Therapeutics: Ribosomal protein S6 kinase 70kDa polypeptide 1 (RPS6KB1; S6K1); mammalian target of rapamycin (mTOR; FRAP; RAFT1)

Cell culture and mouse studies suggest combining inhibitors of glycolysis and the mTOR/RPS6KB1 pathway could help treat cancer. In a human ovarian cancer cell line, the glycolysis inhibitor 2-deoxy-D-glucose plus an RPS6KB1 inhibitor tool compound decreased levels of cell metabolism markers compared with the tool compound alone. In human ovarian and liver cancer cell lines, 2-deoxy-D-glucose plus the RPS6KB1 inhibitor or phenformin - a generic non-specific mTOR inhibitor- decreased cell proliferation compared with either agent alone. In a xenograft mouse model of liver cancer, 2-deoxy-D-glucose plus Afinitor everolimus decreased tumor growth. In xenograft mouse models of liver and ovarian cancers, shRNA targeting the glycolytic enzyme glucose-6-phosphate isomerase (GPI) plus Afinitor or phenformin decreased tumor growth compared with any of the agents alone. Next steps could include testing the efficacy of glycolysis inhibitors plus mTOR inhibitors in additional cancer models.

Novartis AG markets Afinitor, an oral mTOR inhibitor, to treat brain cancer, breast cancer, renal cancer, neuroendocrine tumors, heart transplant rejection and renal transplant rejection. Novartis also has the drug approved to treat liver transplant rejection and graft rejection. ...