PROJECT SUMMARY/ABSTRACT
Children with the Group 3 subtype of medulloblastoma experience poor outcomes, with nearly 50% mortality
despite intensive treatment regimens. Thus, new treatment options are desperately needed. While prior efforts
have studied the ~20,000 known protein-coding genes in medulloblastoma, I have investigated >2,000 non-
canonical proteins that were previously excluded. I have discovered that MYC-driven, Group 3 medulloblastoma
cells are dependent on an upstream open reading frame (uORF) encoded within the ASNSD1 5’ untranslated
region. Perturbation of this uORF impacted the MYC cellular program, and it bound to the prefoldin complex,
which is critical for gene regulation. These findings provide a rationale to study ASNSD1 uORF as an oncogenic
driver in medulloblastoma and suggest that non-canonical proteins are a fertile territory for cancer discovery. To
advance ASNSD1 uORF as a potential therapeutic target, this proposal will pursue two specific aims in the
context of Group 3 medulloblastoma: (1) to validate ASNSD1 uORF in advanced cell line and mouse models of
medulloblastoma and (2) to confirm the role of the ASNSD1-prefoldin complex interaction in medulloblastoma. I
am an Instructor in Pediatric Neuro-oncology with at least 80% protected time for research, who is committed to
uncovering medulloblastoma disease mechanisms to advance patient care. My career goal is to become an
independent physician-scientist with research focused on novel medulloblastoma therapeutic targets. The
purpose of this career development award is to enable me to gain specific research training in medulloblastoma
mouse model systems, proteomics techniques and computational analysis. I seek to use these research skills
to advance my work studying non-canonical proteins as novel medulloblastoma vulnerability genes. I have
chosen an outstanding mentorship team of Drs. Todd Golub and Pratiti Bandopadhayay for this proposal. Dr.
Golub is an authority on the discovery of therapeutic targets and brings over 20 years of experience in mentoring
K08-level physician scientists. I have selected Dr. Bandopadhayay as a co-mentor because she is an innovator
in medulloblastoma and deep knowledge of medulloblastoma model systems. My advisory committee includes
experts reflecting key areas of my training plan: Drs. Steve Gygi (proteomics), Scott Pomeroy (medulloblastoma),
Ernest Fraenkel (computational biology) and Kim Stegmaier (pediatric genomics). Both my mentor, co-mentor,
and advisory committee are committed to my research training, career development and growth into an
independent physician-scientist at the conclusion of this award. I will train at the Dana-Farber Cancer Institute
and the Broad Institute, which are both outstanding institutions with unique research opportunities. This training
environment provides numerous opportunities for me to benefit from didactic coursework relevant to this award,
as well as participate in world-class research conferences. With the mentored research and career development
offered through this K08 award, I will be ideally suited to establish my independent career as a physician-scientist
in pediatric neuro-oncology.