Sloan-Kettering Inst Can Research

NIH Research Projects · FY 2025 · 2007-09

PROJECT ABSTRACT microRNAs (miRNAs) are an abundant class of small regulatory RNAs that typically derive from stepwise cleavages of hairpin transcripts by the Drosha and Dicer RNase III enzymes. The resulting mature miRNAs mediate extensive networks of post- transcriptional regulation, and are implicated in a variety of diseases including cancer. This proposal extends our long-standing commitment to understand atypical and regulated strategies for microRNA biogenesis and function. We build on long-standing research efforts in the lab, as well as very recent developments and knowledge, to propose three parallel directions on miRNA regulation. First, we will dissect regulatory interactions within a miRNA operon, by which an optimal miRNA hairpin can benefit the biogenesis of a neighboring suboptimal member (miRNA cluster assistance). Second, we will uncover how multiple RNA quality control strategies suppress the biogenesis of adventitious miRNA hairpin substrates derived from splicing (mirtrons and splicing- derived, structured RNAs). These may play broad and unrecognized roles in regulating host gene splicing. Third, we introduce data on a novel repressor of miRNA accumulation and function (Alas), and endeavor to place its activity Our studies utilize a wide variety of experimental and computational techniques, and employ both Drosophila and mammalian systems. The data and insights gained from this grant will extend fundamental knowledge on small RNA pathways, have potential to help interpret genetic diseases involving miRNA dysfunction, and may eventually underlie improved methods for therapeutic RNAi.

