Sarcoma SPORE Grant

In 2012, the NCI awarded a five-year, $11.5 million SPORE grant (CA168512) to the Sarcoma Alliance for Research Through Collaboration (SARC), a not-for-profit consortium representing physicians and scientists from several institutions who are dedicated to cooperative research leading to new sarcoma treatments. It was only the second SPORE ever awarded for studying this disease.

Raphael Pollock, MD, PhD, director of The Ohio State University Comprehensive Cancer Center, was principal investigator (PI) for the SPORE, a multi-institutional collaboration that supported four research projects, four core services, a Career Development Program and a Developmental Research Program. Pollock was also co-PI for one of the research projects and lead the administrative core.

Overall Sarcoma SPORE Objectives

  • Provide the infrastructure for collaboration on translational research for sarcoma
  • Determine the biological basis for observations made in individuals with sarcoma
  • Develop novel treatments to improve sarcoma outcomes

Note: In addition to the investigators mentioned below, other collaborators in the SPORE were located at Harvard University, Stanford University, the Albert Einstein College of Medicine in New York City, Cancer Research and Biostatistics (CRAB®) in Seattle, Wash., and the National Cancer Institute.

Sarcoma SPORE Projects

Project 1 - Histone Deacetylase-Based Therapeutic Strategies for the Treatment of Genetically Complex Soft Tissue Sarcoma
Project leaders: Raphael Pollock, MD, PhD, the OSUCCC – James; Shreyaskumar Patel, MD, MD Anderson Cancer Center

The project is designed to improve soft-tissue sarcoma (STS) therapy and patient outcomes.

Specific Aims:

  • Evaluate the activity of an histone deacetylase inhibitor (HDACi) plus doxorubicin combination in patients with metastatic leiomyosarcoma (LMS)
  • Examine the role of autophagy as a novel process contributing to HDACi tolerance
  • Determine the impact of HDACS blockade on STS growth in vitro and in vivo

The knowledge gained will enhance the molecular understanding of genetically complex STS; provide insights into autophagy; identify HDACi mechanisms of function, response and cytotoxic agent synergism; and determine the impact of HDAC8-isoform-specific inhibition. Most importantly, these studies will form a novel platform for future human STS clinical trials.

Project 2Identification of Therapeutic Windows for NF1-Related Malignant Peripheral Nerve Sheath Tumors
Project leaders: Yuan Zhu, PhD, Children’s National Medical Center, Washington, D.C.; Laurence Baker, DO, University of Michigan

Malignant peripheral nerve sheath tumors (MPNSTs) carry one of the highest sarcoma-specific deaths. This project will establish the concept of the progressive pathogenesis of neurofibromatosis type 1 (NFI)-associated MPNST. It will also contribute to the development of strategies to prevent and treat these devastating tumors based on modern genetic inquiry.

Specific Aims:

  • Determine whether neural crest stem cells are the cells-of-origin for a subset of plexiform neurofibromas that has high potential for recurrence and malignant transformation
  • Determine whether, prior to MPNST, there is a critical therapeutic window(s) in which an ERK/MAPK pathway inhibitor (MEKi) can prevent plexiform neurofibroma and MPNST formation
  • Attempt to define a subset of MPNSTs that will respond to MEK inhibition

Project 3Investigating G-Protein Coupled Receptors (GPCRS) as Biomarkers of Aggressive Disease and Novel Therapeutic Targets in Ewing Sarcoma
Project leaders: Elizabeth Lawlor, MD, PhD; Rashmi Chugh, MD; both of the University of Michigan

It is currently impossible to predict which patients with Ewing's sarcoma family tumors (EFT) will relapse, and there is no way to cure this aggressive disease once it has spread. This research will improve the understanding of EFT metastasis, test the efficacy of novel drugs designed to prevent metastasis and validate biomarkers that will identify high-risk patients at the time of diagnosis. These studies could lead to fundamental changes in EFT therapy.

Specific Aims:

  • Evaluate the role of CXCR4-positive EFT cells in mediating metastasis and determine if invasion downstream of CXCR4 is mediated by and dependent on RhoA
  • Test small molecule inhibitors of the RhoA/MKL transcriptional axis in vitro, ex vivo and in vivo to evaluate their efficacy as novel agents for the prevention of EFT metastasis
  • Use retrospectively and prospectively collected EFT samples to validate whether expression of G-protein-coupled receptors can predict high-risk disease in newly diagnosed patients

If the findings show that CXCR4, CXCR7 and/or LGR5 expression can identify patients at high risk of metastatic relapse, it will allow the classification of patients into clinical risk categories. In turn, this will allow for treatment stratification and identification of patients who should be included in future trials that are designed to prevent relapse in high-risk patients.

Project 4 – Development of Quantitative Imaging Biomarkers for Assessing Response to Sarcoma Therapy
Project leaders: Jeffrey Yap, PhD, University of Utah; Lawrence Schwartz, MD, Columbia University

This project is developing new imaging approaches using MRl and PET to non-invasively measure changes in tumor biology and pathophysiology in response to conventional and experimental chemotherapies for sarcoma. This could lead to a powerful set of tools for evaluating treatment efficacy and ultimately improve the development of new drugs and the clinical management of sarcoma patients.

Specific Aims:

  • Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) MRl will be evaluated in a multi-center clinical trial of patients with STS of the extremities who are receiving neoadjuvant chemotherapy
  • Two novel PET apoptosis probes will be evaluated and compared to existing PET probes for glucose metabolism (FDG) and cellular proliferation (FLT)
  • Evaluate two novel PET probes for angiogenesis. Preclinical microPET/CT imaQlno studies will be performed in several sarcoma mouse models using the comprehensive panel of PET probes in treatment studies of various therapeutic agents. Correlations with tumor histopathology will be used to validate the imaging assessments.

Sarcoma SPORE Cores

  • Administration, Evaluation and Planning Core – Coordinate and support the programmatic, fiscal, oversight and developmental endeavors upon which the translational success of the SARC Sarcoma SPORE depends.
  • Sarcoma Pathology and Tissue Procurement Core – Provide SPORE investigators with high-quality tissue samples from patients treated at SPORE and SARC-associated institutions.
  • Clinical Trials Core – Facilitate the translation of laboratory findings into the clinical and correlative studies. The core will provide support and resources for activating, conducting and completing the clinical trials or clinically-related aspects of each of the projects.
  • Biostatistics Core – Plan, conduct and analyze translational and clinical sarcoma research in the main projects.

Developmental Research Program

Provided a plan for selecting new projects for the sarcoma SPORE. It maximized the SPORE’s impact by enabling novel translational sarcoma projects to develop and mature. These projects ensured that the SPORE had a varied portfolio of experimental work to draw upon and that progress remained vigorous.

Career Developmental Program

Offered a mechanism for identifying and supporting talented young investigators in translational or clinical sarcoma research. The program provided the incentive and structure needed to bring junior investigators into the multidisciplinary, translational sarcoma research arena.

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