Since cancer cells crave a reactive form of iron, scientists tweaked an anticancer treatment to exclusively act on those iron-rich cells, leaving the rest of the body’s cells alone to do their jobs.

A drug that has been approved by the FDA can stop the growth of tumors that are caused by mutations in the RAS gene, which are hard to treat and kill about one in four people with cancer.

Scientists at UCSF have used an FDA-approved medicine to block the growth of tumors driven by RAS gene mutations, which are notoriously tough to treat and account for nearly one in four cancer deaths, according to the researchers.

Using what they determined to be cancer cells’ hunger for a reactive form of iron, the researchers modified an anticancer treatment to only act on these iron-rich cells, leaving the rest of the cells to function properly. The breakthrough was published in the Journal of Experimental Medicine today could pave the way for more acceptable chemotherapy for many tumors, where present treatments can be as difficult as the disease itself.

An Iron-Sensitive Cancer Drug

The RAS gene controls the cell’s ability to expand and divide by inhibiting growth and division-promoting pathways. When a gene is mutated, these growth forces are usually unregulated, resulting in cancer.

Current treatments, such as the medicine cobimetinib, do a decent job of blocking the abnormal growth activity caused by the mutation, but they also do so in many other, non-cancerous tissues, resulting in substantial side effects that many patients find intolerable.

“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 the authors.  

The researchers discovered that large levels of ferrous iron—a highly reactive form of the element—are detected in many tumors caused by the KRAS type of RAS mutations, and that this is linked to shorter survival durations.

The authors created a novel form of cobimetinib with a tiny ferrous iron molecular sensor to take advantage of this specific feature of cancer cells. Until it comes into contact with ferrous iron in cancer cells, the sensor effectively shuts cobimetinib off.

After confirming that the new drug, dubbed TRX-cobimetinib, did not cause adverse effects on normal tissues such as skin, which limit dosing in human patients, the researchers tested the compound in mouse models of several KRAS-driven cancers and discovered that it was just as effective as cobimetinib in shrinking tumors.

Finding New Drug Combo

Because of the lower toxicity, the researchers were able to combine TRX-cobimetinib with other synergistic anticancer medications to create combination treatments that were both more effective at reducing tumor development and tolerable than comparable cobimetinib-based combinations.

“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,” according to authors. “That would be the home run for this approach.”

The team is now working on determining whether a similar strategy may be used to target treatment and reduce toxicity in antibiotics, some of which have unfavorable side effects.

Source: 10.1084/jem.20210739

Image Credit: Getty

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