Skip to Content
Translational Research Program (TRP)
Contact CIP
Show menu
Search this site
Last Updated: 10/10/18

SPORE in Soft Tissue Sarcoma

Memorial Sloan-Kettering Cancer Center

Principal Investigator: Samuel Singer, MD, FACS

Principal Investigator Contact Information

Samuel Singer, MD, FACS
Surgical Oncologist
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
H1203
New York, New York 10065
Phone: (212) 639-2940
Email: singers@mskcc.org

Overview

The SPORE in Soft Tissue Sarcoma was established 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. Our research is focused 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 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 therapy.

Our team is an integrated, multidisciplinary group of basic and clinical investigators, armed with a unique resource, a clinicopathologic and outcomes database prospectively collected over 35 years. This database contains data for over 11,840 patients treated for soft tissue sarcoma at MSKCC and is linked to an extensive sarcoma tissue/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 mouse xenograft models of human sarcoma.

The SPORE’s 4 research projects include:

Project 1: Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)

Co-leaders: Cristina Antonescu, MD; Ping Chi, MD, PhD

This project aims to identify new therapeutic targets and develop new treatment strategies for gastrointestinal stromal tumors (GISTs) that do not respond to the major targeted therapy, imatinib. While most GISTs are driven by mutations in the targets of imatinib, Kit and PDGFRA, another subset, mostly affecting pediatric patients, lacks these mutations and does not respond to this drug. We aim to develop therapeutic strategies that modulate another protein required for the survival of both imatinib-sensitive and -resistant GISTs, ETV1. ETV1 is a master regulator of the lineage specification and normal development of the cells from which GIST arises. We will investigate the regulation of ETV1 and develop novel therapeutic strategies targeting ETV1 protein stability using pre-clinical GIST models that we will develop during this project period.

Project 2: CDK4 Inhibitor Therapy: Identification of Biomarkers and Combination Therapies for Liposarcoma

Co-leaders: William Tap, MD; Andrew Koff, PhD

This project seeks to identify a pre-treatment biomarker predictive of prolonged clinical response to CDK4 inhibitor (CDK4i) therapy in well-differentiated/ dedifferentiated liposarcoma (WD/DDLS) and to find drugs that can be combined with CDK4is to synergistically augment response. CDK4is have yielded promising results in this setting, but a significant subset of patients does not respond. We have found that degradation of the protein MDM2, a negative regulator of the p53 tumor suppressor, correlates with response to CDK4is. As such, we propose to identify the pathway regulating MDM2 degradation and other key genes required for therapy-induced senescence,and examine the relationship between patient outcome and two candidate biomarkers of MDM2 degradation using patient tumor samples. Lastly, as we have found that a promoter of MDM2 degradation regulates the HRAS gene, we will evaluate CDK4is in combination with RAS pathway inhibitors.

Project 3: Targeting Oncogenic Pathways in Genetically Complex Sarcomas

Co-leaders: Samuel Singer, MD; Hans-Guido Wendel, MD; Tomoyo Okada, PhD

This project seeks to determine the efficacy and molecular effects of inhibitors of potential targeted therapies, alone and in combination, in myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). These cancers are two of the most common and aggressive types of genetically complex sarcomas; this complexity has made it difficult to find the true drivers of oncogenesis. These studies will further investigate the relevance of potential targets identified by our research so far, including mTOR, PI3K, and MEK (regulators of cell growth, proliferation, and survival), and oncogenic translation (eIF4A). Specifically, we will define the role of the PI3K/mTOR and MAPK pathway activation in sarcomagenesis and identify molecular alterations that associate with outcome. We will also determine the efficacy of mTOR, PI3K, and MEK inhibitors in MFS/UPS cell lines, xenografts and PDX models, combining each of the PI3K and mTOR inhibitors with a MEK inhibitor, to limit adaptive resistance to therapy. Third, we will determine the efficacy and mechanism of action of a new eIF4A inhibitor, CR31B, in MFS, UPS, and DDLS cell lines and xenografts.

Project 4: Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma

Co-leaders: Marc Ladanyi, MD; Scott Lowe, PhD; Neerav Shukla, MD

In this project, CRISPR-based functional genomic screens will be carried out to uncover epigenetic and genetic vulnerabilities in synovial sarcoma, with the aim of discovering drug targets for preclinical and clinical evaluation. Synovial sarcoma is an aggressive pediatric/young adult sarcoma driven by the SS18-SSX fusion oncogene, a multi-faceted disruptor of epigenetic control that causes genome-wide transcriptional deregulation. Based on the hypothesis that SS18-SSX causes synovial sarcoma cells to possess special “epigenetic” dependencies, we will perform a broad functional genomic screen of epigenetic modulators to validate and investigate the mechanism of dependence on one such modulator identified in preliminary studies, KDM2B. We will also perform a functional genomic screen against kinases in human synovial sarcoma cell lines, identify activated kinases by phospho-protein profiling of patient-derived xenografts, and define the targets of pazopanib (a multi-targeted kinase inhibitor active in a subset of patients) by affinity proteomics and PLATO (parallel analysis of translated ORFs). Finally, we will validate the targets identified in the above studies by confirming on-target effects and expression in human tumors, and preclinically evaluate their potential as therapeutic targets in vitro and in vivo.