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Novel selective mTORC1 inhibitors

Project description

Novel therapy for liver cancer could improve prognosis

More than 600 000 people die annually from hepatocellular carcinoma (HCC), the main type of primary liver cancer. HCC is associated with a variety of risk factors (including hepatitis B, hepatitis C and heavy drinking), but most cases occur in low- and middle-resource countries as a result of exposure to toxins. These regions also have reduced access to surveillance, resulting in advanced disease, for which few treatment options are currently available. mTORC1 is a protein complex involved in cellular signalling. Its inhibitors are approved for some advanced cancers, but not HCC, partially due to problems with its efficacy and specificity. The EU-funded inhibiTOR project has developed an assay to identify better mTORC1 inhibitors and test them in vitro, both alone and in combination with currently approved treatment. Better HCC treatment options would significantly enhance the quality and length of life of HCC patients.

Objective

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and the fourth leading cause of cancer-related deaths worldwide. The multikinase inhibitor sorafenib is the only approved drug to treat HCC and on average enhances survival by three months. Thus, the efficacy of current HCC treatment options is very limited. Studies in the context of our ERC-Synergy grant revealed that sorafenib resistance correlates with upregulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. The central role of mTORC1 in conferring therapy resistance suggests that effective therapy against HCC may require combination of a primary inhibitor (e.g. sorafenib) and an mTORC1 inhibitor. The mTORC1 inhibitor rapamycin and its derivatives (rapalogs) are approved for a few advanced cancers, but not for HCC. Their clinical applicability is limited by their effectiveness and safety. Rapalogs fail to completely inhibit mTORC1 as they have little effect on inhibiting phosphorylation of 4E-BP, one of the two main targets of mTORC1. Moreover, rapamycin and rapalogs also inhibit mTORC2 when chronically administered, leading to undesirable effects such as hyperglycemia, hyperlipidemia, and insulin resistance. We have established a biophysical assay to identify selective mTORC1 inhibitors with a novel, rapalog-unrelated, mechanism of action. We predict these inhibitors to be more selective, more effective, and potentially safer than mTORC1 inhibitors currently used in the clinic. In this Proof of Concept project, we aim to study the pharmacological potential of selective and efficient mTORC1 inhibition alone or in combination therapy with sorafenib to treat HCC.

Fields of science

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Host institution

UNIVERSITAT BASEL
Net EU contribution
€ 150 000,00
Address
PETERSPLATZ 1
4051 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Higher or Secondary Education Establishments
Links
Total cost
No data

Beneficiaries (1)