Kate Amato Foundation Awarded Projects

Project Description:

Medulloblastomas are the most common malignant brain cancer of childhood. However, patients with medulloblastomas driven by the oncogene MYC have not benefited from traditional chemotherapies, leading to poor overall survival. MYC is a master regulator of tumor cell growth across many cancer types, yet direct methods to target MYC have remained elusive. Thus, finding ways to inhibit MYC signaling is an unsolved biological question and a critical unmet clinical need.

MYC positively regulates the expression of numerous genes involved in ribosomal biogenesis. The upregulation of ribosomal biogenesis in malignant cells has served as a histopathological marker for cancer diagnosis for over a century. Our preliminary data suggest that CDK8 is crucial for medulloblastoma growth and maintaining MYC activity. Notably, CDK8 inhibition suppresses the level of ribosomal genes and impairs ribosome biosynthesis. Therefore, our objective is to elucidate the mechanistic consequences of CDK8 inhibition on ribosome biogenesis and provide pre-clinical validation of CDK8 inhibitor treatment as a promising therapeutic approach for MYC-driven medulloblastoma.

Mammalian target of rapamycin (mTOR) positively regulates several steps in ribosome biogenesis. We anticipate that the concurrent administration of pharmacological inhibitors targeting both CDK8 and the mTOR pathway could offer an effective treatment strategy for MYC-driven medulloblastoma. If successful, these agents will advance to human clinical trials for further assessment and potential implementation in patient care.