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

Nagendra K Chaturvedi,Don W Coulter,Shantaram S Joshi,Timothy R Mcguire,Varun Kesherwani,Sutapa Ray,Matthew J Kling,J Graham Sharp

doi:10.18632/oncotarget.24618

Nagendra K Chaturvedi, Don W Coulter + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.24618

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Journal: Oncotarget	Publication Date: Mar 30, 2018
Citations: 34	License type: cc-by

Affiliation: University of Nebraska Medical Center

Abstract

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.

Highlights

Medulloblastoma (MB) is the most prevalent pediatric brain tumor and one of the leading causes of brain cancer deaths in children [1]
Our results demonstrate that the combination of BEZ235 and Vismodegib does target the PI3K-mTOR and HH signaling pathways, and thereby decreases cell growth and induces apoptosis in sonic hedgehog (SHH)/MYC-driven MB cells
The combination efficacy of these inhibitors in inducing apoptosis, were consistent with the growth inhibitory effects. These results suggested that inhibitors and cisplatin showed anti-MB efficacies alone, the combination treatments significantly sensitized MB cells to enhanced growth inhibition and apoptosis, in part mediated by targeting HH and PI3K-mTOR pathways

Summary

Introduction

Medulloblastoma (MB) is the most prevalent pediatric brain tumor and one of the leading causes of brain cancer deaths in children [1]. The WNT-MBs subgroup displays the most favorable patient outcomes, while Group 3 and www.oncotarget.com. Group 4 MB patients demonstrate the poorer survival outcomes [1,2,3]. Of these four types, SHH-MBs are most common in infants and adults [4, 5]. Small molecule inhibitors have been developed that largely target the SMO component of SHH signaling [4,5,6]. Understanding the diverse events driving tumor progression and recurrence is necessary for identifying novel, targeted therapeutics and improving survival of patients with MB [9, 10]

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Conclusion