Elucidating Signaling Pathways for GABA-A Receptor Alpha5 in an Aggressive Subtype of Medulloblastomas

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DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant pediatric brain tumor and a significant cause of cancer-related mortality in children. Children surviving medulloblastoma treatments are often severely cognitively impaired and are dependent on their families for continuing care. One of these subtypes, namely Group 3, has high levels of expression of an oncogene (MYC), photoreceptors, and a GABA-A neurotransmitter receptor called GABRA5. For other subtypes, survival of patients with effectively treated medulloblastoma exceeds 70%; while only 20% of patients who have Group 3 tumors survive despite receiving maximal treatment that includes surgery, radiation and chemotherapy. There is therefore a significant demand for therapeutic strategies to treat these treatment-resistant patients. Although neurotransmitter receptors have been well defined in normal cells, their importance in the maintenance and progression of brain tumors is unknown and the effect of targeting these receptors in brain cancers is unexplored. In my recent publication, a novel benzodiazepine derivative that is highly specific for GABRA5, has been shown to be effective in killing Group 3 medulloblastomas, both in cell culture and in the mouse model. Stemming from my prior NINDS R25 research, my 4 year K08 project as junior faculty and principal researcher at the BIDMC will be as follows: to look at DNA damage due to GABRA5 signaling; studying GABRA5 in normal cerebellar and medulloblastoma development; and detecting signaling molecules involved in GABRA5 signaling by tissue mass spectrometry. In addition, tissue mass spectrometry is being piloted in the neurosurgery operating room at the Brigham and Women's Hospital to try and diagnose subtypes of brain tumors rapidly, which would be highly beneficial for clinical trials. It has not been tested for medulloblastoma, and our hope is to diagnose the subtype of medulloblastoma rapidly so as to tailor the treatment that a child receives, thereby reducing treatment toxicity to the child. I would be the solo trainee of ths K08 award.