Biguanides and targeted anti-cancer treatments

Drug repositioning and molecularly targeted novel drug development are two contrasting strategies in cancer research. Yet, certain combinations of the two may bring together the best of both worlds. Drug repositioning, i.e. the use of a drug for treating diseases other than the drug-specified, is a strategy to advance patient care more quickly and efficiently. The idea was promoted in 2012 through the Discovering New Therapeutic Uses for Existing Molecules program, initiated by NIH. Several drugs used for other purposes have proved to be effective anti-cancer agents, including thalidomide, aspirin, and celecoxib. In contrast, novel drug development is a lengthy process. Molecularly tailored drugs fail for various reasons including inadequate bioavailability and adverse side effects, and are often very expensive. Despite drawbacks to targeted drug development, there are also successes in this area of research. Cancer therapeutics designed to inhibit kinases involved in cell growth and survival pathways are potent and selective in the short term. By directly blocking cell signaling, often at the source of over-activation, these drugs kill cancer cells. One example of success in targeted therapy is the development of BRAFV600E inhibitors, vemurafenib and dabrafenib, and their ability to prolong progression-free survival time in melanoma patients. However, a major problem with monotherapy is the inevitable development of resistance. Even with combination treatment using specific inhibitors, such as BRAFV600E and MEK inhibitors in melanoma, improvement in patient outcome is limited [1,2] and resistance emerges. There is increasing interest in combining targeted inhibitors with common metabolic regulators to hinder resistance. This unique combination reaps both the intrinsic benefits of repurposing drugs and the selectivity of targeted therapy. The major biguanides, metformin and phenformin, have known pharmacokinetics, high safety profiles, and are relatively inexpensive. Metformin in particular is widely used for treatment of patients with type 2 diabetes. Although there is evidence in literature for both pro-cancer and anti-cancer effects of metformin on cancer cells, a clear association between metformin therapy and reduced risk of cancer in diabetic patients exists. Recent studies point out direct cellular benefits of combining biguanides with current targeted therapy. Biguanides in combination with targeted inhibitors synergistically reduced cell viability and inhibited tumor growth in BRAFV600E-positive and NRAS mutant melanoma cells [3,4]. In the latter case, even when the driver NRAS mutation was not targeted itself, inhibition of a downstream molecule was more effective when used in combination with metformin [4]. Another study determined that metformin …