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Selective mTORC1 inhibition as an innovative anti-cancer approach

Research Project
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01.08.2021
 - 31.01.2023

Mammalian target of rapamycin (mTOR) is a central controller of cell growth and metabolism. mTOR forms two structurally and functionally distinct protein complexes termed mTORC1 (mTOR complex 1) and mTORC2. mTOR in general, and mTORC1 in particular, is upregulated in approximately 70% of all cancers. Thus, mTOR(C1) is a very attractive target for anti-cancer therapy. Current approaches to inhibit mTORC1 focus on targeting mTOR. Currently approved drugs that inhibit mTORC1 (rapamycin/rapalogs) are used in a limited subset of cancers but are non-efficient and partially non-selective. ATP-competitive mTOR inhibitors (currently in dozens of clinical trials for cancer) are efficient but non-selective and toxic. Thus, there is an unmet medical need for new mTORC1 inhibitors with improved pharmacological profiles that could be applied in multiple cancer indications. This project arises from our fundamental research. We have discovered an innovative approach to selectively inhibit mTORC1 by targeting RAPTOR, the mTORC1-specific subunit responsible for the substrate recruitment. Our approach is unconventional and thus innovative as it targets the mTORC1-specific subunit RAPTOR. Conventional inhibitors target mTOR. Based on a small molecule screen in vitro, we have identified seven promising candidates. We seek support from Krebsliga to determine the effect of the candidates on mTORC1 signaling in particular and on metabolism in general, in a broad variety of human cancer cell lines. The results from this laboratory-oriented research project will be highly significant for the development of new mTORC1-related cancer treatments: i) the compounds with promising effects in cultured cells will be tested in mouse models of cancer (beyond this project) thereby bringing new anti-cancer treatments one step closer to clinical trials and ultimately to cancer patients. ii) In light of emerging efforts in personalized cancer treatments, determination of the effect of the compound candidates in different cancer cell lines will help characterize the most responsive cancer types. Used in the right set of cancer patients, RAPTOR-targeted mTORC1 inhibitors might be particularly effective.

Funding

Selective mTORC1 inhibition as an innovative anti-cancer approach

Foundations / Associations (GrantsTool), 08.2021-01.2023 (18)
PI : Hall, Michael N..

Members (3)

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Michael N. Hall

Principal Investigator
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Asier Gonzalez Sevine

Co-Investigator
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Stefan Imseng

Co-Investigator