Editors' ChoiceCancer therapy

A link closer to glioblastoma therapy

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Sci. Signal.  04 Apr 2017:
Vol. 10, Issue 473, eaan3515
DOI: 10.1126/scisignal.aan3515

A next-generation mTOR inhibitor combines features of its predecessors to more potently and durably inhibit the growth of glioblastoma in mice.

Glioblastoma (GBM) is a highly aggressive brain tumor commonly associated with mutations that activate or enable increased signaling by the PI3K–AKT–mTOR kinase pathway. However, current pharmacological inhibitors targeting the pathway fail to durably suppress mTOR activity in GBM patients. Fan et al. found that a new mTOR kinase inhibitor called RapaLink-1 induced tumor regression in mouse models of GBM. RapaLink-1 combines a second-generation orthosteric inhibitor with rapamycin, a first-generation allosteric inhibitor targeted to the mTOR complex 1 (mTORC1). RapaLink-1 was more potent and durable than either orthosteric or allosteric inhibitors alone at suppressing proliferation and the phosphorylation of mTORC1 substrates in cultured GBM cells, even in those expressing mutant mTOR (typically a cause of drug resistance in patients), as well as in cell line–derived or patient-derived xenografts and in genetically engineered GBM model mice. RapaLink-1 induced tumor regression in some mice and improved survival without apparent toxicity. A clinical challenge of targeting the PI3K-mTOR pathway in GBM is effectively preventing the feedback activation that enables acquired drug resistance. As our understanding of the intricacies of signaling networks evolves, so does the development of more targeted and effective drugs. Further investigation will reveal whether this new mTOR-targeted drug delivers this need for patients and clinicians desperate for a durable therapy.

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