Researcher to cancer: 'Resistance will be futile'

Turning the tables, Katherine Borden at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC) has evoked Star Trek's Borg in her fight against the disease. "Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologist's drug arsenal. Unfortunately, clinical strategies to overcome these lag far behind," Borden explained. "This mismatch likely underlies our inability to implement new durable treatment strategies." However, in her paper published in Cancer Research entitled "When will resistance be futile?", Borden describes one way that cancer goes about this evolution, providing researchers with a possible tool for disarming this defense. The article is inspired by research she published in Nature with her doctoral student Hiba Zahreddine.

Borden, principal investigator at IRIC and professor at the University of Montreal's Department of Pathology and Cell Biology, Zahreddine and their colleagues have in fact uncovered a previously unknown form of multidrug resistance, known as inducible drug glucuronidation. "We discovered this form of resistance when we developing a means to target a specific cancer-causing gene known as elF4E with a drug called ribavirin. Ribavirin prevents some viruses from reproducing their genetic code, and it has been used in two clinical studies to successfully to attack some cancers. However, all patients eventually relapsed," Borden explained. "We found that this was because cancer cells metabolize drugs differently from each other as well as normal cells. We traced the chemical pathway responsible for the decreased sensitivity to the drug to a protein that governs the copying of genetic information. We were able to shut off the protein and restore sensitivity to the ribavirin, and also to Ara-C, another cancer drug that cancer cells were able to defend themselves from by evolving."

The findings are the first step on a great voyage into the unknown. "It seems likely that each cell is able to develop resistance to multiple drugs. Moreover, it is likely that glucuronidation is not the only inducible modification, and finally, that this process can be very rapid, occurring even within weeks," Borden explained. "I'm a cancer researcher, not a doctor, but I'll boldly declare that the findings aren't bad news for those of us who want to live long and prosper. By understanding the extent of these inducible modifications and the chemical pathways that make their assimilation possible, it's a question of when, not if, we will finally be able to tell cancer cells that resistance is futile."

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Financing

This study was supported by National Institutes of Health and Leukemia & Lymphoma Society (LLS) Translational Research Program and Canada Research Chair in Molecular Biology of the Cell Nucleus. Zahreddine holds a Cole Foundation Fellowship and a National Council for Scientific Research Lebanon Fellowship. Katherine Borden also acknowledges support from Pharmascience for this work.

Study cited

Katherine L. B. Borden published "When Will Resistance Be Futile?" in Cancer Research on December 4, 2014. Borden, Hiba Zahreddine and their colleagues published "The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation" in Nature on May 28, 2014.

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