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Raphael Pollock, MD, PhD Principal Investigator

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1 Raphael Pollock, MD, PhD Principal Investigator
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 1 Histone 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 Specific aim 2 Specific aim 3
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 Screeened HDACi 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 2 Identification 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 plexiform neurofibroma 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 plexiform neurofibroma (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 3 Investigating 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. CXCR4 + +/- - 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 Control Control Invasive Active Rac/Cdc42 MKL-inhibitor Rx Non-invasive Inactive Rac/Cdc42 MKL-inhibitor Rx

9 Project 4 Development 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
Recipient Project Z. Duan Dissecting Cdk11 Kinase Pathway in Osteosarcoma J. Fletcher A. Marino-Enriquez Biomarkers for Dystrophin-deficiency in Sarcoma D. Kirsch R. Dodd Translating Mouse Model Discoveries into Metastatic Biomarkers S. Lessnick S. Sharma Epigenetic Targeting of LSD1 for Ewing Sarcoma K. Liu R. Pollock Combined Radiosensitization and Tcell Immunotherapy D. Langenau C. Keller GSK3-beta inhibitors for relapsed rhabdomyosarcoma

12 SARC Sarcoma SPORE Career Development Awards
Developmental Research Program 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 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 2014 Funding Opportunities for CDA and DRP Letter of intent due January 3, 2014 Details at SARC website

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