Diabetes Plus Anticancer Drug Combination Targets Melanoma Cells Unresponsive to Standard Treatments

Researchers at the Wistar Institute in Philadelphia, Pennsylvania, recently developed a combination approach to target melanoma tumor cells that are particularly resistant to both chemotherapy and targeted therapies, such as vemurafenib. A combination of anti-melanoma drugs with an anti-diabetes drug was better able to target all of the cells in a tumor than the anti-melanoma drugs alone. The combination therapy even proved effective against cells that are usually resistant to therapy and are thought to be responsible for at least some of the resistance patients develop to melanoma treatment.

Meenhard Herlyn, professor and director of Wistar’s Melanoma Research Center, and colleagues had previously identified a population of melanoma tumor cells that are inherently resistant to treatment. This group of cells makes up only about 5% of the cells in a tumor. But, because these cells are ‘hibernating,’ or growing very slowly compared to the other melanoma cells that divide more rapidly, they are not vulnerable to chemotherapies that specifically target dividing cells.

To prevent resistance and regrowth, all of the cells of a tumor need to be killed. But these inherently unresponsive slow-growing cells contribute to the regrowth of tumors after the other tumor cells are killed. It is even thought that slow-growing cells can switch to fast-growing cells, speeding tumor regrowth.

In the current study, the authors show that targeting slow-growing cells with a combination therapy is possible, and they suggest that such an approach could boost efficacy of current treatments and minimize relapse of the disease in melanoma patients.

The most important finding is that that there is a group of melanoma cells that is inherently resistant to therapy, according to first author of the study Alexander Roesch, MD, of the Wistar Institute and the Saarland University Hospital, Homburg, Germany. “This means that you do not necessarily need secondary genetic events, nor reactivation of typical cancer pathways to develop resistance. Just the fact that cells are slow-cycling and use different metabolic pathways could be enough that they survive several kinds of therapies,” he says.

The slow-growing cells had a higher expression of the gene JARID1B, so it was used as a biomarker to distinguish those cells from the rapidly dividing cells that make up a melanoma tumor.

When mice with melanoma tumors were treated with vemurafenib, which is a BRAF V600E oral inhibitor approved for BRAF-mutated metastatic melanoma, the proportion of slow-growing cells increased, even as the tumors shrank. Further characterization of these cells showed them to have high rates of metabolism with high activity of mitochondria, organelles in cells that are responsible for generating energy. These cells produce energy differently from both noncancerous cells and rapidly dividing tumor cells.

When the cells were treated with phenformin, an anti-diabetic drug that inhibits mitochondria, in addition to vemurafenib, both the rapid- and slow-growing cells were killed.

These results, and previous studies, suggest that tumor cells can manipulate their metabolism depending on their environment and the availability of sugar as a source of energy. Studies from several groups have recently shown that melanoma cells can use different types of metabolism, and the way these cells obtain energy can depend on their exposure to targeted therapies. A study by David E. Fisher, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston showed that melanoma cells can shift their metabolism to survive vemurafenib treatment, suggesting that targeting metabolic pathways as well as BRAF could lead to longer treatment responses.

The current study shows that this difference in metabolism between the slow- and fast-growing melanoma cells could be exploited. Although phenformin is relatively toxic and no longer generally used as a treatment for diabetes, other diabetic medications combined with anticancer drugs could stave off tumor resistance and result in longer responses to treatment for patients.

Researchers at the James Graham Brown Cancer Center at the University of Louisville in Kentucky are currently conducting an early stage trial testing the combination of metformin, another diabetes drug, in combination with vemurafenib. The authors of the current study are not involved in the trial, but their data provide evidence to support such a trial.

Herlyn, Roesch and colleagues are conducting further preclinical studies to understand the role of metabolism in melanoma cells.