How AML Becomes Drug-Resistant

When patients take anticancer drugs, they are often faced with the reality of drug resistance, followed by a cancer relapse. A new discovery, however, is aiming to change that.

Kathy Borden of the University of Montreal's Institute for Research in Immunology and Cancer (IRIC) and her colleagues have discovered the mechanism that triggers resistance to the drugs used to fight Acute Myeloid Leukemia (AML). The resistance leads to relapses in patients with AML, as well as other types of cancer.

AML is a form of cancer that affects the blood and bone marrow. It impacts myeloid cells, a type of white blood cell that normally develops into a mature blood cell, such as a red blood cell, white blood cell, or blood platelet. AML is one of the most deadly forms of leukemia.

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In the past, Borden asserted that ribavirin, a compound first developed as an antiviral drug, could also help cancer patients. But when the drug was tested on patients with AML at the Segal Cancer Centre at the Jewish General Hospital in Montreal, the patients relapsed. What caused the resistance and subsequent relapse? 

In Borden’s most recent article, she details why ribavirin, along with cytarabine (Ara-C), a standard chemotherapeutic drug, cannot effectively kill cancer cells.

“By studying drug resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said Hiba Zahreddine, a doctoral student in Borden’s laboratory, in a press release.

“With the help of our colleagues at Pharmascience Inc. we were then able to show that this results in a specific chemical change to the drugs, that prevents their toxicity toward the cancer cells,” Borden said in a press release.

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Do we have drugs that can block the activity of GLI1? Yes, and the researchers say these drugs could potentially switch the cancer cells back into a ribavirin-sensitive state. That means the drugs would once again be effective at killing cancer cells. When using a GLI1 inhibitor in combination with ribavirin (or standard chemotherapy), the drugs could prevent resistance and relapses.

The team will now move forward to test the drug combination and see if it works. Borden said the researchers have approval for the trial and are waiting to hear about funding.

“If all goes well, we will start the trial in October,” she said.

What does the discovery—and the potentially positive results of testing—mean for cancer patients?

“If this new approach is successful, it could have very broad applications since the mode of action of ribavirin suggests that it could be effective against up to 30 percent of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., in a press release.

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