Nucleoside analogs: ready to enter the era of precision medicine?

ABSTRACT

Introduction: The term ‘precision medicine’ has garnered significant attention in the oncological setting in relation to attempts to optimize anticancer treatment. Precision medicine is mostly associated with oral targeted therapies and biotherapies, however, to date classic cytotoxics still remain the backbone of most regimens for treating solid tumors or in hematology, both in children and in adults. Among the existing cytotoxic therapies, nucleosides are widely used for treating a variety of cancerous diseases, alone or as part of combination therapies.

Areas covered: Several markers at the tumor or the germinal levels have been identified as being associated with clinical outcome (e.g. CDA, DPD, EONFS1, hENT1, TYMS, MTHFR), however little effort has been made to implement bioguided therapy with nucleoside analogs. Still, growing clinical evidence has demonstrated how the efficacy-toxicity balance of these drugs could be improved by developing bioguided strategies at the bedside. This review covers the current knowledge regarding putative markers to be used with nucleoside analogs, what is known on their pharmacokinetic/pharmacodynamic relationships, and provides clues for implementing precision medicine with those old, yet pivotal drugs.

Expert opinion: Through a variety of strategies ranging from pharmacogenetics, tumor genomics and pharmacokinetically-driven adaptive dosing procedures, nucleoside analogs could enter the era of precision medicine in oncology.

KEYWORDS:

• Nucleoside analogues
• pharmacokinetics
• therapeutic drug monitoring
• pharmacogenetics
• adaptive dosing

Article highlights

• Nucleoside analogues are represented by a small, yet critical number of antimetabolite agents widely prescribed to treat a variety of cancers.

• All these drugs share complex activation/deactivation patterns, narrow therapeutic window and wide inter-patient variability in pharmacokinetic parameters.

• Several genetic polymorphisms or deregulations affecting membrane transporters, enzymes and targets have been identified as possible cause for erratic clinical outcome (i.e. loss of efficacy or severe toxicities). In particular, CDA (gemcitabine) and DPD (capecitabine) deficient status have been repeatedly linked with life-threatening toxicities.

• The exact role played by other polymorphisms (e.g. TYMS, MTHFR, ENOFS1) remains to be fully elucidated prior to be used in decision-making.

• Developing covariate-based model plus pharmacokinetically-guided dosing strategies could help to increase treatment efficacy while limiting the risk for severe toxicities in patients with cancer.

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Declaration of interest

J Ciccolini has a patent on CDA testing (US 20130011392 A1; January 2013). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.