PTPS-26PIN1, A THERAPEUTIC TARGET IN HEDGEHOG-DRIVEN MEDULLOBLASTOMA

Abstract

Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements, but are achieved at a high cost to quality of life. Aberrant upregulation of the hedgehog (Hh) pathway drives cerebellar tumorigenesis in ∼30% of medulloblastoma patients. Hh pathway inhibitors such as the SMO antagonist Vismodegib are currently being tested in Hh-activated medulloblastoma and the preliminary results are encouraging. However, resistance to SMO inhibition can be acquired, leading to relapse. Alternative therapeutic approaches are needed. We aim to uncover novel Hh signal modulators that are essential in medulloblastoma to maintain tumorigenic potential. Using our proteomic platform for systematic protein interaction mapping, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hh signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the post-phosphorylation conformation of its substrates. Our results support a molecular model in which PIN1 protects GLI1 from ITCH-driven proteasomal degradation, thus contributing to the positive regulation of Hh signals. Most importantly, our in vivo functional analyses of PIN1 in mouse models of Hh-driven medulloblastoma demonstrate that the loss-of-PIN1 impairs tumor development and increases survival by 3 fold, from 57 to 158 days (P < 0.0001), establishing PIN1 as a key factor in Hh-driven medulloblastoma tumorigenesis. Finally, in human medulloblastoma tumor samples, the GLI1 and PIN1 proteins are correlated in their expression, supporting the relevance of the GLI1/PIN1 interaction in this disease context. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in medulloblastoma tumorigenesis. If our hypothesis is validated, i.e., PIN1 inhibitors can improve survival in mouse models of Hh-driven medulloblastoma, our project will strongly justify testing the clinical relevance of PIN1 blockade in medulloblastoma patients.