Vidya Gopalakrishnan

Pediatrics Research & Molecular and Cellular Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA


Abstract:

Medulloblastoma is a poorly differentiated malignant pediatric brain tumor that occurs mainly in the cerebellum. Current treatments for medulloblastoma are decided following patient stratification into standard and high-risk groups using clinical features. However, a subset of patients with standard risk features have unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and the development of novel treatments. We observed that poor differentiation, which is a hallmark of medulloblastomas, is associated with elevated expression of a repressor of neuronal differentiation called Repressor Element-1 Silencing Transcription Factor (REST). The goals of this work were to evaluate if REST elevation had prognostic significance for medulloblastoma patients, to dissect its role in medulloblastoma etiology and finally to assess if REST activity could be pharmacologic manipulated for therapeutic purposes. REST levels in patient tumors were measured by immunohistochemistry and stratified into negative, low/moderate- (+/++/+++), and high-REST (++++) groups. Kaplan–Meier curves revealed that patients with high-REST tumors had a higher incidence of recurrence and metastasis and therefore had a worse overall and event-free survival compared to patients with REST-negative or REST-low tumors. We next studied the requirement for REST in medulloblastoma development in mouse orthotopic models using primary neural progenitors engineered to express higher levels of REST alone or in combination with Myc, an oncogene that is frequently co-elevated with REST in human tumors. We observed that REST cooperated with Myc in the development of poorly differentiated tumors in the cerebellum. These results suggest that REST contributes to tumor progression. REST is an epigenetic silencer of neuronal gene expression and requires the activity of chromatin remodeling enzymes such as histone deacetylases (HDACs) and histone methyl transferases (HMTs) with which is associated. Since pharmacological inhibitors of HDAC activity are clinically important, we evaluated a panel of HDAC inhibitors (HDACIs) for their differentiation promoting and growth inhibiting abilities. Of the agents tested, suberoylanilide hydroxamic acid (SAHA) was the most efficacious in promoting the expression of REST-target neuronal differentiation genes and inhibiting medulloblastoma growth. These findings suggest that SAHA, a drug that is currently in phase-II clinical trials for pediatric tumors, may have therapeutic applications against REST-expressing tumors. In summary, our work has identified REST as a novel indicator of poor prognosis for medulloblastoma patients, discovered a role for REST in medulloblastoma development and demonstrated the therapeutic potential of HDACIs such as SAHA for patients with RESTpositive tumors.