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Publications of the Week

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

By July 25, 2018No Comments

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 This week we profile a recent publication in Clinical Pharmacology & Therapeutics from the Canadian Pharmacogenomics Network for Drug Safety Consortium and Dr. Galen Wright (pictured) at BC Children’s Hospital Research Institute.

Can you provide a brief overview of your lab’s current research focus?

I am currently a member of the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), working at the BC Children’s Hospital Research Institute, University of British Columbia. Our area of research is focused on explaining why certain patients develop potentially life-threatening adverse drug reactions, while others do not. One of the ways to go about studying this is to perform pharmacogenomic research, which assesses whether slight changes in the DNA put certain individuals at an increased risk for developing these reactions.

For more than a decade, the CPNDS has been using active surveillance at sites throughout Canada to recruit patients receiving various medications and collect information relating to adverse drug reactions. This has allowed us to assemble one of the largest clinical databases for drug safety research that can be used to perform pharmacogenomic studies. Fortunately, the price of genomic technologies has dropped dramatically in recent years. This has enabled us to study more patients and investigate a large proportion of their genetic variants at a reasonable cost, helping us identify novel biological findings. The ultimate goal of our research is to make drugs both safer and more effective, by using a patients’ genetics to guide their treatment.

What is the significance of the findings in this publication?

Survival rates for pediatric cancer patients have improved dramatically in recent years, increasing to over 80% in certain world regions. Unfortunately, these life-saving medications are also associated with harmful side effects. This publication focused on a drug called vincristine, which is an important component of many treatment protocols for pediatric cancer. Although this cancer drug is highly effective, it is also associated with a severe and debilitating adverse drug reaction known as neuropathy (i.e. damage to the nerves), which limits its clinical use. Up to 50% of patients experience this reaction, with symptoms ranging from diminished strength and abnormal sensation to severe pain and burning sensations.

At present, it is difficult to predict which patients will develop this harmful side effect. We therefore performed a pharmacogenomic study in a group of children with the most common form of pediatric cancer, leukemia. Notably, the genetic variant that was shown to be most significantly associated with neuropathy caused by vincristine occurred in a gene that is known to play a role in transporting vincristine out of cells. Another important finding that this study uncovered was that certain genes that cause rare disorders characterized by neuropathies, were also shown to be important for the development of neuropathy as a result of vincristine treatment. These pharmacogenomic variants are not as harmful to the genes as those that cause rare inherited neuropathies, but it appears that they may become important when a patient is exposed to vincristine. Finally, we were able to provide confirmatory evidence for a previously identified vincristine neuropathy genetic biomarker, taking this variant a step closer towards clinical implementation.

What are the next steps for this research?

The senior authors on this study, Drs. Colin Ross and Bruce Carleton, have recently been awarded a $10.5 million grant from Genome Canada, which will allow us to expand our pediatric cancer pharmacogenomic research for vincristine, along with three other drugs that are essential for the large majority of cancer treatment protocols. In this regard, we plan on scanning the genomes of over 6,000 pediatric patients to discover novel biomarkers for debilitating adverse drug reactions. Another significant component of this study is that we are going to start implementing pharmacogenomic biomarkers for pediatric cancer medications in select hospitals across Canada.

This research was funded by:

Our work was supported by the Canadian Foundation for Innovation/Canadian Institutes of Health Research, a CIHR Team Grant for the Drug Safety and Effectiveness Network, as well as the BC Children’s Hospital Foundation.

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