Stefanski J, Nikhamin Y, Imperato specific EGFR mutations predict Taguchi T, Yuan J, Wolchok JD, Allison G, Sadelain M, Riviere I, Brentjens treatment outcome of stage IIIB/ JP, DeMatteo RP . Imatinib mesylate Multifactorial Optimization of RJ . IV chemotherapy-naive NSCLC potentiates anti-tumor T cell responses Gammaretroviral Gene Transfer into patients receiving first-line gefitinib in gastrointestinal stromal tumor Human T Lymphocytes for Clinical monotherapy . J Clin Oncol. 2008 Jun through the inhibition of Ido. Nat Med. Application . Hum Gen Ther. 2007 1;26(16):2745-53 2011 Aug 28;17(9):1094-100 . Dec18;(12): 1253-60 . Bean J, Brennan C, Shih JY, Riely G, Filippo G . Giancotti, MD, PhD Zakrzewski JL, Suh D, Markley JC, Viale A, Wang L, Chitale D, Motoi N, Okada T, Esposito I, Sinha S, Lopez- Smith OM, King C, Goldberg JM, Jenk Szoke J, Broderick S, Balak M, Chang Lago M, Schiavon G, Abele C, Sapino A, R, Holland AM, Gurbin J, Cabrera-Perez WC, Yu CJ, Gazdar A, Pass H, Rusch V, Inghirami G, Giancotti FG . Loss of Rnd1 J, Brentjens RJ, Lu SX, Rizzuto G, Gerald W, Huang SF, Yang PC, Miller Drives Mammary Tumorigenesis and Sant-Angelo DB, Riviere I, Sadelain M, V, Ladanyi M, Yang CH, Pao W . MET Epithelial-to-Mesenchymal Transition Heller G, Zuniga-Pflucker JC, Lu C, van amplification occurs with or without by Activating . Nat Cell Biol . 2015 Jan; den Brink MR . Tumor Immunotherapy T790M mutations in EGFR mutant lung 17(1): 81–94 . across MHC barriers using allogeneic T tumors with acquired resistance to cell precursors . Immunol Rev. 2014 Jan gefitinib or erlotinib . Proc Natl Acad Sci Andrew Lassman, MD 25;7(1):226-36 . doi: 10 .1111/imr .12142 . U S A . 2007 Dec 26;104(52):20932-7 . Grommes C, Oxnard GR, Kris MG, Miller Gabriela Chiosis, MA, PhD Hans Wendel, MD VA, Pao W, Lassman AB . “Pulsatile” high dose weekly erlotinib for central Solit DB, Chiosis G . Development and Mavrakis KJ, H Zhu, RL Silva, JR Mills, nervous system (CNS) metastases application of Hsp90 inhibitors . Drug J Teruya-Feldstein, SW Lowe, W Tam, from EGFR-mutant non-small cell Discov Today. 2008 Jan 13; (1-2):38-43 . J Pelletier, HG Wendel . Tumorigenic lung cancer . Neuro Oncol . 2011 activity and therapeutic inhibition of Chiosis G, Kang Y, Sun W . Discovery Dec;13(12):1364-9 Rheb GTPase. Genes Dev. 2008 Aug and development of purine-scaffold 15;22(16):2178-88 . Hsp90 inhibitors .Expert Opin Drug Jason S . Lewis, PhD Discov . 2008 Jan 3; (1):99-114 . Holland JP, Caldos-Lopes E, Divilov 2008 V, Longo VA, Taldone T, Zatorska Taldone T, Gozman A, Maharaj R, D, Chiosis G, Lewis JS . Measuring James Fagin, MD Chiosis G, Targeting Hsp90: small- the pharmacodynamic effects of a molecule inhibitors and their clinical Leboeuf R, Baumgartner JE, Benezra novel Hsp90 inhibitor on HER2/neu development . Curr Opin Pharmacol . M, Malaguarnera R, Solit D, Pratilas expression in mice using 89Zr-DFO- 2008 Aug 8;(4):370-4 . C A, Rosen N, Knauf JA, Fagin JA . trastuzumab . PLoS One . 2010 Jan BRAFV600E mutation is associated 25;5(1):e8859 . Xuejun Jiang, PhD with preferential sensitivity to Wang X, Shi Y, Wang J, Huang G, mitogen-activated protein kinase Lebedev AY, Holland JP, Lewis JS . Jiang X . The Crucial Role of the kinase inhibition in thyroid cancer cell Clickable bifunctional radiometal
