La Jornada newspaper
Wednesday, September 1, 2021, p. 2
Madrid. Researchers at the University of British Columbia School of Medicine and Cancer Research Institute in Canada discovered a weak point in a key enzyme that solid tumor cancer cells depend on to adapt and survive when oxygen levels are high. low.
The findings, published in the journal Science Advances, will help develop new treatment strategies to limit the progression of solid cancer tumors, which account for the majority of those that arise in the body.
These tumors depend on the blood supply for oxygen and nutrients to help them grow. As they progress, the blood vessels are unable to provide that element and nourishment to all its parts, which results in poorly oxygenated areas. Over time, this environment causes a build-up of acid inside cells.
To overcome this stress, cells adapt by releasing enzymes that neutralize the acidic conditions in their environment, allowing them not only to survive, but to develop into a more aggressive form of tumor capable of spreading to other organs. One such protein is carbonic anhydrase IX (CAIX).
Cancer cells depend on it for survival, which ultimately makes it their Achilles heel. By inhibiting its activity, we can effectively stop its growth, explains Shoukat Dedhar, lead author of the study and professor in the department of biochemistry and molecular biology at the School of Medicine and distinguished scientist at the Cancer Research Institute.
Dedhar and his colleagues previously identified a unique compound, SLC-0111 – which is being evaluated in phase 1 clinical trials – as a potent inhibitor of the CAIX enzyme. Although preclinical models of breast, pancreas, and brain cancers have shown the efficacy of this compound in suppressing tumor growth and spread, other cellular properties diminish its efficacy.
In this study, the research team, including Shawn Chafe, a research associate in Dedhar’s lab, along with Franco Vizeacoumar and colleagues at the University of Saskatchewan, set out to examine these cellular properties and identify other weak points in the enzyme. CAIX using a powerful tool known as a Genome-Wide Synthetic Lethal Screen.
This tool examines the genetics of a cancer cell and systematically deletes a gene to determine if a diseased cell can die by feeding the CAIX enzyme along with another specific gene.
According to Dedhar, the results of his examination were surprising and point to an unexpected role for proteins and processes that control a form of cell death called ferroptosis, which occurs when iron accumulates and weakens the tumor’s metabolism and cell membranes.
“We now know that CAIX prevents cancer cells from dying as a result of ferroptosis,” says Dedhar. The combination of enzyme inhibitors, including SLC-0111, with compounds known to cause ferroptosis, which causes catastrophic cell death and weakens tumor growth. “
A great international effort is currently underway to identify drugs that can induce ferroptosis. This study is an important step in that search, the researchers say.