Identifying and Characterizing Novel Targets against Rhabdomyosarcoma Disease Relapse

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue pediatric sarcoma. Patients with relapsed or metastatic disease are faced with a poor survival outlook. Self-renewal of tumor propagating cells (TPCs) is believed to be responsible for driving RMS disease relapse through resistance to conventional therapies and recapitulation of RMS tumor heterogeneity. Identifying novel regulators of TPC activity may provide insight into potential therapeutic targets. In this dissertation, I identify and characterize GRK5 and HDAC6 as novel regulators of RMS cell growth and self-renewal. GRK5, a G-protein receptor kinase, regulates cell cycle in a kinase-independent manner to promote RMS tumor cell growth. Loss of GRK5 results in significant reduction of RMS self-renewal capacity due to increased cell death. HDAC6, a histone deacetylase, promotes RMS tumor growth by modulating cell cycle progression and tumor cell differentiation. Depletion of HDAC6 reduces RMS self-renewal capacity by limiting dilution assays and expression of stem-cell markers SOX2, NANOG and OCT4. In vivo inhibition of GRK5 and HDAC6 with small molecule inhibitors results in reduced RMS tumor cell growth, demonstrating their potential as therapeutic targets. Current in vitro approaches for studying RMS TPCs are unspecific, with in vivo methods being time intensive and costly. I will present preliminary data identifying CD133 as a potential marker for embryonal rhabdomyosarcoma (ERMS) TPCs for rapid in vitro characterization of TPC behavior. Collectively, my findings demonstrate the potential of RMS TPCs as therapeutic targets against RMS disease relapse and metastasis.