Cancer’s ‘Achilles’ heel’ discovered by scientists

**BillyCarpenter** · 08-29-2021

Cancer’s ‘Achilles’ heel’ discovered by scientists

ANCOUVER, British Columbia — Scientists may be one step closer to defeating cancer after finding what researchers at the University of British Columbia call the disease’s “Achilles’ heel.”

Their study has uncovered a protein that fuels tumors when oxygen levels are low. It enables the cancerous growths to adapt and survive and become more aggressive.

The enzyme, called CAIX (Carbonic Anhydrase IX), helps diseased cells spread to other organs. It could hold the key to new treatments for the deadliest forms of the disease, including breast, pancreatic, lungs, bowel, and prostate cancers.

“Cancer cells depend on the CAIX enzyme to survive, which ultimately makes it their ‘Achilles heel.’ By inhibiting its activity, we can effectively stop the cells from growing,” says study senior author Professor Shoukat Dedhar in a university release.

The findings, published in the journal Science Advances, will help researchers develop drugs that destroy solid tumors. These are the most common types that arise in the body. They rely on blood supply to deliver oxygen and nutrients which help tumors grow.

As the tumors advance, the blood vessels are unable to provide enough oxygen to every part. Over time, the low-oxygen environment leads to a buildup of acid inside the cells. They overcome the stress by unleashing proteins, or enzymes, that neutralize the acidic conditions.

Stopping cancer before it spreads
This process is behind the spread, or metastasis, of cancer cells to other organs — which is what can kill patients. Finding a way to prevent cancer from metastasizing is the “Holy Grail” of cancer research. One of the enzymes which appears to do this is CAIX.

The Canadian team previously identified a unique compound known as SLC-0111 as a powerful inhibitor. It is currently being tested in clinical trials. Experiments in mice with breast, pancreatic, and brain cancers revealed its effectiveness.

The compound suppressed tumor growth and spread, although there were side-effects, with other cellular properties diminished. Now, the researchers have demonstrated other weaknesses in CAIX using a technique called genome-wide synthetic lethal screening. The powerful tool systematically deletes one gene at a time to determine if a cancer cell can be killed by eliminating the enzyme.

Surprisingly, results pointed to an unexpected role of proteins and processes that control a form of cell death called ferroptosis. This process happens when iron builds up and weakens a tumor’s metabolism and cell membranes.

“We now know that the CAIX enzyme blocks cancer cells from dying as a result of ferroptosis,” Dr. Dedhar adds. “Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumor growth.”

A large international effort is currently underway to identify drugs that induce ferroptosis. The study is a major step forward in this quest.