38 GEOFFREY BEENE CANCER RESEARCH CENTER chelates for peptide labeling . de Pontual L, Yao E, Callier P, Faivre L, and risk assessment . Clin Cancer Res. Chem Commun (Camb) . 2010 Mar Drouin V, Cariou S, Van Haeringen A, 2012 Sep 1;18(17):4485-90 . 14;46(10):1706-8 . Geneviève D, Goldenberg A, Oufadem M, Manouvrier S, Munnich A, Vidigal John H .J . Petrini, PhD Ruggiero A, Holland JP, Lewis JS, JA, Vekemans M, Lyonnet S, Henrion- Foster S, Balestrini A, Petrini JH . Grimm J . Cerenkov luminescence Caude A, Ventura A, Amiel J . Germline Functional interplay of the Mre11 imaging of medical isotopes . J Nucl deletion of the miR-17~92 cluster nuclease and Ku in the response to Med. 2010 Jul;51(7):1123-30 . causes growth and skeletal defects replication-associated DNA damage . in humans . Nature Genetics . PMCID: Mol Cell Biol . 2011 Nov;31(21):4379-89 . Holland JP, Divilov V, Bander NH, PMC3184212 Smith-Jones PM, Larson SM, Lewis Stracker TH, Petrini JH . The MRE11 JS . 89Zr-DFO-J591 for immunoPET 2010 Complex: Starting from the ends . Nat imaging of prostate-specific membrane Rev Mol Cell Biol. 2011 Feb;12(2):90-103 . antigen (PSMA) expression in vivo. J Filippo Giancotti, MD, PhD Nucl Med . 2010 Aug;51(8):1293-300 . Howard I . Scher, MD Huson SM, Acosta MT, Belzberg AJ, Danila DC, Anand A, Sung CC . Ruggiero A, Villa CH, Holland JP, Bernards A, Chernoff J, Cichowski K, MPRSS2-ERG Status in Circulating Sprinkle SR, May C, Lewis JS, Gareth Evans D, Ferner RE, Giovannini Tumor Cells as a Predictive Biomarker Scheinberg DA, McDevitt MR . Imaging M, Korf BR, Listernick R, North KN, of Sensitivity in Castration-Resistant and treating tumor vasculature Packer RJ, Parada LF, Peltonen J, Prostate Cancer Patients Treated With with targeted radiolabeled carbon Ramesh V, Reilly KM, Risner JW, Schorry Abiraterone Acetate.Eur Urol. 2011 nanotubes . Int J Nanomedicine. 2010 EK, Upadhyaya M, Viskochil DH, Zhu Y, Nov;60(5):897-904. Oct 5;5:783-802 . Hunter-Schaedle K, Giancotti, FG . Back to the future:Proceedings from the 2010 Heneweer C, Holland JP, Divilov V, Danila DC, Fleisher M, Scher HI . NF Conference . Am J Med Genet A. 2011 Circulating tumor cells as biomarkers in Carlin S, Lewis JS . Magnitude of Feb;155A(2):307-21 enhanced permeability and retention prostate cancer . Clin Cancer Res. 2011 Jun 15;17(12):3903-12 . (EPR) effect in tumors with different Cooper J, Li W, You L, Schiavon phenotypes – 89Zr-albumin as a G, Pepe-Caprio A, Zhou L, Ishii R, Danila DC, Pantel K, Fleisher M . model system . J Nucl Med . 2011 Giovannini M, Hanemann CO, Long SB, Circulating tumors cells as biomarkers: Apr;52(4):625-633 Erdjument-Bromage H, Zhou P, Tempst progress toward biomarker P, Giancotti FG . Merlin/NF2 functions Dimitar B . Nikolov, PhD qualification . Cancer J. 2011 Nov- upstream of the nuclear E3 ubiquitin Dec;17(6):438-50 . Seegar TC . Tie1-Tie2 interactions ligase CRL4DCAF1 to suppress mediate functional differences oncogenic gene expression . Sci Signal. Olmos D Brewer D, Clark J . Blood between angiopoietin ligands . Mol Cell. 2011 Aug 23;4(188):pt6 . mRNA expression signatures can 2010 Mar 12;37(5):643-55 . stratify castration resistant prostate Kalamarides M, Acosta MT, Babovic- cancer patients and predict poor Andrea Ventura, MD, PhD Vuksanovic D, Carpen O, Cichowski K, outcome . Lancet Oncol. 