Mechanism of resistance to ribavirin in acute myeloid leukemia is identified
A mechanism that enables the development of resistance to acute myeloid leukemia (AML) anticancer drugs, thereby leading to relapse, was identified. Drug resistance is the cause of relapse in many patients.
The new discovery, recently published in Nature (2014; doi:10.1038/nature13283), constitutes a major breakthrough in the fight against AML, one of the deadliest forms of leukemia. This discovery immediately suggests strategies to overcome drug resistance. Furthermore, the type of drug resistance the team identified is likely implicated in other cancers, and a successful new treatment regimen based on these findings could have broad applications in treating cancer.
"This first clinical study yielded extremely promising results in most patients, including remissions, with no significant treatment-related toxicity. However, as is often the case when using a single drug, all patients eventually relapsed," recalled Sarit Assouline, MD, and Wilson Miller, MD, of the Segal Cancer Center at the Jewish General Hospital in Montréal, Quebec, Canada. The multicenter study also included patients from the Hôpital Maisonneuve-Rosemont (HMR) in Montreal and the McMaster University/Hamilton Health Sciences Center in Hamilton, Ontario, Canada.
The article describes why, in most of the patients, ribavirin as well as the standard chemotherapeutic drug cytarabine (Ara-C), eventually become ineffective at killing 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," explained first author Hiba Zahreddine, doctoral student in the laboratory of senior author Kathy Borden, PhD, at the University of Montreal's Institute for Research in Immunology and Cancer.
"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," continued Borden.
Fortunately, drugs that inhibit the activity of GLI1 are currently available and the scientists showed that these drugs could switch the cancer cells back into a ribavirin-sensitive state. It is hoped that when used in combination-therapy with ribavirin (or more standard chemotherapy), these drugs will prevent the development of drug resistance in patients. The team has now received approval from Health Canada to undertake a new clinical trial to test the novel drug combination in AML patients. As part of its research partnership with Université de Montréal, Pharmascience Inc. will continue to manufacture and provide the ribavirin necessary for this clinical trial.
"If this new approach is successful, it could have very broad applications. The mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML," explains Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc.