Pharmacogenomics in Pediatric Oncology: Review of Gene-Drug Associations for Clinical Use.

Vid Mlakar,Chakradhara Satyanarayana Uppugunduri,Patricia Huezo-Diaz Curtis,Maja Krajinovic,Marc Ansari

doi:10.3390/ijms17091502

Abstract

During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer and harmonization of pharmacogenetic testing from research into clinics, to bring together basic and translational research and to educate health professionals throughout Europe. The objective of this review was to provide the attendees of the meeting as well as the larger scientific community an insight into the compiled evidence regarding current pharmacogenomics knowledge in pediatric oncology. This preliminary evaluation will help steer the committee’s work and should give the reader an idea at which stage researchers and clinicians are, in terms of personalizing medicine for children with cancer. From the evidence presented here, future recommendations to achieve this goal will also be suggested.

Highlights

Twenty percent of pediatric cancer patients do not respond to standard therapy [1] and 22% of all hospital admissions in this population is due to adverse drug reactions (ADRs) [2]
Thiopurines are applied as prodrugs that are converted into thioguanine nucleotides (TGNs) by hypoxanthine guanine phosphoribosyl transferase (HPRT) (Figure 2)
Upon reviewing the evidence gathered, sorted and published by PharmGKB, only the thiopurines/thiopurine S-methyltransferases (TPMT) pair satisfies the highest standard of evidence needed for incorporation into clinical practice

Summary

Introduction

Twenty percent of pediatric cancer patients do not respond to standard therapy [1] and 22% of all hospital admissions in this population is due to adverse drug reactions (ADRs) [2]. The therapeutic agents used in cancer chemotherapy are often administered at high doses [3], which due to inter-patient variability and narrow therapeutic ranges result in a spectrum of outcomes from severe toxicities to underexposure. Part of this variability can be attributed to heritable genetic variations affecting the drug pharmacokinetics and pharmacodynamics. Patients respond differently to medication due to their constitutive genetic variations and due to mutations or epigenetic signatures acquired during the process of neogenesis or treatment. The intention of this review is to focus on germline variations that might affect treatment efficacy and toxicity. For a detailed revision of acquired mechanisms of cancer resistance, we recommend reviews by Holohan et al and Longley et al [6,7]

Objectives

Methods

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Conclusion