Modern medicine has provided many cancer drugs with life-saving capabilities, but often toxic effects on healthy cells and resulting side effects stop them from reaching their full potential. Modifications to an existing drug promise to overcome this problem for a common and deadly form of cancer, with the scientists hailing the breakthrough as a potential "home run" for next-generation treatments.
The focus of this new study is the RAS gene, which can play an important role in the body's defenses against cancer by regulating pathways in cells that enable them to grow and divide. Mutations in this gene remove these checks and balances, making for uncontrolled growth and the development of tumors. Tumors arising from these mutations are in turn famously difficult to treat and account for around one in four cancer deaths.
“RAS mutations, by themselves, cause more misery than all other cancers combined, and take so many lives worldwide,” said Eric Collisson, a senior author of the study from the University of California, San Francisco. “This study brings us much closer to addressing the unmet need for better treatment of these cancers.”
The advance Collisson refers to came about by studying a type of mutation in the RAS gene called KRAS mutations. The scientists found that a lot of the tumors driven by these mutations contain high concentrations of ferrous iron, a highly reactive form of iron, and that there was a connection between these elevated iron levels and shorter survival times for patients.
To take advantage of the tumors' "ferroaddiction," the scientists used an FDA-approved cancer drug called cobimetinib as their starting point. This drug is effective at halting the out-of-control cell growth brought on by KRAS mutations, but is unable to do so selectively, having toxic effects on healthy tissues that leads to severe side effects for patients.
“Cobimetinib is a classic example of an anticancer drug that we know works well on its target, but it hasn’t achieved its clinical potential because the same target is important in the skin and other normal tissues,” said co-senior author Adam Renslo.
The scientists were able to synthesize a new form of cobimetinib equipped with a molecular sensor for ferrous iron. This means the drug remains inactive until it comes across ferrous iron in the cancer cells, which switches it on and selectively activates its anti-cancer effects.
The team demonstrated the effectiveness of the new drug, dubbed TRX-cobimetinib, through experiments on mouse models of KRAS-driven cancers. This showed that it was just as effective as cobimetinib at shrinking tumors, but did so without the typical adverse effects. With lower levels of toxicity, the scientists could then bring other cancer drugs into the mix to ramp up the attack, enabling combination treatments that could prevent tumor growth with even greater effectiveness.
“By removing toxicity from the equation, you’re talking not just about one new drug, but 10 new combinations that you can now think about exploring in the clinic,” said Renslo. “That would be the home run for this approach.”
The scientists believe the approach could also be applied to antibiotics, and are studying how targeting similar mechanisms could help reduce their unwanted side effects.
The research was published in the Journal of Experimental Medicine.
