INS and cancer: The notion that conventional phase I and II trials must explore the possibility of exposing tumors to the higher biguanide concentrations used in many preclinical models is certainly supported by the strong anti-cancer efficacy of the intraperitoneal high-dose exposure to metformin observed in PI3K-mutated, insulin-independent human cancer xenotumors, in which the anti-cancer effects of metformin necessarily involve mechanisms distinct from those that might operate with the doses used in the clinical management of type 2 diabetes [8].