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Last Updated: 09/10/21

SPORE in Soft Tissue Sarcoma

Memorial Sloan Kettering Cancer Center

Principal Investigator(s):

Samuel Singer, MD
Samuel Singer, MD

Principal Investigator(s) Contact Information

Samuel Singer, MD
Chief, Gastric and Mixed Tumor Service
Director, MSK Sarcoma Center
Vincent Astor Chair of Clinical Research
Memorial Sloan Kettering Cancer Center
1275 York Avenue
New York, NY 10065
(121) 263-9294 x0

Overview

The SPORE in Soft Tissue Sarcoma seeks to reduce 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. The SPORE’s 4 translational research projects each aim to identify new therapeutic targets via defining molecular mechanisms of sarcomagenesis and of resistance to targeted therapies, to clinically validate those targets in patient sample, establish new clinical trials, and discover predictors of outcome and response to targeted therapy. Our team leverages a unique resource, a clinicopathologic and outcomes database including over 12,000 patients treated for soft tissue sarcoma at MSK, linked to an extensive sarcoma tissue/blood bank, genetic and epigenetic data, and primary sarcoma cell lines and xenograft models. The SPORE includes 4 research projects:

  • RP1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GIST
  • RP2: CDK4 Inhibitor Therapy: Identification of Biomarkers and Combination Therapies for Liposarcoma
  • RP3: Targeting Oncogenic Pathways in Genetically Complex Sarcomas
  • RP4: Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma

These projects are supported by 4 shared resources:

  • Core 1: Biospecimen Repository
  • Core 2: Biostatistics and Bioinformatics
  • Core 3: Clinical Trials and Advocacy
  • Administration Core

This SPORE also supports a Career Enhancement Program to support the career development of junior investigators in soft tissue sarcoma research and a Developmental Research Program to support innovative pilot projects, diversifying the research the SPORE facilitates.

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Project 1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GIST

Project Co-Leaders:
Ping Chi, MD, PhD (Basic Co-Leader)
Cristina R. Antonescu, MD (Clinical Co-Leader)

Gastrointestinal stromal tumor (GIST), which arises in nerve cells located in the walls of the digestive system called the interstitial cells of Cajal, represents one of the most prevalent sarcoma subtypes and is the most common sarcoma of the GI tract. Most GISTs can be divided into two molecular classes with distinct clinical behaviors: the majority harbor activating cancer-promoting “driver” mutations in cell membrane receptors that transmit growth factor signals, such as KIT or PDGFRA, and the remainder carry defects that reduce the function of the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle. As SDH-altered GISTs are resistant to the current first-line therapy, imatinib, and KIT/PDGFRA-mutant GISTs also usually develop resistance, new therapies are needed for this disease. To that end, we recently identified ETV1 as a master regulator for the lineage specification and normal development of interstitial cells of Cajal and shown that it is required for the growth and survival of imatinib-sensitive and -resistant GISTs in vitro and for tumor initiation and maintenance in vivo. This project aims to understand the regulation of ETV1 protein stability, and to develop novel therapeutic strategies targeting ETV1 protein stability using various preclinical GIST models. In parallel, we are analyzing clinical samples from prior and ongoing clinical trials designed to target ETV1 protein stability to better understand the molecular mechanisms of therapeutic resistance. Among these trials is a recently completed phase II study of the combination of imatinib with the MEK inhibitor binimetinib, which reported a 68% overall response rate among 38 evaluable patients, supporting the combination’s efficacy.

The KIT–ETV1-positive feedback circuit in GIST is interrupted by targeting ETV1 via inhibition of KIT and MAPK signaling

The KIT-ETV1-positive feedback circuit in GIST is interrupted by targeting ETV1 via inhibition of KIT and MAPK signaling. In GIST cells, constitutive activation of the oncogenically activated KIT receptor tyrosine kinase leads to target gene binding of the ETS transcription factor ETV1 via MEK-MAPK signaling (A). One important ETV1 target gene is KIT itself, enhancing its own expression via positive feedback. This loop is interrupted by inhibition of KIT or MAPK signaling, resulting in rapid degradation of ETV1 and reduced binding of ETV1 to target gene enhancers (B). MEKi, MEK inhibitor. From Duensing A, Cancer Discov 2015; ;5(3):231-3.

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

Project Co-Leaders:
Andrew Koff, PhD (Basic Co-Leader)
William D. Tap, MD (Clinical Co-Leader)

Well-differentiated and dedifferentiated liposarcoma (WD/DDLS) is one of the more common sarcomas; DDLS carries a two-thirds chance of death from disease, and while WDLS does not metastasize, it causes substantial morbidity and an ~40% chance of death through repeated recurrences or progression to DDLS. Clinical trials for CDK4 inhibitors (CDK4is) have been promising in the treatment of WD/DDLS, leading to disease stability in the majority and tumor shrinkage in a subset. To maximize the impact of these agents, research is needed to identify predictors of which WD/DDLS patients will respond and which will not, as well as potential targets for other agents with which CDK4i may be combined.

