MEDU-37. CHOLESTEROL BIOSYNTHESIS REPRESENTS A NOVEL THERAPEUTIC TARGET FOR THE SONIC HEDGEHOG TYPE OF MEDULLOBLASTOMA

Abstract

AbstractAberrant activation of Sonic hedgehog (Shh) signaling leads to formation of numerous malignancies, including the most common pediatric brain tumor - medulloblastoma (MB). Despite recent advances in MB treatment, a significant proportion of patients still succumb to this disease. MB survivors often suffer from severe, long-lasting effects of therapy, including cognitive and endocrine disorders, as well as increased incidence of secondary tumors. Therefore, targeted therapies for MB treatment are urgently needed. Proposed strategies are aimed at blockade of Shh signaling through inhibition of its effector transmembrane protein, Smoothened (Smo). This approach is problematic as the high doses required for tumor regression are toxic and cause developmental disorders and drug resistance. Cholesterol plays a pivotal role in Shh signaling. We observed an enhanced expression pattern of cholesterol synthesis genes in Shh-driven MB. Here, we demonstrate that tumor cell-derived cholesterol is required for Shh-driven MB tumorigenesis in vivo. Additionally, ablation of Shh signaling by cholesterol depletion, both genetically and via cholesterol synthesis inhibitors, results in dramatic inhibition of tumor cell proliferation and allograft growth. Because cholesterol and traditional Smo antagonists interact with distinct sites on the Smo protein, we proposed that altering both mechanisms of Shh pathway activation could synergize to result in further tumor reduction. Excitingly, we found that combination therapy with cholesterol inhibitor simvastatin and a low dose of Smo antagonist vismodegib in an allograft model of MB results in a synergistic effect, decreasing MB tumor burden. This strategy offers a promising new avenue of therapy for this population of pediatric patients and offers further implications for other Shh-dependent malignancies.