Improved therapy for medulloblastoma: targeting hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy
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Nagendra K. Chaturvedi1, Matthew J. Kling2, Don W. Coulter1, Timothy R. McGuire3, Sutapa Ray1, Varun Kesherwani4, Shantaram S. Joshi2 and J. Graham Sharp2
1Departments of Pediatrics, Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE 69198, USA
2Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 69198, USA
3Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE 69198, USA
4Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 69198, USA
Nagendra K. Chaturvedi, email: email@example.com
Keywords: medulloblastoma; hedgehog/PI3K-mTOR pathway; MYC; small molecule inhibitors; chemotherapy
Received: December 21, 2017 Accepted: February 21, 2018 Published: March 30, 2018
Aberrant activation and interactions of hedgehog (HH) and PI3K/AKT/mTOR signaling pathways are frequently associated with high-risk medulloblastoma (MB). Thus, combined targeting of the HH and PI3K/AKT/mTOR pathways could be a viable therapeutic strategy to treat high-risk patients. Therefore, we investigated the anti-MB efficacies of combined HH inhibitor Vismodegib and PI3K-mTOR dual-inhibitor BEZ235 together or combined individually with cisplatin against high-risk MB. Using non-MYC- and MYC-amplified cell lines, and a xenograft mouse model, the in vitro and in vivo efficacies of these therapies on cell growth/survival and associated molecular mechanism(s) were investigated. Results showed that combined treatment of Vismodegib and BEZ235 together, or with cisplatin, significantly decreased MB cell growth/survival in a dose-dependent-fashion. Corresponding changes in the expression of targeted molecules following therapy were observed. Results demonstrated that inhibitors not only suppressed MB cell growth/survival when combined, but also significantly enhanced cisplatin-mediated cytotoxicity. Of these combinations, BEZ235 exhibited a significantly greater efficacy in enhancing cisplatin-mediated MB cytotoxicity. Results also demonstrated that the MYC-amplified MB lines showed a higher sensitivity to combined therapies compared to non-MYC-amplified cell lines. Therefore, we tested the efficacy of combined approaches against MYC-amplified MB growing in NSG mice. In vivo results showed that combination of Vismodegib and BEZ235 or their combination with cisplatin, significantly delayed MB tumor growth and increased survival of xenografted mice by targeting HH and mTOR pathways. 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.
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