Progress

From GATC to CPNDS

CPNDS began in 2005 as Genotype-specific Approaches to Therapy in Childhood (GATC). GATC was renamed CPNDS in 2009 as it evolved to reflect its larger role and new funding. In January 2009 when GATC evolved to become CPNDS, there were already more than 18,000 ADR cases and matched controls enrolled in the project.

The GATC consortium established an active ADR surveillance network that is unique in the world. It began with one surveillance site at BC Children’s Hospital, an agency of the Provincial Health Services Authority, and grew to include 13 major paediatric teaching hospitals across Canada. GATC developed its first pharmacogenomic panel of single nucleotide polymorphisms (SNPs) to study the genetics of ADRs in 2005. This panel allowed for the detection of genetic variation in over 220 key candidate genes that influence the way patients respond to a given medication. Over time, additional SNP panels have been developed for specific drug pathways and the initial panel has been further refined to include the most relevant and important SNP markers for solving drug safety problems.

We Grew!

In 2009, we expanded our pharmacogenomics research capacity by building a new, dedicated facility capable of housing both our clinic and lab-based teams. This facility also allows us to do high-throughput genome sequencing. It is located on more than 750 square metres of lab and work space at the BC Children’s Hospital Research Institute, on the campus of Children’s and Women’s Health Centre of British Columbia, an agency of the Provincial Health Services Authority, in Vancouver, British Columbia.

As of 2021, the CPNDS network includes 14 paediatric and 18 adult surveillance sites across Canada and has developed a multitude of international collaborations. In our database, we currently have over 95,000 reports of medication use, which includes cases of drug-induced harm and matched controls.

Because of our efforts, we were able to discover the genetic basis of infant mortality from maternal use of codeine, as well as the genetic basis of cisplatin-induced hearing loss, anthracycline-induced cardiotoxicity, and vincristine-induced toxicity in children.

Our Key Impacts

Discovery of codeine-related genetic variants that can cause infant mortality in breastfed infants

CPNDS researchers published studies that led to new labelling of prescriptions containing codeine, a common pain reliever that until recently, was considered to be compatible with breastfeeding. Network investigators discovered that in some mothers, codeine can be metabolized into toxic amounts of morphine that are life-threatening for breastfed infants. As a result, Health Canada, the U.S. Food and Drug Administration, other regulators worldwide and the pharmaceutical industry changed labelling to alert consumers of the potential dangers of codeine.

Discovery of cisplatin-related genetic variants that can cause serious and permanent hearing loss

CPNDS has discovered genetic causes of cisplatin-induced hearing loss in children. These identified genetic markers can be used to identify high-risk patients who can then be monitored more closely for hearing needs and potentially provided with safer treatment options, in cases where such options exist. We have implemented a pharmacogenetics testing program in pediatric oncology at BC Children’s Hospital for cisplatin. By collecting patient DNA prior to chemotherapy treatment, our goal is to identify patients at high risk of severe adverse drug reactions and implement drug-safety solution strategies.

Discovery of anthracycline-related genetic variants that cause cardiotoxicity

CPNDS has also identified multiple genetic variants associated with the risk of and protection from anthracycline-induced cardiotoxicity, which are used to identify high-risk patients who can undergo greater monitoring and be provided with safer treatment options. We have implemented a pharmacogenetics testing program in pediatric oncology at BC Children’s Hospital for anthracycline. By collecting patient DNA prior to chemotherapy treatment, our goal is to identify patients at high risk of severe adverse drug reactions and implement drug-safety solution strategies.

Discovery of vincristine-related genetic variants that cause neurotoxicity

CPNDS has discovered multiple genetic variants associated with the risk of vincristine-induced neuropathy, which are used to identify high-risk patients who can undergo greater monitoring and be provided with safer treatment options. These findings will help with the development of neuroprotective strategies for vincristine-induced neuropathy in order to optimize care on an individualized basis for oncology patients.

Research Direction

Through national and international collaborations, we have replicated and validated our findings in different populations. This helps us understand the generalizability and robustness of our discovery findings.

We are also:

• Investigating the mechanisms of drug response variation in cell and animal models
• Developing new ADR targets in response to critical drug safety needs identified by clinicians and regulators
• Creating and implementing pharmacogenomic testing panels

Learn more about our current projects and ways to collaborate.