EXTH-28. ENHANCING SELUMETINIB-MEDIATED KILLING OF SHH MEDULLOBLASTOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: Guppy, Brent; Liang, Lisa; Porter, Chris; Werbowetski-Ogilvie, Tamra
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi91
• Page End: vi91
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.377
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer and consists of at least 5 distinct molecular subgroups. Of these subgroups, Sonic Hedgehog (SHH) MB exhibits extensive cellular heterogeneity, increased SHH signaling, and has an intermediate prognosis. Treatment strategies employing SHH pathway inhibitors showed initial promise, however, acquired drug resistance has led to therapy failure in clinical trials. Consequently, improved chemotherapeutic strategies designed to better treat SHH MB must be identified. A major contributing factor to cellular heterogeneity, and thus drug resistance and disease progression, are rare putative brain tumor-propagating cells (TPC). As a result, identifying robust TPC biomarkers can reveal novel subgroup-specific therapies capable of targeting these elusive cell types. We recently identified the neurotrophin receptor (CD271) within the SHH MB subgroup as a promising biomarker delineating TPC populations and associated with elevated MEK/ERK signaling. Moreover, we showed that selumetinib, a MEK inhibitor, reduced CD271 levels, decreased TPC growth, and extended survival in mouse models. While promising, the mice in our in vivo studies ultimately succumb to disease progression; thus, an enhanced selumetinib-based chemotherapeutic strategy is merited. In this study, we employed RNA-sequencing to identify 543 genes differentially expressed in selumetinib resistant xenografts relative to controls. Further, gene set enrichment analysis revealed significant changes in specific signaling pathways predicted to underlie selumetinib resistance and contribute to SHH MB progression. Accordingly, to ultimately enhance survival, we employ our high-content tumorsphere assay to systematically evaluate candidate blood brain penetrant inhibitors that are highly predicted to elicit therapeutic synergy in combination with selumetinib in vivo . In addition, we will test selumetinib in combination with current SHH MB standard of care chemotherapeutics to characterize survival. Our studies will reveal mechanisms of SHH MB drug resistance, and identify novel drug combinations that may ultimately enhance MB patients' survival and quality of life.