MBB researcher studying against the grain strategy to improve cancer treatment

July 10, 2023
From left: Drs. Faezeh Borzooee, Mani Larijani and Justin King, presenting a conference poster describing the AID/APOBEC small molecule inhibitors, 2022

Chemotherapy is a life-saving treatment for many cancer patients. Unfortunately, many cancer drugs also cause cancer cells to mutate, which over time leads them to become more aggressive and harder to treat.

SFU Molecular Biology and Biochemistry researcher Mani Larijani has received $672,000 in funding from the Lotte and John Hecht Memorial Foundation to explore an unconventional approach to address this issue and improve treatment outcomes for cancer patients.

“Drug resistance is a major problem in cancer treatment,” Larijani says. “Cancers can become resistant within months or even weeks. When this happens, treatment options can be switched, but mutations are an ongoing process, so cancer often develops multi-drug resistance.”

Previous research in this area has focused on finding strategies to harness the cells’ DNA damage response (DDR) to increase mutations in cancer cells to lethal levels. DNA mutations are a normal biological process that happens in all cells. In healthy cells, the body’s DDR machinery repairs these mutations, but in cancer cells this process is impaired, and mutations accumulate without repair.

But what if therapeutics could help prevent DNA mutations before they occur? Thanks to breakthroughs in Larijani’s research, this approach is showing promise.

Larijani’s research program focuses on DNA-mutating enzymes known as APOBECs which are a leading generator of mutations in cancer cells. These enzymes have been found in both human cancer cells and mice to directly cause drug resistance and more aggressive tumors. Much of Larijani’s research has focused on a member of the APOBEC family called activation-induced deaminase (AID), which is linked to leukemia and lymphoma.

Until recently the AID/APOBEC family of enzymes were thought to be “undruggable,” and their characteristics were not fully understood, because their structure could not be solved through conventional methods.

“We developed a new method involving computational modelling and studying its evolutionary history, which we call the evolutionary-biochemical-computational method to solve its structure,” Larijani explains.

“We discovered a totally new mode that enzymes like AID/APOBECs are regulated. We saw that the enzyme spontaneously opens and closes its active site "the catalytic pocket" which is the part responsible for mutating DNA. This was an important discovery because this type of self-regulation had not been known about before in such enzymes, or in fact any cancer-causing molecule.”

This new understanding of AID/APOBEC structure opens up possibilities for developing new drugs that could inhibit these enzymes’ role in mutating cells. Larijani’s team recently published a paper which describes the first small molecule inhibitors of AID and APOBECs with drug like properties. They are now exploring avenues to refine these molecules and discover new ones that may be used alongside conventional drugs to significantly lower drug-resistance in breast, ovarian, lung and other cancers.

Larijani credits two trainees, Drs. Justin King and Faezeh Borzooee for spearheading this work and says “One of our biggest successes is the multiple collaborations that this work has led to. We are going to be working closely with several different colleagues across the globe who specialize in treatment of different cancers.”

“We hope to harness recent breakthroughs in computational drug design to make more intelligent decisions on how to optimize small molecules towards therapeutics.”