We found that accelerated degradation of MDM2, which regulates tumor suppressors such as p53, can distinguish whether CDK4 inhibitors cause quiescence or senescence in WD/DDLS cells. CDK4i-induced loss of MDM2 was positively correlated with patient response in a pilot study. We also showed that the chromatin remodeler ATRX is required for CDK4i-induced MDM2 degradation. Thus, we are investigating the mechanism of MDM2 regulation by ATRX and another known regulator, cadherin 18 (CDH18), in cells induced to exit the cell cycle following CDK4 inhibition in order to identify biomarkers to predict patient response. As we have also found that ATRX represses expression from the HRAS locus in senescent cells, and that reducing HRAS promotes the transition from quiescence to senescence, we will also evaluate CDK4 inhibitors in combination with Ras pathway inhibitors.

Schematic of CDK4 inhibitor (CDK4i)-induced senescence

Schematic of CDK4 inhibitor (CDK4i)-induced senescence. Dissociation of herpesvirus-associated ubiquitin-specific protease (HAUSP) from MDM2 depresses MDM2 autoubiquitination, which allows MDM2 degradation and progression to senescence. The 3 molecules and events in red prevent CDK4i-induced senescence and have been documented to affect the efficacy of CDK4i in vitro. Senescence defined by the presence of the senescence-associated secretory phenotype (SASP), senescence-associated heterochromatin foci (SAHF), and SA-β-gal accumulation.

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Project 3: Targeting Oncogenic Pathways in Genetically Complex Sarcomas

Project Co-Leaders:
Hans Guido Wendel, PhD (Basic Co-Leader)
Samuel Singer, MD (Clinical Co-Leader)

Our overall goal is to find effective targeted therapies for two of the most common and aggressive types of genetically complex sarcomas: myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS), which usually arise in the arms or legs and are of unknown cellular origin. The development of new targeted therapies is urgent and vital for improving outcomes of these patients. However, the complexity of alterations in these sarcomas has made it difficult to find the true drivers of oncogenesis. We found that high expression of ITGA10 (integrin-α10) in MFS and UPS drives sarcomagenesis by activating RAC/PAK and PI3K/mTOR signaling, and that 85% of MFS and UPS harbor alterations that can activate the PI3K/mTOR signaling cascade. Signaling in this cascade stimulates protein translation, and our preliminary results suggest that MFS and UPS, as well as dedifferentiated liposarcoma (DDLS), rely on oncogenic translation enabled by the RNA helicase eIF4A. We are therefore defining the role of PI3K/mTOR and MAPK pathway activation in sarcomagenesis, identifying molecular alterations that associate with outcome, and determining the efficacy of mTOR, PI3K, and MEK inhibitors in MFS/UPS cellular and in vivo models. We will also determine the efficacy and mechanism of action of new eIF4A inhibitors, CR31B and TDI7663, including discovering which mRNAs require eIF4A for their translation by ribosome footprinting. Based on evidence that MFS and UPS commonly harbor copy number alterations or mutations in the tumor suppressor genes RB1 and TP53, which engender dependence on the oncogenic protein Skp2, we examined Skp2’s function and potential as a therapeutic target in MFS/UPS. Skp2 drives proliferation of patient-derived MFS/UPS cell lines deficient in both Rb and p53 by degrading p21 and p27. Inhibition of Skp2 using the neddylation-activating enzyme (NAE) inhibitor pevonedistat decreased growth of Rb/p53-negative patient-derived cell lines and mouse xenografts. Motivated by these findings, we are working with the NCI Cancer Therapy Evaluation Program (CTEP) to establish a trial of the NEDD8 inhibitor pevonedistat in Rb-deficient undifferentiated pleomorphic sarcoma and high-grade myxofibrosarcoma.

Model for tumorigenic signaling in MFS/UPS with ITGA10, MET, and ETV1 upregulation

Model for tumorigenic signaling in MFS/UPS with ITGA10, MET, and ETV1 upregulation. Oncoproteins amplified in MFS/UPS are shown in red and tumor suppressors deleted in MFS/UPS are in blue. Wide gray arrows indicate translational regulation. Shown in purple are inhibitors being examined in this project.

