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The ubiquitin-proteasome pathway in adult and pediatric brain tumors: biological insights and therapeutic opportunities

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Abstract

Nearly 20 years ago, the concept of targeting the proteasome for cancer therapy began gaining momentum. This concept was driven by increased understanding of the biology/structure and function of the 26S proteasome, insight into the role of the proteasome in transformed cells, and the synthesis of pharmacological inhibitors with clinically favorable features. Subsequent in vitro, in vivo, and clinical testing culminated in the FDA approval of three proteasome inhibitors—bortezomib, carfilzomib, and ixazomib—for specific hematological malignancies. However, despite in vitro and in vivo studies pointing towards efficacy in solid tumors, clinical responses broadly have been evasive. For brain tumors, a malignancy in dire need of new approaches both in adult and pediatric patients, this has also been the case. Elucidation of proteasome-dependent processes in specific types of brain tumors, the evolution of newer proteasome targeting strategies, and the use of proteasome inhibitors in combination strategies will clarify how these agents can be leveraged more effectively to treat central nervous system malignancies. Since brain tumors represent a heterogeneous subset of solid tumors, and in particular, pediatric brain tumors possess distinct biology from adult brain tumors, tailoring of proteasome inhibitor-based strategies to specific subtypes of these tumors will be critical for advancing care for affected patients, and will be discussed in this review.

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Acknowledgements

The authors gratefully acknowledge research support from the Center for Cancer Epigenetics at MD Anderson, NIH (P30 CA016672, P50 CA127001, R21 NS093387 (to J.C.) and is R01 NS079715 (to V.G.)), and the Thomas Scott Family Foundation.

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  1. Children’s Cancer Hospital, Division of Pediatrics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Wafik Zaky, Christa Manton, Claudia P. Miller, Soumen Khatua, Vidya Gopalakrishnan & Joya Chandra

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  1. Wafik Zaky
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  2. Christa Manton
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Correspondence to Joya Chandra.

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Contribution for Cancer and Metastasis Reviews Special Issue: “The Proteasome: an important player in tumor progression and a novel target for cancer therapy.”

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Zaky, W., Manton, C., Miller, C.P. et al. The ubiquitin-proteasome pathway in adult and pediatric brain tumors: biological insights and therapeutic opportunities. Cancer Metastasis Rev 36, 617–633 (2017). https://doi.org/10.1007/s10555-017-9700-2

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