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Presentation date

Summer 8-12-2021

Faculty Mentor

Sidharth Mahapatra

Research Mentor

Sidharth Mahapatra

Abstract

Medulloblastomas (MB) are devastating brain tumors originating in the cerebellum most commonly in children. There are four distinct subgroups of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. The most malignant tumors possess an aggressive phenotype characterized by c-Myc amplification and deletions to chromosome 17p; they belong to group 3. Prior investigations into the significance of genes on 17p revealed that miR-1253, which is found on locus 17p13.3, is significantly downregulated in medulloblastoma and has important tumor suppressive properties. Amongst its oncogenic targets is B7-H3 (CD276), a highly deregulated oncoprotein that attenuates the immune response to MB tumors. We chose to elucidate the oncogenic properties of B7-H3 in group 3 MB using synthetic inhibitors. After screening 100,000 different compounds for: 1) docking ability, 2) oral bioavailability, 3) potential CNS activity, and 4) number of metabolic side reactions, we selected two N-terminal inhibitors: B7-H3-Ni1 and B7-H3-Ni3. In HDMB03 cells (with c-Myc amplification and i17q), we found an IC50 of 3.7 𝛍M for B7-H3-Ni1 and no discernible effect of B7-H3-Ni3. We confirmed CD276 expression inhibition using B7-H3-Ni1 via Western blotting and concurrently noted elevations in cleaved PARP (apoptosis) and reduction in p-Akt (proliferation marker), providing us preliminary insights into the mechanism of inhibition. Notably, a remarkable decline in migration and wound healing and abrogation of colony formation were observed with B7-H3-Ni1. Collectively, our findings substantiate the inhibitory properties of B7-H3-Ni1 in vitro, potentially serving as a therapeutic agent for in vivo group 3 MB tumors.

Keywords

B7-H3, CD276, medulloblastoma, B7-H3 inhibitor, Group 3 medulloblastoma, pediatric tumor

Investigating the Anti-tumorigenic Properties of Synthetic Inhibitors of B7-H3 in Group 3 Medulloblastoma

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