NIH Research Projects · FY 2026 · 2007-07

PROJECT SUMMARY/ABSTRACT Lung cancer remains the leading cause of cancer related deaths in the US. In 2021, 134,592 people died from lung cancer, comprising 22% of all cancer-related deaths. The morbidity of lung cancer surpasses that of breast, prostate, and colorectal cancers combined, underscoring the critical importance of elucidating its molecular underpinnings and developing effective therapeutic strategies. Lung cancer is a multifaceted disease with diverse pathological and molecular subtypes, each with its own distinct biological features that necessitate a tailored therapeutic approach. Over the course of nearly two decades, the MSK Lung Cancer P01 has focused its efforts on understanding the molecular drivers of lung cancer and the mechanisms that impart on lung cancer cells the ability to metastasize to distant sites. Inherent in its mission has been the discovery of novel therapeutic targets, or the discovery of novel therapies for well-defined targets, always aiming to improve the outcomes of patients with lung cancer. The realization that targeted therapies only rarely, if ever, lead to cures has informed the longitudinal objective to better understand the determinants of sensitivity and resistance, with a particular emphasis on the mechanisms leading to rapid adaptation or treatment tolerance, as well as the genetic events that drive acquired resistance. Given that clinical outcomes are determined by biological processes, we hypothesize that unraveling the mechanisms of intracellular signaling and metastasis in lung cancers will uncover novel therapeutic targets, significantly improving outcomes for individuals battling this disease. Our 4 research projects and 3 cores build on a longstanding iterative and highly synergistic research program that integrates clinical observations with laboratory discoveries to identify targets for therapies in lung cancers. Project 1 identifies mediators of metastasis and immune evasion that can serve as targets for intervention. Project 2 uses novel therapeutics to interrogate the role of the mutant KRAS nucleotide cycle in the biological features of lung cancer with a focus on cancer cell dormancy and therapeutic resistance. Project 3 elucidates signaling pathways that contribute to cancer cell survival during MAPK signaling inhibition, seeking to identify improved combination therapies. Project 4 investigates the role of extrachromosomal DNA amplification in the evolution of lung cancer and its role in mediating resistance to therapy. The Models, Profiling and Pathology (MPP) Core crystallizes nearly two decades of experience in precise pathologic characterization and the modeling of lung cancers in animal models. The Computational Biology and Bioinformatics (CBB) Core provides rigorous computational analysis and ensures consistency in biostatistical analyses. The Administrative Core has created an organizational structure that assures integration and interaction by facilitating communication and dissemination of findings and providing a forum for the investigators to interact with each other and the Scientific Advisory Committees to accelerate progress.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY/ABSTRACT The mission of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is to “evaluate promising therapeutic approaches in multi-institutional clinical trials to improve the outcomes of blood and bone marrow transplantation and other cellular therapies for patients facing life-threatening blood disorders.” Memorial Sloan Kettering Cancer Center (MSK) is an NCl-designated Comprehensive Cancer Center with one of the largest BMT programs in the country. The BMT program at MSK, founded in 1973 and divided into pediatric and adult services, is a FACT-accredited program for both hematopoietic cell transplant (HCT) and immune effector cell (IEC) therapy. MSK has been a Core Clinical Center (CCC) of the BMT CTN since its inception. Dr. Perales (Service Chief, Adult BMT; PI, MSK BMT CTN), Dr. Giralt (Deputy Head, Division of Hematologic Oncology; Co- I), Dr. Boelens (Service Chief, Pediatric BMT and Cell Therapy; Co-I), and all members of the Adult and Pediatric BMT and Cellular Therapy Services consider participation in the BMT CTN an integral part of their mission. In this proposal, we detail our ongoing commitment to the success of the Network through an oversight structure that includes a BMT CTN MSK Executive Committee, a BMT CTN Protocol Management Team, and a BMT CTN Internal Advisory Board, which leverage senior leadership of the Division of Hematologic Oncology and Pediatric BMT Service as well as outstanding scientists and investigators at MSK. As part of our continued commitment to Network leadership, we propose a multicenter phase II clinical trial in adults and children with severe sickle cell disease (SCD), in which we will evaluate a pharmacologic immunosuppressive strategy prior to reduced toxicity myeloablative mismatched unrelated (MMUD) HCT, using post-transplant cyclophosphamide (PTCY)- based graft-versus-host disease (GvHD) prophylaxis. The trial will employ a novel platform to mitigate the risk of graft failure in a patient population at high risk for allograft rejection and treatment-related complications, as well as pharmacokinetic-based models to guide individualized dosing of fludarabine, busulfan, and rabbit ATG for optimal drug exposure. We propose 3 specific aims: (1) Demonstrate MSK has the clinical and translational expertise, novel cell and gene therapy capabilities, and early- and late-phase trial experience to fulfill the obligations of a BMT CTN CCC and advance the Network’s mission and goals; (2) Complete a phase II study in which patients with severe SCD will receive an HCT from an MMUD donor with PTCY-based GvHD prophylaxis (the primary endpoint will be to estimate primary graft failure at 1-year post-HCT); and (3) Describe how MSK’s operational and scientific approaches to conducting HCT trials will support the mission and activities of the BMT CTN. The proposed study is highly relevant to the BMT CTN, as it addresses an unmet need for a well-tolerated alternative donor platform with stable engraftment in patients with SCD, and is in line with the goal of the BMT CTN to prioritize clinical studies that advance HCT approaches for non-malignant blood diseases.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY/ABSTRACT Over the past 20 years, the SPORE in Prostate Cancer at Memorial Sloan Kettering Cancer Center has made significant advances in prostate cancer research and treatment, using the evolving mechanistic understanding of the drivers of tumor growth to improve patient management across the clinical spectrum of the disease. Applying a biomarker- based, risk-adapted approach, our work has led to the development of new diagnostic blood tests and prognostic models to distinguish indolent from clinically significant cancers, the discovery of new therapeutic targets, their validation in preclinical models, and the successful development of drugs directed to them in trials designed according to the recommendations of the Prostate Cancer Working Group 3. Our efforts have impacted clinical practice worldwide. The overall objectives of our SPORE are: 1) to interrogate the genomics and molecular pathways relevant to prostate cancer progression, 2) to identify and validate clinically relevant biomarkers, and 3) to develop novel agents and therapeutic strategies. In the next 5 years, we propose 3 research projects to address new clinical challenges that have emerged in the context of the evolving landscape of prostate cancer. For localized disease, the challenges are to identify patients at high risk for metastasis and death and to determine optimal upfront treatment to improve cure. To address this, RP-1 will determine germline and somatic genomic features associated with disease progression in high-risk localized disease and RP-2 will determine the role of signaling from the prostate microenvironment in resistance to androgen-deprivation therapy and determine the efficacy of targeting these signals. For patients with metastatic disease, the widespread adoption of potent next-generation androgen receptor (AR) signaling inhibitors has changed the landscape of prostate cancer, highlighting the need for therapeutic strategies for cancers that develop AR independence. Previously our SPORE characterized the AR-independent “lineage plasticity” disease state as driven by TP53 and RB1 loss. RP-3 now seeks to better define the genomic heterogeneity inherent in this disease state and evaluate novel therapeutic strategies. PARP inhibitors were recently approved for metastatic cancers with DNA damage repair mutations, but the response rate is only ~50%. RP-1 will define the genomic context that predicts for PARP inhibitor response.

