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Principal Investigator: SAMUEL SINGER
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $2,375,406
Funding agency: National Cancer Institute
ABSTRACT
The long-term goal of the SPORE in Soft Tissue Sarcoma is to reduce the morbidity and mortality from soft tissue
sarcoma by developing therapies targeted to specific molecular, genetic, epigenetic, and signaling pathway
alterations or specific sarcoma type and subtype. To pursue this, we will focus our efforts on 4 broad translational
research objectives: 1. Define shared and type-specific molecular mechanisms of sarcomagenesis to identify
new rational therapeutic targets; 2. Define mechanisms of resistance to targeted and immune therapies; 3.
Clinically validate new therapeutic targets and treatments in soft tissue sarcoma patients and facilitate the
development, recruitment, and application of clinical trials that serve both the adult and pediatric populations; 4.
Discover specific molecular alterations and new biomarkers that predict outcome and response to targeted and
immune therapy. To achieve these goals, we have marshaled an integrated, multidisciplinary group of basic and
clinical investigators, all armed with a unique resource, a clinicopathologic and outcomes database prospectively
collected over a 41-year period. This database now contains data for over 14,990 patients treated for soft tissue
sarcoma at MSK. The database is linked to an extensive sarcoma tissue and blood bank, which in turn is linked
to an extensive multi-platform molecular genetic and epigenetic dataset and a collection of primary sarcoma cell
lines and patient-derived xenograft (PDX) models of human sarcoma. The SPORE is structured around 3
research projects, 4 cores, and career enhancement and developmental research programs. Each research
project focuses on two or more of the 4 broad translational research goals listed above. RP1 (GIST
Pathogenesis) aims to elucidate the molecular mechanisms and role of MAX/MGA/MYC genetic perturbations
in driving GIST pathogenesis and to develop novel biomarkers and predictive models to improve patient risk
assessment and selection for adjuvant therapy. RP2 (Targeting Hippo Dependence) seeks to characterize the
role of the Hippo pathway and the eIF4FA complex in genetically complex sarcomas, test the efficacy and toxicity
of a new eIF4A inhibitor, TDI-7663, and develop biomarkers of innate and acquired resistance to eIF4A inhibition.
RP3 (Synovial Sarcoma Vulnerabilities) seeks to identify novel epigenetic vulnerabilities and immuno-oncologic
strategies in synovial sarcoma and potential synergies between them by discovering H3K36 methylation-related
dependencies on specific epigenetic regulators, preclinical development of T cells genetically engineered to
express a T cell receptor against the SS18::SSX public neoantigen, and a conceptually innovative clinical trial of
a multivalent mRNA vaccine encoding the SS18::SSX(1/2) junction sequence and the major cancer-testis
antigens in synovial sarcoma.
Terms: <21+ years old><Adjuvant Therapy><Adult><Adult Human><Animal Cancer Model><Automobile Driving><Biological><Biological Markers><Biology><Blood Banks><Body Tissues><CCSG><Cancer Center Support Grant><Cancers><Cell Line><CellLine><Childhood><Clinic><Clinical><Clinical Investigator><Clinical Research><Clinical Study><Clinical Trials><Collaborations><Collection><Combined Modality Therapy><Complex><Core Facility><Data><Data Bases><Data Set><Databases><Dedications><Dependence><Development><Diagnosis><Disease><Disorder><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Experimental Therapies><Generalized Growth><Genetic><Goals><Grant><Growth><Heterograft><Heterologous Transplantation><Histologic><Histologically><Human><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Infrastructure><Institution><Investigation><Investigational Therapies><Investigational Treatments><Link><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Neoplasms><Malignant Soft Tissue Neoplasm><Malignant Tumor><Medical Informatics><Methylation><Modeling><Modern Man><Molecular><Molecular Genetics><Morbidity><Morbidity - disease rate><Multimodal Therapy><Multimodal Treatment><Natural History><Operative Procedures><Operative Surgical Procedures><Outcome><PDX model><Pathogenesis><Pathologic><Pathway interactions><Patient Care><Patient Care Delivery><Patient derived xenograft><Patient risk><Patients><Population><Prognosis><R-Series Research Projects><R01 Mechanism><R01 Program><RNA vaccine><RNA-based vaccine><Research><Research Grants><Research Project Grants><Research Projects><Research Resources><Research Specimen><Resistance><Resources><Risk Assessment><Role><SYS-TX><Sarcoma><Scientist><Signal Pathway><Soft tissue sarcoma><Specimen><Standardization><Strains Cell Lines><Structure><Surgical><Surgical Interventions><Surgical Procedure><Synovioma><Systemic Therapy><T-Cell Antigen Receptors><T-Cell Receptor><Therapeutic><Tissue Banks><Tissue Collection><Tissue Growth><Tissue repository><Tissues><Toxic effect><Toxicities><Translating><Translational Research><Translational Science><Xenograft><Xenograft procedure><Xenotransplantation><adjuvant treatment><adulthood><advanced disease><advanced illness><animal model development><bio-markers><biologic><biologic marker><biomarker><biomarker identification><biomarker validation><cancer/testis antigen><care for patients><care of patients><career><caring for patients><clinical applicability><clinical application><clinical care><combination therapy><combined modality treatment><combined treatment><computer based prediction><cultured cell line><data base><design><designing><develop therapy><developmental><driving><efficacy testing><engineered T cells><epigenetically><experience><experimental therapeutic agents><experimental therapeutics><genetically engineered T-cells><human model><identification of biomarkers><identification of new biomarkers><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><inhibitor><innovate><innovation><innovative><insight><inter-institutional><intervention development><mRNA vaccine><mRNA-based vaccine><malignancy><malignant soft tissue tumor><marker identification><marker validation><model of human><mortality><multi-modal therapy><multi-modal treatment><multidisciplinary><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><new drug target><new druggable target><new marker><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel biomarker><novel drug target><novel druggable target><novel marker><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><outcome prediction><pathway><patient derived xenograft model><patient population><pediatric><pre-clinical development><preclinical development><predictive biomarkers><predictive marker><predictive modeling><predictive molecular biomarker><prognostication><programs><prospective><recruit><resistance mechanism><resistant><resistant mechanism><response><risk selection><social role><specific biomarkers><surgery><synergism><synovial cell sarcoma><synovial sarcoma><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><therapy development><transgenic T- cells><translation research><translational investigation><treatment development><tumor><xeno-transplant><xeno-transplantation>