Phenformin-mTOR inhibitor combination shows promise in HCC

A combination of mTOR inhibitors and Phenformin leads to an increase in overall survival…

Hepatocellular Carcinoma (HCC)

Researchers from the Metabolism and Cancer group at the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr Sara Kozma, have unveiled a new potential combined treatment for Hepatocellular Carcinoma (HCC), the second cause of cancer mortality worldwide. The combination of mTOR inhibitors together with the mitochondrial inhibitor Phenformin has shown positive results in an in vitro HCC cells, leading to a striking increase in tumour-bearing mice overall survival.

“Currently available therapeutic options for HCC are very limited and offer poor outcomes, prompting the search for new therapeutic approaches”, explains Dr Kozma, last author of the article. “Inhibitors of the mTOR pathway had already been explored as an alternative treatment, given that this pathway is hyperactivated in most HCCs, but they showed little clinical efficacy. However, as recent data suggested that mTOR inhibitors may promote cancer cell survival by maintaining mitochondrial oxidation and/or autophagy, we set out to examine their use combined with inhibitors of mitochondrial activity,” she adds.

In their study, researchers show that treatment of HCC cells in vitro with Phenformin, a mitochondrial Complex1 inhibitor, causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation. “These changes sensitise orthotopic liver tumours in mice to dual inhibition of mTOR, which improves tumour-bearing mice overall survival”, says Dr Sonia Veiga.

“Given the recent approval of Phenformin in a clinical trial for melanoma, it will be exciting to explore this regimen clinically in HCC”, says Dr Kozma. According to Dr Veiga, next steps include testing this combination in human samples thanks to the collaboration with Bellvitge Unversity Hospital and the Catalan Institute of Oncology, as well as comparing the results obtained with those of current treatments for HCC.

The study has been recently reported in Clinical Cancer Research.