Pharmacogenomics insights into precision pediatric oncology

Abstract

Purpose of review Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future. Recent findings The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while ‘poor metabolizer’ haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform. Summary The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future.

Current Status and Trends of Research on Anthracycline-Induced Cardiotoxicity from 2002 to 2021: A Twenty-Year Bibliometric and Visualization Analysis

“…Emerging evidence established significant polygenic contributions that predispose to ACT. And pharmacogenomics could be used to identify those at higher risk of complications [ 107 ]. For instance, literature reported that a missense variant rs2229774 in the retinoic acid receptor- γ (RARG) gene is associated with increased susceptibility to ACT.…”

Importance of pharmacologic considerations in the development of targeted anticancer agents for children

“…A critical feature of this regimen is a long maintenance phase, characterized by prolonged, repetitive dosing with 6-mercaptopurine (6-MP) and methotrexate (MTX). Both of these drugs have established pharmacogenomic modifiers, namely thiopurine methyltransferase (TPMT) and reduced folate transporters [17][18][19][20]21 ]. TPMT polymorphisms have been extensively studied as a key player in 6-MP metabolism [22,23].…”

Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile-Specific DNA Adenine Methyltransferase

“…10,11 SAM-dependent methyltransferases (MTases) catalyze methyl transfers onto a wide variety of substrate molecules, including both macromolecules (DNA, RNA, polysaccharides, lipids, and proteins) and micromolecules (such as catechol, arsenic, histamine, nicotinamide, and thiopurine). Given the significance of epigenetic methylation of macromolecules in cancer, immunity, cardiovascular and many other diseases, as well as methylation of anticancer drugs such as thiopurine, 12,13 SAM-dependent MTases are increasingly becoming therapeutic targets. 14−19 SAM analogs are versatile tools for studying and therapeutically inhibiting SAM-dependent MTases.…”

“…SAM is involved in a wide range of biochemical reactions including (but not limited to) transmethylation reactions, , radical SAM reactions, − polyamine biosynthesis, and SAM-sensing riboswitches. , SAM-dependent methyltransferases (MTases) catalyze methyl transfers onto a wide variety of substrate molecules, including both macromolecules (DNA, RNA, polysaccharides, lipids, and proteins) and micromolecules (such as catechol, arsenic, histamine, nicotinamide, and thiopurine). Given the significance of epigenetic methylation of macromolecules in cancer, immunity, cardiovascular and many other diseases, as well as methylation of anticancer drugs such as thiopurine, , SAM-dependent MTases are increasingly becoming therapeutic targets. − …”