SARC (Sarcoma Alliance for Research
through Collaboration)
Principal Investigator:
Raphael Pollock, MD, PhD
Overall Abstract
Currently, there are limited programs that have the capability to provide the infrastructure for collaboration on translational research for sarcoma. Because sarcoma is a relatively uncommon disease, this SARC Sarcoma SPORE will provide the infrastructure for translational research to develop and test the feasibility of cancer-relevant interventions in humans and/or determine the biological basis for observations made in individuals with sarcoma.
The main goals of the SARC Sarcoma SPORE are the translation of biological and technological advances into improvements in prevention, diagnostics, predictors of outcome, and - particularly - advances in the treatment of sarcoma. The SARC Sarcoma SPORE is anchored by multiple researchers from SARC, Harvard, MD Anderson Cancer Center, The University of Michigan and the NCI intramural program, but also includes key individual researchers from Stanford University and Columbia University. The researchers represent medical and pediatric oncology and the projects explore both soft tissue and bone sarcomas. Four major projects are proposed and these projects are integrated and supported by four corresponding cores. There is also a Developmental Research Program that includes a plan for selection of new projects and a Career Developmental Program that outlines a mechanism for the identification and support of talented young investigators in translational or clinical sarcoma research. The projects, cores and programs are highly integrated and are poised to take maximum advantage of the SPORE mechanism to achieve translational goals.
This SPORE joins state-of-the-art research projects with the multi-institution, collaborative strength of SARC and commitments from leading institutions to produce translational advances.
Project 1: Histone deacetylase inhibitor (HDACi)-based therapeutic strategies for the treatment of genetically complex soft tissue sarcoma
Co-Leader – Lab:
Dina Chelouche Lev, MD
Co-Leader – Clinical:
Shreyaskumar Patel, MD
The lack of effective systemic therapies is the major unresolved clinical problem in genetically complex soft tissue sarcomas (STSs). Preclinical studies suggest a promising therapeutic role for broad spectrum histone deacetylase inhibitors (HDACis) against multiple STS histologies. The current application aims to translate these findings into the clinic through a phase-II clinical trial testing a combination of HDACi and chemotherapy in patients with advanced STS, specifically, metastatic leiomyosarcoma (LMS) patients. In addition, investigations will focus on evaluating the role of HDACi-induced autophagy in therapeutic response by targeting HDAC8. Taken together, the overarching long term goal of the proposed studies is to advance STS therapy and improve patients’ outcome. Three goals are proposed:
- Evaluate the activity of an HDACi/doxorubicin combination in patients with metastatic LMS
- Examine the role of autophagy as a novel process contributing to HDACi tolerance
- Determine the impact of HDAC8 blockade on STS growth in vitro and in vivo
Knowledge gained will enhance the molecular understanding of genetically complex STS, generate insights into autophagy, identify HDACi mechanisms of function, response, and cytotoxic agent synergism, and will determine the impact of HDAC8-isoform specific inhibition. Most importantly, studies here will will form a novel platform for future human STS clinical trials and will hopefully significantly impact patient management.
Project 2: Identification of therapeutic windows for NF1-related malignant peripheral nerve sheath tumor
Co-Leader – Lab:
Yuan Zhu, PhD
Co-Leader – Clinical:
Laurence Baker, DO
Malignant peripheral nerve sheath tumors (MPNSTs) are genetically complex soft-tissue sarcomas that have one of the highest risks of sarcoma-specific deaths.NF1-associated MPNST often arises within a subpopulation of benign peripheral nerve sheath tumor (PNST), plexiform neurofibroma (PNF), which is hypothesized as a congenital lesion caused by NF1 inactivation in multipotent neural crest stem cells (NCSCs) during nerve development. Thus, NF1-associated MPNST may represent the only sarcoma with a defined developmental basis and a critical benign precursor lesion. Recent studies showed that loss of NF1 activates Ras-mediated extracellular-signal-regulated/mitogen-activated protein kinase (ERK/MAPK) signaling pathway in MPNST cell lines. The overall goal of this proposal is to:
- Determine whether multipotent NCSCs are the cell-of-origin for a subset of plexiform neurofibromas that have high potentials 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 PNF and MPNST formation
- Define a subset of MPNSTs that will respond to MEKi
The experiments proposed not only will establish the concept regarding the progressive pathogenesis of NF1-associated MPNST, but also contribute to the development of prevention and treatment strategies for these devastating human tumors based on modern genetic inquiry.
Project 3: Investigating G-protein coupled receptors (GPCRs) as biomarkers of aggressive disease and novel therapeutic targets in Ewing sarcoma
Co-Leader – Lab:
Elizabeth Lawlor, MD, PhD
Co-Leader – Clinical:
Rashmi Chugh, MD
Ewing sarcoma family tumors (EFT) are highly malignant bone and soft tissue tumors that primarily affect children, adolescents and young adults. One of the biggest impediments to improving outcomes and quality of life for patients with EFT is our inability to predict who is at risk for metastatic relapse and to effectively identify and target the mechanisms that underlie this process.
It is our overall goal to improve outcomes for patients with EFT by preventing metastatic relapse. In an effort to achieve this goal we will address three specific aims:
- Study cell lines to evaluate the role of CXCR4 positive EFT cells in mediating EFT metastasis. We will also 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.
- Utilize retrospectively and prospectively collected EFT samples to validate whether expression of G-protein coupled receptors can be used to predict high-risk disease in newly diagnosed patients.
Demonstration that CXCR4, CXCR7 and/or LGR5 expression can be used to identify patients at high risk of metastatic relapse will allow classification of patients into clinical risk categories.
The studies in this proposal will improve our understanding of how EFT metastasizes, test the efficacy of novel drugs designed to prevent metastasis, and validate biomarkers that may be used to identify high risk patients at the time of diagnosis.
Project 4: Development of quantitative imaging biomarkers for assessing response to sarcoma therapy
Co-Leader – Lab:
Jeffrey Yap, PhD
Co-Leader – Clinical:
Lawrence Schwartz, MD
This translational research project will develop quantitative imaging biomarkers for assessing therapeutic response in Sarcoma using advanced quantitative imaging approaches in PET and MRI. The specific goals are to:
- Perform dynamic contrast enhanced (DCE) and diffusion weighted (DW) MRI prior to and at the conclusion of chemotherapy to evaluate the correlation between treatment response and tumor histopathology obtained from surgical resection.
- Evaluate and compare two novel PET apoptosis probes (18F-ML-10 and 124I-Diannexin) to existing PET probes for glucose metabolism (FDG) and cellular proliferation (FLT).
- Evaluate two novel PET probes for angiogenesis (18F-FPP(RGD) and 89ZR-bevacizumab).
In addition, DCE and DW MRI imaging will be performed in the same studies to compare the more specific PET assessments of metabolism, proliferation, angiogenesis, and apoptosis with the MRI perfusion and diffusion measurements that are more clinically available.
This project will develop new imaging approaches using MRI and PET to non-invasively measure various aspects of tumor biology and pathophysiology in response to conventional and experimental chemotherapies. This will enable a powerful set of tools to evaluate treatment efficacy and ultimately improve the development of new drugs and clinical management of sarcoma patients.