NIH Research Projects · FY 2025 · 1999-09

PROJECT SUMMARY/ABSTRACT Since its inception in 1999, the primary objective of the T32 Urologic Oncology Research Training Program at Memorial Sloan Kettering Cancer Center (MSK) has been to train select urologists for productive careers as surgeon-scientists in translational research in urologic oncology. Dedicated research training in urologic oncology is essential to the mission of the National Cancer Institute (NCI) to reduce morbidity and mortality from genitourinary cancers, which cause about 10% of all cancer-related deaths in the United States and which are expected to rise steadily in incidence as the population ages. To achieve our primary objective, we seek to continue our interactive, multidisciplinary research training strategy that integrates the following: (1) a multidisciplinary faculty of basic, clinical, and translational researchers spanning the disciplines of surgery, medicine, cancer biology and therapeutics, molecular pathology and genetics, immunotherapy, molecular radiology, biostatistics and epidemiology, computational oncology, biomarkers, and health services and health disparities research; (2) an intensive mentored research practicum tailored to the T32 trainee’s research interests and goals; (3) a core curriculum of required didactic and discussion-based courses to enhance the quality of the hands-on research training; (4) structured career development workshops in grant writing and career development awards; and (5) elective activities that will allow T32 trainees to further immerse themselves in the world of cancer research and to network with peers and established leaders. We continue to enhance the program by revising and adding new elements to these 5 components of our training strategy, as well as maintaining an outstanding cadre of program faculty mentors who are selected based on research relevance and productivity, qualifying funding, and quality of mentoring. Each year, 2 highly committed postdoctoral trainees from the Urologic Oncology Fellowship Program at MSK are selected for the T32 Urologic Oncology Research Training Program. They must have an MD, must have completed residency training in urology, and must be board-eligible urologists. These 2 trainees are supported by this T32 training grant during 2 years dedicated to urologic oncology research training, with appointment to the 2nd year contingent on suitable progress. At the completion of their training, graduates of theT32 Urologic Oncology Research Training Program are expected to be attractive candidates for junior faculty appointments at research-focused academic organizations. In the past 15 years, 87% of T32 trainee graduates have matriculated to faculty positions at academic institutions and are engaged in laboratory and/or clinical research aimed at understanding and overcoming genitourinary cancers.

NIH Research Projects · FY 2026 · 1997-01

ABSTRACT Memorial Sloan Kettering Cancer Center (MSK) is a free-standing NCI-designated Comprehensive Cancer Center dedicated to improving the standards of cancer treatment, prevention, and control. MSK’s research programs are grouped into three categories: Basic Research (Regulation of Cell Behavior, Developmental and Stem Cell Biology, Genomic Integrity, and Structural and Chemical Biology); Bridge Research (Cancer Biology and Experimental Pathology, Experimental Therapeutics, Immunology and Transplantation, and Imaging and Radiation Sciences); and Patient-Oriented Research (Clinical Research and Population Sciences Research). The programs are designed to optimize the use of a large patient population and an extensive, multi-disciplinary staff of clinical and laboratory-based investigators. MSK seeks to encourage the application of scientific discoveries in a way that advances the prevention, detection, diagnosis, and treatment of the many forms of cancer that are relevant to the population in our catchment area. Scientific work in the 10 research programs depends on services provided by 20 core facilities. Over the next five years, MSK will continue to enhance its clinical and research facilities and its research and training programs in emerging research areas. We are requesting funding from the Cancer Center Support Grant (CCSG) to partially defray CCSG member usage fees for the 20 core facilities. Support is also requested for Community Outreach and Engagement initiatives, and for Clinical Protocol and Data Management and Cancer Center Administrative Core personnel. We request Developmental Funds to support cross-disciplinary pilot project research and faculty recruitment in high-priority areas identified by Center leadership.

