Melanoma is an easily treatable and curable form of cancer, with cure rates as high as 95 percent if caught early. If left to later stage, however, melanoma can become one of the deadliest cancers, with survival rates below 20 percent. By that time, the cancer can become resistant to many common cancer therapies and spread throughout the body, further complicating treatment. For these reasons, researchers are looking into new drug combinations to combat these drug resistances. A new study out of the Wistar Institute at the University of Pennsylvania has shown that the combination of a diabetes drug with cancer medications can make melanoma susceptible to treatment.

"We have found that the individual cells within melanoma tumors are not all identical, and tumors contain a sub-population of cells that are inherently drug resistant, which accounts for the fact that advanced melanoma tumors return no matter how much the tumor is depleted," said Meenhard Herlyn, D.V.M., D.Sc., professor and director of Wistar's Melanoma Research Center, in a press release. "We found that these slow-growing, drug-resistant cells are marked by a high rate of metabolism, which makes them susceptible to diabetes therapeutics."

The researchers used both mouse and cell models to show that a combination of phenformin, a diabetes drug taken off of the market in the 1970s, was able to enhance chemotherapy treatment of melanoma. The drugs that worked in combination were cisplatin and the targeted therapy vemurafenib, which targets melanomas with the BRAF mutation. Nearly half of all advanced cases of melanoma have a mutation in the BRAF gene. Because phenformin has the side effect of lactic acidosis in some patients, 50 percent of which were shown to die of the condition, researchers are looking for alternate forms of the chemical that will be effective.

"Our findings suggest a simple strategy to kill metastatic melanoma — regardless of cell type within the tumor — by combining anticancer drugs with diabetes drug," Herlyn said. "The diabetes drug puts the brakes on the cells that would otherwise repopulate the tumor, thus allowing the anticancer drug to be more effective."

In 2010, the same research group published data showing that melamoma tumors had a small population of cells that was highly resistant to drug treatments. When drug-susceptible cancer cells were killed with treatment, the hearty drug-resistant cells remained, which can make drug treatments notoriously difficult. "These are not dormant cells -- they divide once every six or seven weeks as opposed to every other day like the rest of the melanoma cells," Herlyn explained. "These slow-growing cells are apparently kept in check by the rest of the tumor, somehow--indeed, if you remove them from a tumor, they grow like crazy."

When the researchers surveyed these slow-growing cells, they saw that they were in metabolic overdrive, producing massive quantities of glucose. Because some diabetes drugs target glucose production, the researchers saw a possible avenue of treatment. The group is now working on new compounds and clinical trials to develop and exploit this type of synergistic cancer treatment.

Source: Roesch A, Vultur A, Bogeski I, et al. Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells. Cancer Cell. 2013.