Solid tumors use several strategies to thrive in harsh conditions. Scientists at the University of British Columbia and BC Cancer Research Institute zeroed in on one of those strategies—the ability of cancer cells to withstand acidic conditions—and found a way to thwart it.
As tumors grow, their surrounding environment becomes more and more acidic due to a lack of oxygen. Cancer cells adapt by spewing enzymes that neutralize the acid. The researchers discovered that inhibiting one of those enzymes, Carbonic Anhydrase IX (CAIX), while simultaneously promoting a form of cancer-cell death, slows tumor growth. They published their findings in the journal Science Advances.
The UBC-led team had previously identified a drug that inhibits CAIX and showed in animal models that it can slow the growth of breast, pancreatic and brain tumors. That drug, dubbed SLC-0111, is now in a phase 1 trial in patients with pancreatic cancer.
Problem is, cancer cells can suppress CAIX inhibition, but it’s not clear how. So the researchers used a tool called a genome-wide synthetic lethal screen to scrutinize the properties of cancer cells and try to identify other ways CAIX could be crippled. They eliminated the CAIX enzyme from the cells, then deleted one gene at a time to try to find a combination that would kill the cells.
During that process, they realized that the CAIX enzyme can prevent cancer cells from dying in a process called “ferroptosis,” a recently discovered form of cell death that depends on iron.
“Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumor growth,” said senior author Shoukat Dedhar, Ph.D., a professor of medicine at UBC, in a statement.
Ferroptosis has become a hot target in oncology research. In June, for example, Kojin Therapeutics raised $60 million to advance work initiated at Harvard University and the Dana-Farber Cancer Institute that involves using small molecules to destroy cells that are most vulnerable to ferroptosis.
The more well-known form of cell death, apoptosis, remains a popular target in cancer, too. Last month, Ipsen teamed up with BAXX Therapeutics to develop a drug designed to activate BCL-2 associated protein (BAX) and promote apoptosis. Under the deal, worth $14.5 million up front and a potential $837.5 million in milestones, the companies will develop a BAX activator in leukemia, lymphoma and solid tumors.
The trial of the CAIX inhibitor SLC-0111 at UBC is designed to test the safety of combining the compound with the chemotherapy drug gemcitabine in pancreatic cancer patients who test positive for the enzyme. There’s a simultaneous effort underway to find drugs that can induce ferroptosis, the university said.