NIH Research Projects · FY 2026 · 1992-09

Abstract Regulatory T (Treg) cells, serving as life-long guardians of the immune system, are distinguished by constitutive expression of transcription factor (TF) Foxp3, playing a critical role in their differentiation, function and fitness. Our previous studies showed that Foxp3 expression is stable in fully differentiated Treg cells, while recently generated Treg cells can lose Foxp3 expression. Furthermore, Treg cell functionality and Foxp3 expression can be compromised in severe disease settings. Although the unresolved issue of resilience vs. vulnerability of Foxp3-dependent Treg functional program is of major basic and clinical significance, presently the role for Foxp3 protein in functional and transcriptional program of differentiated Treg cells in vivo remains unknown. Our preliminary studies of induced degradation of Foxp3 protein in vivo using novel optimized Foxp3 auxin-degron model raise the possibility of a remarkable resilience of ‘mature’ Foxp3-dependent Treg cell function and gene regulatory network (GRN) in adulthood, but not of ‘immature’ ones in early life. Based on our published and preliminary studies we hypothesize that during Treg differentiation, initially vulnerable Foxp3 dependent GRN approaches a temporally self-sustained (attractor) state over a surprisingly long timescale due to a requirement for persistent Foxp3 activity for this ‘maturation’. Upon assumption of this state, its resilience ensures extended stability of Treg function even upon the loss of Foxp3 expression. In this proposal we will test this hypothesis by elucidating Foxp3 GRN underlying Treg cell function, dynamics of its establishment and its resilience to Foxp3 loss in physiologic and inflammatory settings using genetic gain- and loss-of-function approaches. The following Specific Aims will be pursued: 1) elucidate a role of Foxp3 in the functional program of Treg cells and its resilience in early life and adulthood under physiologic conditions and upon inflammatory challenges; 2) investigate dynamic of Foxp3-dependent regulation of gene expression and chromatin in Treg cells using chemogenetic gain- and loss-of-function approaches; 3) elucidate mechanisms of resilience of Foxp3-dependent gene expression and functional programs using CRISPR and CRISPRi/a Perturb-seq approaches. These studies will provide mechanistic, gene-regulation level framework for understanding of Treg cell differentiation and function in health and disease and inform novel approaches for therapeutic targeting of Treg cells and development of adoptive Treg cell therapies for autoimmune and inflammatory disorders.

NIH Research Projects · FY 2025 · 1985-02

ABSTRACT The Clinical Scholars Biomedical Research Training Program (CSTP) at Memorial Sloan Kettering Cancer Center (MSK) provides a mentored laboratory training experience in cancer research for outstanding MD and MD/PhD residents/fellows who are emerging clinician-scientists. The CSTP is unique among training programs at MSK since it prepares clinically active investigators, from a range of research disciplines, to pursue research across the translational research spectrum. The goal of the program is to prepare highly qualified physician- scientists for an independent research career at the interface of cancer biology and clinical research. The Clinical Scholars in CSTP are trained by principal investigators with an exceptionally broad range of scientific interests spanning most areas of modern cancer research. Out of 42 preceptors, 27 (67%) are physician- scientists who excel at laboratory research, clinical research, and academic clinical practice and represent strong role models for young investigators pursusing careers in oncology research. The CSTP consists of a structured and cohesive two-year curriculum that combines laboratory research, didactic course work in cancer biology, bioinformatics and computational training, and career development workshops. Trainees have access to all resources of MSK, an instituion where basic, translational, and clinical research activites take place in close proximity in a highly collaborative research environment. The research areas of principal emphasis include: 1) human cancer biology, mouse models of cancer, genetics, epigenetics and molecular pathology; 2) drug development and mechanism-based therapeutics; 3) signaling pathways involved in control of cell proliferation; 4) regulatory pathways involved in developmental biology and cell differentiation; 5) cell-cell interactions, adhesion and protein targeting; 6) tumor immunology, immunotherapy and transplantation biology. The CSTP has had a long and successful training history with nearly all of its graduates continuing in highly productive biomedical research careers. Thus, the CSTP has had signficant impact in meeting the national need for physician-scientists who can play leading roles in translating basic discoveries in cancer biology into clinical practice.

