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Tumours driven by mutations in the RAS gene are difficult to treat and account for about one in four cancer deaths. Now, scientists at the University of California, San Francisco, have successfully leveraged an FDA-approved drug to halt growth of such type of tumours. They believe that the new cancer drug with an iron sensor could lead to the development of more tolerable chemotherapy for many 'difficult to treat' cancers.
For developing the new drug, the researchers focussed on what they discovered to be the cancer cells' appetite for a reactive form of iron. They then tweaked the anticancer drug 'cobimetinib' to operate only in these iron-rich cells, leaving other cells to function normally. They have named the new drug 'TRX-cobimetinib'.
Cancers with RAS mutations cause more misery than all other cancers combined, and take so many lives worldwide, said senior author Eric Collisson, MD, a member of the UCSF Helen Diller Family Comprehensive Cancer Center.
He hopes that their study could help in "addressing the unmet need for better treatment of these cancers."
Collisson collaborated with lead author Honglin Jiang, MD, and Adam Renslo, PhD, a pharmaceutical chemist, both from UCSF.
For the study, the research team focussed on RAS-mutated pancreatic and gastrointestinal cancers. The RAS gene helps in tamping down pathways in the cell that drive it to grow and divide. When there are mutations in the gene, these growth forces go unchecked, which leads to cancer.
Current cancer treatments, such as the drug cobimetinib, can block this excessive growth activity set in motion by the mutation. But they also impact other non-cancerous tissues, leading to serious side effects that many patients find intolerable.
The researchers discovered that many tumours driven by the KRAS form of RAS mutations have elevated concentrations of ferrous iron -- a form of the element that is highly reactive -- and that this is correlated with shorter survival times.
Taking advantage of this unique characteristic of the cancer cells, the researchers created a new version of cobimetinib bearing a small, molecular sensor of ferrous iron. The sensor keeps cobimetinib off until it encounters ferrous iron in the cancer cells, the researcher stated.
the researchers tested TRX-cobimetinib in mouse models of several KRAS-driven cancers and found that the drug was just as effective as cobimetinib in shrinking tumours, as well as prevented adverse effects on normal tissues.
Due to the reduced toxicity, TRX-cobimetinib could be combined with other synergistic anticancer drugs to provide combination treatments. The new drug combinations proved even better at inhibiting tumour growth and were better tolerated than comparable combinations using cobimetinib, the researchers said.
Their achievement was described in the March 9, 2022 issue of the Journal of Experimental Medicine.
Renslo is now studying whether a similar approach can be applied to antibiotics to improve their efficacy and reduce toxicity.
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