Unexpected Drug Benefits

I have written before of drugs that were developed for a particular disease, but, surprisingly, were later found to be effective against a completely unrelated one. Perhaps the most famous is thalidomide, used in the 1950s in England as a treatment for morning sickness. Because of the horrific birth defects that resulted from its use, sales were banned. But following elucidation of its mechanism of action, thalidomide has been repurposed as an effective treatment for a number of cancers as well as leprosy (but certainly not to be taken by pregnant women!).

In Medieval Europe, herbalists prescribed French lilac to patients with polyurea (excessive urination), a condition now known as a symptom of type II diabetes. In the 20th century, doctors isolated the active ingredient from the lilac plant, and this led to the development of biguanide drugs to lower blood sugar. One of these drugs, phenformin, was first prescribed in the 1950s, but it was withdrawn in the 1970s due to potentially dangerous side effects. A safer biguanide, metformin, was approved by the FDA in 1995 and has since become the most common drug prescribed for type II diabetes in the United States. And 10 years after its approval, scientists found potent antitumor activity in the drug.

I have been taking metformin for a number of years and must admit I am delighted that the drug protects against a number of cancers. If you have watched late night television, you have probably experienced pitches for specific drugs (“Ask your doctor about…”) that usually include a dizzying list of undesirable side effects, some quite frightening. In contrast, the anti-cancer action of metformin is a rather nice “side effect” to contend with.

Lab studies have shown that both phenformin and metformin exhibit antitumor activity. However, although researchers have shown that diabetics taking metformin are statistically less likely to develop cancer, clinical trials of metformin for treating preexisting cancers have been underwhelming. A new study argues that phenformin may have greater potential, particularly in combination with immunotherapies. Though phenformin is more toxic than metformin, it is relatively safe in the context of chemotherapy (it is less toxic than several chemotherapeutic drugs). Half of melanoma skin cancers possess changes in the BRAF gene that leads to uncontrollable cell division. In lab-based studies, phenformin enhances the ability of BRAF inhibitor drugs to block the activity of this mutant gene.

Clinical trials are now underway with this combinational therapy against melanomas. If
successful, they may be expanded to include additional drug combinations as well as testing against other cancers.  A proposed mechanism for the action of phenformin on both diabetes and cancer is that it alters the gut microbiota, that important bacterial population in the digestive tract that effects so many aspects of physiology.