2012 Nov; Mu P, Han YC, Betel D, Yao E, Squatrito Evans DG, Giancotti FG, Hanemann 13(11): 1114–1124 . M, Ogrodowski P, de Stanchina E, CO, Ingram D, Lloyd AC, Mayes DA, Messiaen L, Morrison H, North K, Packer D’Andrea A, Sander C, and Ventura A . 2011 (2009) . Genetic dissection of the miR- R, Pan D, Stemmer- Rachamimov A, Upadhyaya M, Viskochil D, Wallace -17~92 cluster of microRNAs in Myc- Michael Berger, PhD induced B-cell lymphomas . Genes Dev MR, Hunter-Schaedle K, Ratner N . Iyer G, Hanrahan AJ, Milowsky MI, 23, 2806-2811 . PMCID: PMC2800095 Neurofibromatosis 2011: a report of the Children’s Tumor Foundation annual Al-Ahmadie H, Scott SN, Janickraman Ventura A, and Jacks T . (2009) . meeting . Acta Neuropathol. 2012 M, Priun M, Sander C, Socci ND, MicroRNAs and cancer: short RNAs go Mar;123(3):369-80 . Ostrovnaya I, Viale A, Heguy A, a long way . Cell 136, 586-591 . PMCID: Peng L, Chan TA, Bochner B, Bajorin PMC3910108 Li W, Cooper J, Karajannis MA, DF, Berger MF, Taylor BS, Solit DB . Giancotti FG . Merlin: a tumour Defining a Genetic Basis for Everolimus Yang JS, Phillips MD, Betel D, Mu P, suppressor with functions at the cell Sensitivity through Whole-Genome Ventura A, Siepel AC, Chen KC, Lai EC cortex and in the nucleus.EMBO Rep. Sequencing of a Clinical Outlier . (2011) . Widespread regulatory activity 2012 Mar;13(3):204-15 . Science. 2012 Oct 12; 338(6104):221 . of vertebrate microRNA* species . Rna 17, 312-326 . PMCID: PMC3022280 Ladanyi M, Zauderer MG, Krug LM, Catalanotti F, Solit DB, Pulitzer MP, Ito T, McMillan R, Bott M, Giancotti Berger MF, Scott SN, Iyriboz T, Yao E, and Ventura A . (2011) . A new role FG . New strategies in pleural Lacouture ME, Panageas KS, Wolchok for miR-182 in DNA repair . Molecular mesothelioma: BAP1 and NF2 as novel JD, Carvajal RD, Schwartz GK, Rosen cell 41, 135-137 . PMCID:21255724 targets for therapeutic development N, Chapman PB . Phase II trial of MEK
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Dinshaw Patel, PhD Yang H, Patel DJ . Inhibition mechanism of an anti-CRISPR suppressor targeting SpyCas9 . Mol Cell. 2017 Jul 6;67(1):117- 127 .e5 .2
Stewart Shuman, MD, PhD Remus BS, Goldgur Y, Shuman S . Structural basis for the GTP specificity of the RNA kinase domain of fungal tRNA ligase . Nucleic Acids Res . 2017 Dec 15;45(22):12945-12953 .
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ADMINISTRATION
Christie Park Sr . Project Portfolio Manager Geoffrey Beene Cancer Research Center Collaborative Research Centers Parkc1@mskcc .org 646-888-3241
Ederlinda Paraiso, MPA Senior Director, Research Operations Collaborative Research Centers Human Oncology & Pathogenesis Program paraisoe@mskcc .org 646-888-2132
42 GEOFFREY BEENE CANCER RESEARCH CENTER Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Image by Kevin O’Rourke of the Lowe lab.
10 YEAR REPORT | 2007–2017 4 Geoffrey Beene Cancer Research Center 1275 York Ave. Box 20 New York, NY 10065
1 GEOFFREY BEENE CANCER RESEARCH CENTER