Iron and Cancer
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iron and cancer

Many therapies used to treat cancer have side effects because they not only kill cancer cells, but they also affect normal cells, particularly fast-growing cells like those in the skin, the gut lining and the bone marrow. Scientists are always looking for new targets in cancer cells that are more specific so they can reduce the side effects of cancer treatments. Now scientists have found that cancers with a specific mutation in the KRAS gene seem to accumulate abnormal amounts of iron. They have designed a cancer therapy that takes advantage of this accumulated iron and reduces side effects.

Cancers develop as the result of the accumulation of mutations in certain genes called oncogenes which, when activated, drive cancer cell growth. Cancers can also have mutations in tumor suppressor genes which also contribute to tumor growth. In normal cells, these two types of genes keep cells healthy and off the track to becoming cancerous. It usually takes the accumulation of several mutations in these two families of genes to turn normal cells into cancer cells.

One oncogene that is mutated in several cancers is called KRAS. This mutated gene causes sarcomas, a type of tumor that develops in connective tissue, such as bone, cartilage or muscle, but fortunately only in rats. The human KRAS gene is found mutated in 22% of all cancers. Cancers that most often have this mutated oncogene include pancreatic cancer, non-small-cell lung cancer and colorectal cancers. The KRAS gene represents a good potential target for the development of a cancer therapy.

There are few drug therapies directly targeting KRAS, but the ones available now have numerous serious side effects that make patients' lives miserable. However, the accumulation of iron in tumors with KRAS mutations provides an opportunity to target a therapeutic and reduce the side effects. Iron is most well-known for its role carrying oxygen throughout the body as part of hemoglobin in red blood cells. Iron is an essential nutrient, but too much of it is toxic to cells. To keep it in check, the body has a highly sophisticated regulation system to meet the iron demands of cells while preventing excess accumulation.

We do not know why cancers with mutated KRAS genes accumulate iron. Iron also plays roles in certain enzymes involved in cell growth, energy production, and expression of genes, some of which could play roles in cancer. So, scientists decided to link a drug that is used to treat KRAS tumors, cobimentinib, with a delivery system that only releases the drug in the presence of high amounts of iron. This new version of the drug is called TRX-cobimentinib. In experiments with mice, the drug killed pancreatic tumors with elevated levels of iron without obvious side effects.

Of course, now comes the hard part: clinical trials in humans to determine if the TRX-cobimentinib is as safe and effective as it has been in mice. With so many cancers having the KRAS mutations, it could be a very useful therapy.

For more information…

Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. ..

This New Drug Turns Cancer's Secret Addiction Against Itself
In a new study published in the Journal of Experimental Medicine on Wednesday, a team of researchers at the University of California, San Francisco found certain cancer cells harbor a mutation in a gene called KRAS, allowing them to hoard large amounts of iron. The UCSF team took advantage of this iron addiction to develop a novel anti-cancer treatment that can specifically hone in and target certain types of cancer-while sidestepping the infamously debilitating and toxic effects of chemotherapy and similar treatments...