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 University of Utah National Cancer Institute Cancer Research and Biostatistics (CRAB)
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
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 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
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 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
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.
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
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
CXCR4
+ +/- -
CXCR4 is reversibly induced by growth-factor deprivation (shown), hypoxia and growth-restriction.
AMD3100 blocks CXCR4- mediated invasion
Aim 2: Inhibition of MKL2 restores the actin cytoskeleton and blocks cell invasion
ControlInvasiveActive Rac/Cdc42
MKL-inhibitor Rx Non-invasiveInactive Rac/Cdc42
Inter- and intra-tumor heterogeneity of CXCR4 in primary tumors
Control
MKL-inhibitor Rx
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
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
Developmental Research Program Grants
Recipient Project
Z. Duan Dissecting Cdk11 Kinase Pathway in Osteosarcoma
J. FletcherA. Marino-Enriquez
Biomarkers for Dystrophin-deficiency in Sarcoma
D. KirschR. Dodd
Translating Mouse Model Discoveries into Metastatic Biomarkers
S. LessnickS. Sharma
Epigenetic Targeting of LSD1 for Ewing Sarcoma
K. LiuR. Pollock
Combined Radiosensitization and Tcell Immunotherapy
D. LangenauC. Keller
GSK3-beta inhibitors for relapsed rhabdomyosarcoma
SARC Sarcoma SPORE
Career Development Awards
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
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
2014 Funding Opportunities for CDA and DRP Letter of intent due January 3, 2014 Details at SARC website