NIH Research Projects · FY 2025 · 1984-09

The Surgical Oncology T32 research training program at Memorial Sloan Kettering Cancer Center (MSK) is designed to provide qualified trainees with 2-year training in laboratory-based, translational, or clinical research. Our T32 supports 6 postdoctoral (MD or MD/PhD) trainees per year, most of whom enter this program after 2 to 3 years of surgical residency training. This renewal application requests funding for years 36 to 40 to continue to provide 2 years of full-time research training to trainees interested in a career as independent surgeon–scientists with a focus on cancer. Our Surgical Oncology T32 program focuses on 3 oncology research themes that represent the full spectrum of cancer care: 1) Cancer Diagnostics, Genetics, & Tumor Microenvironment; 2) Cancer Immunology; and 3) Cancer Outcomes and Survivorship. This thematic organization enables us to provide training in all aspects of surgical oncology research, ranging from basic science to cancer treatment outcomes and epidemiology. The T32 Program Faculty members have research programs that emphasize or involve translational research focusing on one of these 3 themes. They have primary appointments in Surgery, Neurosurgery, Medicine, Radiation Oncology, Medical Physics, Epidemiology & Biostatistics, Psychiatry & Behavioral Sciences, Cancer Biology & Genetics, Computational & Systems Biology, Immunology, Molecular Biology, and Molecular Pharmacology. Our program curriculum combines mentored research training tailored to the research interest of the trainee with required and elective courses to provide an intensive research experience in (1) hypothesis formulation, (2) experimental design, (3) data analysis, (4) laboratory/project management, (5) oral and written presentation, and (6) grant writing and other career development skills. The overall training objective is to provide each T32 trainee with a broad perspective of the range of approaches, concepts, and opportunities in cancer research and prepare the next generation of surgeon–scientists for their chosen career path in oncology in academic, government, non-profit, industrial, or other sectors. Since its inception in 1984, the Surgical Oncology T32 has trained 102 surgeon–scientists, most of whom have transitioned to successful careers in academic surgical oncology.

NIH Research Projects · FY 2025 · 1984-05

Overview: Over the past 41 years, the training efforts of the Memorial Sloan Kettering (MSK) Cancer Center’s Department of Psychiatry & Behavioral Sciences have been greatly facilitated by the institutional research training grant, Psychosocial Palliative and Community Research in Cancer (T32 CA009461). This grant, first awarded in 1984, was the first in this country to provide support for research training in psychiatry and pain in oncology. Based on the successful establishment and maintenance of a productive research training program, this training grant has received successive five-year renewals since 1989, making it the oldest continuous research training program in the country solely dedicated to psychiatric issues in cancer. Now in its 41st year, this NCI-funded T32 program has successfully trained 134 postdoctoral and 35 predoctoral investigators in psycho-oncology (a total of 169 former/current trainees). Approximately 75% of our former fellows have established productive scientific careers with research positions mostly as faculty in NCI-designated comprehensive cancer centers but also academic medical centers, universities, and in industry. We currently maintain 6 postdoctoral slots and 2 predoctoral slots (and per NCI policy changes, will reduce to 6 slots total in 9/1/2026). There are now 16 Primary Research Mentors and 21 Other Mentors who provide depth and breadth in psycho-oncology research and constitute our Participating Research Training Faculty. Goals: Our overarching programmatic goals are to strengthen the psycho-oncology workforce and expand capacity to address ongoing psychosocial challenges across the entire cancer control continuum. Our overall objective is to enable the next generation of social and behavioral science researchers to address the intrapersonal, interpersonal, and sociocultural processes that contribute to behavioral risk factors for cancer, the adoption of cancer screening and early detection strategies, as well as treatment initiation and adherence. Specific Objective 1: To recruit highly qualified postdoctoral trainees to receive outstanding research training and to provide mentoring necessary for the development of new independent investigators well prepared for academic research careers in psycho-oncology. Specific Objective 2: To provide research training and mentoring for promising predoctoral fellows thereby encouraging them to pursue academic careers in psycho-oncology. Specific Objective 3: To maintain a strong didactic curriculum designed to provide pre-and postdoctoral fellows with a solid foundation in relevant literature, theoretical frameworks, research design and professional development skills needed to become independent investigators. Specific Objective 4: To monitor, evaluate, and continuously refine each component of the training program by examining the quality of recruitment strategies, faculty mentorship, didactic curriculum, trainee productivity, and early career development.

