A new review article published in the journal Trends in Cancer is presenting a promising case for phenformin, an old diabetes drug related to metformin, being repurposed as an adjunct to new immunotherapy cancer treatments. A phase 1 clinical trial is already underway to test the safety of the combination treatment for skin cancer.
Metformin, a common drug prescribed to manage diabetes, is currently the subject of a number of compelling investigations into potential alternate uses, from slowing age-related cognitive decline to possibly even extending a person’s lifespan.
Retrospective epidemiological studies have also suggested metformin could possess anti-tumor properties. Preclinical and animal studies have been promising but so far early clinical work has delivered mixed results when repurposing the drug, either alone for cancer treatment, or in combination with other therapies.
Metformin is part of a class of oral antihyperglycemic drugs called biguanides. Phenformin is another biguanide, more potent than metformin and discontinued as a diabetes treatment back in the mid-1970s due to reports of lactic acidosis.
Now researchers are looking back to phenformin, this time as a potential adjunct to newly developed cancer immunotherapies. The hypothesis is that phenformin’s increased potency compared to metformin could help bridge the gap from successful preclinical research to human clinical trials.
"While the outcomes of various clinical studies of metformin in cancer patients have been underwhelming, research from our laboratory and others suggests that phenformin may have greater potential, particularly in combination with immunotherapies," explains Bin Zheng, senior author on the new study.
The new study presents a body of preclinical evidence demonstrating the potential of phenformin to significantly increase the anti-tumor activities of immunotherapy treatments. Zheng suggests there are several plausible mechanisms to justify how phenformin could amplify the effectiveness of cancer immunotherapy.
"We have found, for example, that phenformin, but not metformin, enhances the efficacy of BRAF inhibitors in suppressing the proliferation of BRAF-mutant melanoma cells and BRAF-driven tumor growth in animal models,” Zheng notes.
The toxic side effects that led to phenformin being pulled from the market nearly 50 years ago are relatively low when compared to the adverse effects seen in current cancer treatments such as chemotherapy. This toxicity profile made the drug unsuitable as a long-term diabetes treatment, but Zheng suggests it is well within the limits of what is acceptable for a short-term cancer treatment.
A phase 1 clinical trial is currently underway testing phenformin alongside dabrafenib/trametinib, a combination immunotherapy treatment for metastatic melanoma.
"If the safety of phenformin is confirmed in this trial, combinations of phenformin with targeted immunotherapies such as anti-PD-1 (programmed cell death 1 antibodies, which stimulate anti-tumor immunity) could be explored for patients with various types of solid tumors," says Zheng.
Alongside the burgeoning interest in phenformin, other experimental biguanides have been developed to more specifically target cancer. IM156, for example, is a novel molecule derived from phenformin and recently demonstrated promising results from a phase 1 human trial.
The new research was published in the journal Trends in Cancer.
Source: Massachusetts General Hospital
