Abstract 161: Medulloblastoma therapy targeting Hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy

Abstract

Abstract Medulloblastoma (MB) is the most frequent malignant brain tumor in children. MB patients with high-risk disease have poorly understood biology and few targeted therapies available. Preclinical studies and molecular profiling of MB have revealed that the aberrant activation and interaction of the SHH and PI3K/AKT/mTOR signaling networks are frequently associated with poor prognosis MB cases. Emerging evidence also demonstrate the key role of activated PI3K/AKT/mTOR pathway components in SHH-driven MB therapy-resistance, thus combined targeting of the SHH and PI3K/AKT/mTOR pathways may be a viable therapeutic strategy to treat high-risk patients. Therefore, we investigated the combined efficacy of SHH inhibitor vismodegib and PI3K-mTOR dual inhibitor BEZ235 or their combination, individually with the chemotherapeutic drug cisplatin against high-risk MB. Using four MB cell lines, including non-MYC and MYC amplified cell lines, and a xenograft mouse model, the in vitro and in vivo efficacies of the proposed therapies on cell growth/survival along with associated molecular mechanism(s) were investigated. Our results showed that both inhibitors as single agents significantly decreased MB cell growth and induced apoptosis by targeting the key molecules of the associated pathways in vitro. BEZ235 as single agent showed a greater anti-MB efficacy compared to vismodegib. Combined treatment of vismodegib and BEZ235 together or with cisplatin significantly decreased MB cell growth/survival and anchorage-independent growth in a dose-dependent fashion compared to single agent activity. Corresponding changes in the expression of the targeted molecules following therapy were observed. Results from the combined approach suggested that the inhibitors not only suppressed MB cell growth/survival when combined, but also significantly enhanced the cytotoxic effects of cisplatin. Of these combinations, BEZ235 exhibited a significantly greater efficacy in enhancing the cisplatin-mediated MB cytotoxicity. In vitro studies also demonstrated that the MYC amplified MB cell lines showed a higher sensitivity to these combined therapies compared to relatively non-MYC amplified cell lines. Therefore, as a next logical step, we tested the efficacy of above combined approaches against MYC-amplified MB in vivo using NSG mice. Our in vivo results showed that the combination of vismodegib and BEZ235 or their combinations individually with cisplatin significantly delayed tumor growth and increased survival of xenograft mice compared to single agent activity. These combination not only significantly reduced tumor growth and increased survival of the mice but also significantly enhanced anti-MB efficacy by targeting SHH and mTOR pathways in MB in vivo. Thus, our studies lay a foundation for translating these combined therapeutic strategies to the clinical setting to determine their efficacies in high-risk MB patients. Citation Format: Nagendra K. Chaturvedi, Don W. Coulter, Timothy R. McGuire, Matthew J. Kling, Sutapa Ray, Shantaram S. Joshi, John G. Sharp. Medulloblastoma therapy targeting Hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 161. doi:10.1158/1538-7445.AM2017-161