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.