NIH Research Projects · FY 2026 · 1977-09

PROJECT SUMMARY/ABSTRACT The goal of the T32 Investigational Cancer Therapeutics Training Program (ICTTP) at Memorial Sloan- Kettering Cancer Center (MSK) is to provide highly select physician trainees in hematology and medical oncology with the research training necessary for successful careers in the translation of cancer biology discoveries into novel molecular, immune, or cell-based therapeutics, and those experimental treatments into clinical trials that have the potential to change standards of care. The T32 ICTTP program accomplishes this goal by combining a comprehensive mentored training program, an extensive didactic curriculum in clinical and translational research methodologies, and experiential programs supporting development of the critical career skills (e.g. collaboration, research management, grant writing) necessary for academic success. Each year, we select 4 highly committed postdoctoral trainees from the pool of outstanding physicians at MSK who have completed at least 3–4 years of both internal medicine and oncology/hematology clinical training. T32 trainees are then supported for 2 consecutive years so that ≥ 80% of their time and effort is dedicated to research training. Based on individual research interests and career goals, ICTTP trainees develop either a laboratory- based or a prospective clinical research program with guidance from their mentors, who are established, independently funded investigators. These programs involve extensive collaborative scientific interactions, including additional clinical scientist mentorship for laboratory-based trainees and laboratory scientist mentorship for clinical research trainees. The T32 ICTTP supplements mentored research training with a curriculum of symposia, workshops, in-person didactic programs, and online courses that prepares trainees to conduct successful, independently supported research at the faculty level. We continue to enhance the program by revising and adding new educational programs in clinical research methodology, research ethics, national and international clinical trial requirements and conduct, as well as hands-on writing workshops for grants and protocols. Participating faculty mentors are continually reviewed and selected based on strict criteria for research productivity, independent funding, and quality of mentoring. T32 ICTTP mentors have research programs on cancer genetics, genomics, epigenetics, signal transduction, and metabolism; tumor immunology and immunotherapy; drug and cellular therapeutic development; and tumor evolution, using systems and computational approaches. Projects conducted by T32 ICTTP trainees in the proposed funding period continue similar themes in cancer therapeutics research. All T32 ICTTP graduates from the last funding cycle are continuing in faculty or pharmaceutical industry positions in cancer research, with the majority having secured independent research funding. This success continues the ICTTP's 40-year track record of training leaders in cancer therapeutic development and translational research.

NIH Research Projects · FY 2026 · 1977-07

Since 1977, the Memorial Sloan Kettering Cancer Center (MSK) Summer Research Fellowship Program has empowered approximately 1,500 first- and second-year U.S. medical students to contribute to cutting-edge cancer research. This unique cancer education initiative immerses 30 participants in laboratory and clinical investigations under the direct mentorship of MSK's clinical faculty. Students gain invaluable experience by collaborating with mentors in both basic and clinical research, attending a wealth of didactic programs, mastering the integration of scientific principles with clinical applications, and sharing their research with audiences within a premier academic medical center. The MSK Summer Research Fellowship Program helps a significant challenge in the field of oncology. The need for more oncologists, especially physician-scientists: A significant shortfall in the oncology workforce, particularly among physician-scientists, threatens to impede the progress of cancer research and patient care. This escalating issue, highlighted in 2014 reports by the American Society of Clinical Oncology (ASCO) and the National Institutes of Health (NIH) | (.gov), stems from an aging population and a diminishing pool of experienced professionals. To overcome this critical challenge, our program seeks to foster student interest in oncology research careers.