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Project 4: Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma

Project Co-Leaders:
Scott Lowe, PhD (Basic Co-Leader)
Marc Ladanyi, MD (Clinical Co-Leader)

RP4 focuses on synovial sarcoma, an aggressive pediatric/young adult sarcoma driven by the SS18-SSX fusion oncogene. SS18-SSX has emerged as a multi-faceted disruptor of epigenetic control that mediates genome-wide transcriptional deregulation, resulting in proliferation and aberrant or arrested differentiation. Our overall goal is to probe the basic pathobiology of synovial sarcoma in order to nominate potential therapeutic targets. Via functional genomic screens, we are uncovering vulnerabilities among chromatin/transcriptional regulators such as the histone demethylase KDM2B, as well as among kinases. So far, validated vulnerabilities include members of the polycomb repressive complex 1.1 (PRC1.1) such as BCOR and PCGF1, as well as components of poorly characterized variant PRC1 complexes such as PRC1.3. Given that KDM2B is an H3K36me2 demethylase, we are also examining the role of SETD2, the H3K36 trimethylase (the only lysine methyltransferase that can deposit the H3K36me3 mark), in synovial sarcoma survival, as we have found it to be recurrently inactivated by mutations in a subset of these cancers. We are now using proteomic and protein interaction analyses to define targetable kinase vulnerabilities. Finally, we are validating targets identified in the preceding studies by confirming on-target effects and expression in human tumors, and preclinically evaluating their potential as therapeutic targets in vitro and in vivo. Supporting these efforts, we have established a library of patient-derived xenograft (PDX) models and patient-derived cell lines, as well as isogenic, immortalized cell lines carrying the SS18-SSX fusion, which represent a rich resource for preclinical studies in synovial sarcoma.

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Administrative Core

Core Director:
Samuel Singer, MD

The Administrative Core manages and coordinates the activities of the SPORE program by providing administrative direction and structure, fiscal and programmatic oversight, and coordination with internal and external advisory committees. The Core also assists the directors of the Developmental Research and Career Enhancement Programs in administering those programs.

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Biospecimen Repository Core

Core Directors:
Cristina R. Antonescu, MD (Co-Director)
Narasimhan P. Agaram, MBBS (Co-Director)

The Biospecimen Repository Core coordinates the collection, annotation, storage, distribution, and tracking of tissue and blood biospecimens from soft tissue sarcoma patients enrolled in research protocols, and ensures linkage of those samples with clinical data in collaboration with project leaders, the bioinformatics core, and the administrative core. The Core also provides SPORE investigators with expert histopathological evaluation of tumor samples from both patients and genetically engineered and xenograft models and assists in performing and interpreting immunohistochemical and in situ hybridization assays.

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Biostatistics and Bioinformatics Core

Core Directors:
Nicholas Socci, PhD (Co-Director)
Li-Xuan Qin, PhD (Co-Director)

The Biostatistics and Bioinformatics Core supports investigators of the Soft Tissue Sarcoma SPORE in the computational and statistical aspects of their research efforts, including the design, analysis, and interpretation of laboratory experiments, molecular profiling assays, and clinical trials. For analyses for which current methodologies are inadequate, Core staff develop new, alternative methods. The Core also facilitates the management and updating of the clinical sarcoma database in collaboration with the leaders of research projects and the other 3 cores.

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Clinical Trials and Advocacy Core

Core Directors:
William D. Tap, MD (Co-Director)
Paul A. Meyers, MD (Co-Director)

The Clinical Trials and Advocacy Core facilitates the establishment and conduct of novel clinical trials in soft tissue sarcoma that span age groups. CF3 bridges the adult and pediatric sarcoma programs at MSK; the basic science, translational, and clinical aspects of the various SPORE projects; the Administrative, Biospecimen, and Biostatistics and Bioinformatics Cores; and other Sarcoma SPOREs. Critically, CF3 assists SPORE investigators in acquiring funding for clinical trials through cooperative/government funding mechanisms, pharmaceutical companies, advocacy groups, and immune and developmental therapeutic programs; and promotes the engagement and involvement of minority participants in clinical research. Finally, the Core is developing a program to involve patient advocacy and support groups to ensure that MSK sarcoma clinical trial protocols best serve patient needs and generally stimulates conversation between researchers and patients, caregivers, and advocates.

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Developmental Research Program

Program Directors:
Marc Ladanyi, MD (Director)
Samuel Singer, MD (Co-Director)

To enable SPORE investigators to rapidly develop innovative research programs with strong potential for clinical impact, the Developmental Research Program (DRP) provides seed funding for pilot projects on the pathogenesis, progression, and treatment-driven evolution of sarcoma. With institutional support, the MSK SPORE in Soft Tissue Sarcoma DRP provides up to 7 awards annually, and solicits proposals both within MSK and from neighboring institutions. Projects that yield promising data will be considered for incorporation into the SPORE as Research Projects in future funding cycles.

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Career Enhancement Program

Program Directors:
Meera R. Hameed, MD (Director)
Hedvig Hricak, MD, PhD (Co-Director)

The Career Enhancement Program (CEP) encourages more translational researchers to focus on soft tissue sarcoma research by providing research support for early-stage projects proposed by junior investigators. One to two awardees per year are selected based on their previous accomplishments and their commitment to a career in academic sarcoma research. The CEP also enhances awardees’ career training by providing sarcoma-specific mentorship and integration into the SPORE program through participation in conferences and presentations.

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