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SARC Sarcoma SPORE

SARC Sarcoma SPORE. Raphael Pollock, MD, PhD Principal Investigator. SARC Sarcoma SPORE. Awarded September 2012 Multicenter collaboration Ohio State University MD Anderson Cancer Center Dana Farber/Harvard University of Michigan Children’s National Hospital Columbia University

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SARC Sarcoma SPORE

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  1. SARC Sarcoma SPORE Raphael Pollock, MD, PhD Principal Investigator

  2. SARC Sarcoma SPORE • Awarded September 2012 • Multicenter collaboration • Ohio State University • MD Anderson Cancer Center • Dana Farber/Harvard • University of Michigan • Children’s National Hospital • Columbia University • University of Utah • National Cancer Institute • Cancer Research and Biostatistics (CRAB)

  3. Project 1Histone deacetylase inhibitor (HDACi)-based therapeutic strategies for the treatment of genetically complex STS • Co-Leaders • Raphael Pollock, MD, PhD (Ohio State) • Shreyaskumar Patel, MD (UTMDACC) • Specific Aims • Aim 1: To evaluate the activity of an HDACi/doxorubicin combination in patients with metastatic LMS • Aim 2: To examine the role of autophagy as a novel process contributing to HDACi tolerance • Aim 3: To determine the impact of HDAC8 blockade on STS growth in vitro and in vivo

  4. Specific aim 1 • Phase 2 of mocetinostat and gemcitabine in chemorefractory LMS • Study cohort • > age 18 • Metastatic LMS • Progression after treatment with a gemcitabine-based regimen • Sponsor • SARC • N=30 • Specific aim 2 • ScreeenedHDACi for pan-HDAC isoform inhibitors • Screened complex karyotype cell lines for IC50, doubling time, in vivo growth, induction of autophagy • Performed autophagy-related gene array analysis (5 genes identified) • Specific aim 3 • Performed growth and clonigenicity assays • Moved lab to OSU

  5. Project 2Identification of therapeutic windows for NF1-related malignant peripheral nerve sheath tumor • Co-Leaders • Yuan Zhu, PhD (CNMC) • Laurence Baker, DO (UM) • Specific Aims • Aim 1: To investigate the cell-of-origin of PNST and clonal relationship between plexiformneurofibroma and MPNST in humans • Aim 2: To determine phenotypic consequences of Erk/MAPK pathway inhibition during initiation phases of PNST development • Aim 3: To define a subset of NF1-associated MPNSTs responsive to MEKi

  6. Project 2 Update • Aim 1: (1) IRB for the German site was approved. (2) All the methodologies including cell cultures for human Schwann cells and melanocytes as well as targeted NF1 sequencing were established. IRB for US sites are completed. • Aim 2: Multiple treatment protocols (n = 4) using an MEK inhibitor (MEKi from Pfizer) were employed on a mouse model for benign plexiformneurofibroma (PNF). Preliminary data were encouraging. This aim is expected to complete within a year. Parallel studies with rapamycin treatment were also conducted. The results were very promising and would be a nice comparison to human Rapa and MEKi clinical trials. • Aim 3: MEKi treatment showed no effect on established MPNSTs. Current efforts are to prepare for a manuscript to publish the new MPNST mouse models.

  7. Project 3Investigating G-protein coupled receptors (GPCRs) as biomarkers of aggressive disease and novel therapeutic targets in Ewing sarcoma • Co-Leaders • Elizabeth R. Lawlor, MD, PhD (UM) • Rashmi Chugh, MD (UM) • Specific Aims • Aim 1: Determine if C-X-C chemokine receptor type 4 (CXCR4)-mediated activation of RHO promotes invasion and metastasis • Aim 2: Evaluate the efficacy of Rho/MKL transcriptional antagonists as inhibitors of EFT cell invasion and metastasis • Aim 3: Validate the utility of GPCRs as biomarkers of aggressive disease in EFT

  8. Two Manuscripts in preparation Aim 1: CXCR4 expression in Ewing sarcoma is highly variable, dynamic and is induced by stress. CXCR4 promotes SDF1α (CXCL12)-dependent invasion via activation of Rac/Cdc42 CXCR4 is reversibly induced by growth-factor deprivation (shown), hypoxia and growth-restriction. Inter- and intra-tumor heterogeneity of CXCR4 in primary tumors AMD3100 blocks CXCR4- mediated invasion Aim 2: Inhibition of MKL2 restores the actin cytoskeleton and blocks cell invasion CXCR4 Control CXCR4 Control Invasive Active Rac/Cdc42 MKL-inhibitor Rx Non-invasive Inactive Rac/Cdc42 MKL-inhibitor Rx + +/- -

  9. Project 4Development of quantitative imaging biomarkers for assessing response to sarcoma therapy • Co-Leaders • Jeffrey Yap, PhD (Utah) • Lawrence Schwartz, MD (Columbia) • Specific Aims • Aim 1: Clinical validation of perfusion and diffusion MRI imaging • Aim 2: Development and preclinical validation of imaging biomarkers for apoptosis • Aim 3: Development and preclinical validation of imaging biomarkers for angiogenesis

  10. Project 4 Update • MRI acquisition protocols tested in healthy subjects for future clinical trial (Columbia, Utah, Michigan, Ohio State) • Preliminary mouse imaging studies performed using novel probes for angiogenesis ([89Zr]bevacizumab) and apoptosis ([18F]WC-II-89) • Future studies using 18F-fluciclatide and 124I-Diannexin are being developed

  11. Developmental Research Program Grants

  12. SARC Sarcoma SPORE Career Development Awards Developmental Research Program To identify and support talented researchers in the area of sarcoma translational research To promote interdisciplinary research and move basic research findings from the laboratory to clinical settings • To identify and support talented new researchers in the area of sarcoma translational research • To enforce adequate protected time of clinically oriented young investigators to facilitate the development of independent translational researchers 2014 Funding Opportunities for CDA and DRP Letter of intent due January 3, 2014 Details at SARC website

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