Mentor Name: Vijay Ramaswamy

Medulloblastoma is the most common malignant brain tumour of childhood. Currently treatments are woefully inadequate where high-risk patients are failing current therapy, and survivors are left with devastating consequences of current therapy. In addition, survival rates have been stagnant for 40 years, necessitating new approaches. Unfortunately despite worldwide efforts to conduct many genomic studies, a lack of mutations in medulloblastoma has precluded us from identifying currently available therapies. As such, there is an urgent unmet need to develop new treatment approaches. This proposal seeks to test a novel new combination of drugs that are currently approved and available for other cancers; specifically we have identified a process called neddylation which likely represents a unique therapeutic vulnerability in MYC and MYCN amplified medulloblastoma's. We have so far performed mass spectrometry to identify preferentially neddylated targets in MYC amplified Group 3 compared with normal tissues and are performing Crispr-Cas9 dropout screens--which have identified potential novel combinatorial therapies, which likely represent unique therapeutic vulnerabilities. Processes not previously described in medulloblastoma such as spliceosome assembly have been identified as highly significant preferential binding partners for which there are several drugs suggesting untapped therapeutic avenues. We will test these combinations in the highest risk group of medulloblastoma, specifically MYC amplified Group 3 and TP53 mutant SHH patents, first in vitro and then in vivo using a robust drug screening pipeline in our group which employs 12 point dose response curves. Potentially effective combinations will be prioritized for in vivo pre-clinical studies and further mechanistic validation. Indeed, our preliminary results suggest that neddylation is a unique modulator of protein turnover in other MYC/MYCN driven brain tumours suggesting a broader application. Should we find that this combination is effective in our proposed pre-clinical studies in this proposal, we can rapidly translate these findings into an early phase clinical trial, and moreover test this combination in other brain tumours that have MYC amplifications and/or TP53 mutations such as diffuse intrinsic pontine glioma and glioblastoma.