The Dependency on MYOD for Growth in Rhabdomyosarcoma

Project Summary Rhabdomyosarcoma (RMS) is the most common extra-cranial solid tumor in the pediatric population of the United States by incidence. RMS is a high-grade neoplasm composed of cells that resemble skeletal myoblasts and express some markers of myogenic differentiation but do not form functional myotubes. The standard systemic therapy

for RMS consists of intensive multi-agent chemotherapy and has not significantly changed in nearly five decades. These

compounds target general vulnerabilities of rapidly dividing cells and are not specific to the pathophysiology of RMS. As such, treatment is accompanied by a suite of toxicities with potentially lifelong repercussions in pediatric patients. Approximately 20% of RMS patients present with metastatic disease at diagnosis, and the failure-free survival rate for

these patients is only 30% after five years. Hence, there is a pressing need for specific yet potent therapies for RMS. High-throughput, negative-selection genetic screens across cell lines of varying tumor types have the potential to

reveal growth dependencies specific to a given cancer. Our results from these functional genomics experiments identified myogenic differentiation 1 (MYOD) as the most potent growth dependency factor specific to RMS. MYOD is a member

of the basic Helix-Loop-Helix family of transcription factors and is a master regulator of muscle differentiation. MYOD is one of the predominant myogenic markers used in the clinical diagnosis of RMS but has long been thought to be

functionally inactive in RMS, as this cancer does not complete the myogenic differentiation program. However, in light of

our genetic screening data, we hypothesize that RMS exploits the transcriptional activity of MYOD to drive growth of the tumor. The proposed research aims to determine the molecular mechanisms by which MYOD regulates growth of RMS. The outlined experiments will identify features of MYOD necessary for sustaining RMS growth (Aim 1), uncover the

genetic targets of MYOD that mediate growth (Aim 2), and evaluate the functional significance of MYOD targets (Aim 3). Data from these experiments will provide insight into the molecular pathophysiology of RMS and may reveal critical nodes in this program that warrant therapeutic investigation. The requisite skills and knowledge to carry out this research proposal will be supported by the integrated basic

and medical science education in the Medical Scientist Training Program at Stony Brook University (SBU). The mentorship and environments at SBU and Cold Spring Harbor Laboratory will provide all of the necessary resources for a tailored training program to effectively develop the applicant into an independent experimentalist, analyst, and

communicator of cancer research.