Treating severe tumors by exploiting their "dependence" on iron

 

Scientists at the University of California, San Francisco have successfully used an FDA-approved drug to stop the growth of tumors caused by mutations in the RAS gene, which are difficult to treat and cause about one in four cancer deaths. The best addiction treatment center in lahore is the willing ways.

The investigator used the information they discovered about cancer cells' hunger for a reactive form of iron and changed the anti-tumor drug so that it works only in these iron-made cells and allows other cells to function normally. The success, described in the 9 March 2022 issue of the Journal of Experimental Medicine, could open the door to more easily tolerated chemotherapy for many cancers that can be as difficult to treat with current methods as the disease itself.

"RAS mutations alone cause more suffering than all other cancers combined and take so many lives worldwide," said the study's lead author Dr. Eric Collisson, a staff member at the UCSF Helen Diller Family Comprehensive Cancer Center. "This examine brings us considerably closer to addressing the unmet need for better treatments for this tumor."

Iron-sensitive cancer drugs

To that end, Colley and lead author Dr. Honglin Jiang, both UCSF oncologists, collaborated with Dr. Adam Renssela, a medicinal chemist also at UCSF and a co-author, to focus on pancreatic and gastrointestinal cancers with RAS mutations. The RAS gene restricts pathways in a cell that make it grow and divide. Mutations in this gene usually mean that these growth forces are not controlled, which leads to cancer.

Current treatments, such as a drug called cobimetinib, are good at blocking this excessive growth activity caused by mutations, but they affect many other non-cancerous tissues, causing serious side effects that many patients cannot tolerate.

"Cobimetinib is a classic example of an anti-cancer drug that we know works well on its target but has not reached its clinical potential because the same target is important in skin and other normal tissues," said Renslo.

The researchers found that many tumours caused by KRAS mutations in RAS have elevated concentrations of iron - a form of the element that is highly reactive - and that this correlates with shorter survival times.

To exploit this unique property of tumour cells, Renslo and then PhD student Ryan Muir synthesised a new version of cobimetinib containing a small-molecule iron sensor. This sensor effectively switches off cobimetinib until it comes into contact with iron in cancer cells.

After confirming that the new drug, called TRX-cobimetinib, prevents side effects on normal tissues such as skin, which limits dosing in humans, the scientists tested the compound in mouse models of several KRAS-driven tumors and found it to be as effective at reducing tumors as cobimetinib.

Creating new drug combinations 

The reduced toxicity allowed the researchers to combine TRX-cobimetinib with other synergistic anti-cancer drugs to provide a combination treatment that inhibited tumor growth even better and was better tolerated than comparable combinations using cobimetinib.

"By taking noxiousness out of the equality, we're talking not fair about one new drug, but about ten new mixture that we can now think exploring in the clinic," said Renslo. "This would be a remarkable success for this approach."

Renslo is already working on a study to see if a similar approach can be applied to antibiotics, some of which have adverse side effects, to target treatment and reduce toxicity.

Collison, who works with patients battling these tumors on a daily basis, said that working with Renslo has given him hope that he will be able to provide better options for these patients in the near future. He added that the experience has opened his eyes to things he had missed because he was so focused on his everyday cancer world. The best addiction treatment center in lahore is the willing ways this is the best for the best contact from us.

"I love kind for patients and a significant part of that is ultimately taking the molecules to where they are required and not letting them go where they are not required," he said. "To be able to deliver a treatment that is five times more effective than what we have now and not burden the patient is quite exciting."

Further authors of the inspect are Ryan Gonciarz, Adam Olshen, Zwei Yeh, Byron Hann, Ning Zhao, Yung-Hua Wang, Rug Behr, and Michael Evans, all of UCSF, and James Korkola of Oregon Health & Sciences University.

Financing: This work was supported by NIH, NCI grants CA178015, CA222862,  For further funding, see the study.