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.
Rhabdomyosarcoma (RMS) is a pediatric cancer long overdue for potent treatments that target pathways specific to the disease. Myogenic differentiation factor 1 is a strong growth dependency specific to RMS, and this study aims to understand the molecular mechanisms underlying this relationship. Knowledge gained from this proposal will advance understanding of RMS pathophysiology and provide a foundation for investigation of novel therapeutics.
