Abstract 1166: Genetic and pharmacologic suppression of pink1 prolongs survival in sonic hedgehog driven medulloblastoma and related mouse model.

Abstract Mitochondrial quality control plays a key role in helping cancer cells survive, but its impact on medulloblastoma is still not well understood. Here, we examined how the mitochondrial kinase PINK1 contributes to medulloblastoma growth by blocking its activity pharmacologically and by genetic loss-of-function approaches in mouse brain tumor models. Human medulloblastoma cells, MB004 and D425, were pretreated with a PINK1 inhibitor prior to orthotopic implantation. Kaplan-Meier analysis demonstrated significantly prolonged survival in mice receiving PINK1-inhibited tumor cells compared with controls (MB004: p = 0.0288; D425: p = 0.0284), indicating that disruption of PINK1 enhances therapeutic vulnerability. To further assess the role of Pink1 in vivo, we generated a genetically engineered mouse model without Pink1 in a Trp53-/-; Ptch1+/- background. This is a spontaneous tumor formation model at 90% rate. Pink1 deletion significantly increased survival compared with Pink1-active Trp53-/-; Ptch1+/- mice (p = 0.0491), supporting a tumor-promoting role for Pink1 in Sonic Hedgehog-driven medulloblastoma. Histopathological analysis of hematoxylin and eosin stained brain sections presented normal brain structure in the control animals, while Trp53-/-; Ptch1+/- mice developed high-grade tumors. Interestingly, Trp53-/-; Ptch1+/-; Pink1-/- brains showed reduced tumor burden and retained more tissue structure, consistent with the observed survival advantage. Together, these findings demonstrate that PINK1 is required for efficient medulloblastoma growth and that its inhibition—either through acute pharmacologic targeting or permanent genetic disruption—improves survival and reduces tumor pathology. Targeting mitophagy pathways such as disruption of PINK1 activity may therefore represent a promising therapeutic strategy for medulloblastoma, particularly in resistant or high-risk disease. Citation Format: Bahauddeen M. Alrfaei, Amani Almuaysib, Ahmed Aloraidi, Ali Assiri. Genetic and pharmacologic suppression of pink1 prolongs survival in sonic hedgehog driven medulloblastoma and related mouse model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1166.