Improved therapy for medulloblastoma: targeting hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy.

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