Pharmacogenomics of genes involved in antifolate drug response and toxicity in osteosarcoma

ABSTRACT

Introduction: Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity.

Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities. Here, we summarize the pharmacogenomic information reported so far for genes involved in antifolate metabolism and transport and in MTX-related toxicity in HGOS patients.

Expert opinion: Identification and validation of genetic biomarkers that significantly impact clinical antifolate treatment response and related toxicity may provide the basis for a future treatment modulation based on the pharmacogenetic and pharmacogenomic features of HGOS patients.

KEYWORDS:

• Osteosarcoma
• methotrexate
• pharmacogenomic
• pharmacogenetic
• toxicity
• treatment response

Article highlights

• The antifolate methotrexate (MTX) is widely used at high-doses in standard first-line chemotherapy protocols for high-grade osteosarcoma (HGOS).

• Not all HGOS patients are equally responsive to MTX. The mechanisms that have been reported as most relevant for both experimental and clinical resistance to MTX in HGOS are the impaired drug transport due to a decreased expression of the membrane-located solute carrier family 19 (folate transporter) member 1 (SLC19A1; also known as reduced folate carrier, RFC or reduced folate carrier 1, RFC1) and increased dihydrofolate reductase (DHFR) levels.

• HGOS is a rare tumor, and numbers of patients carrying genotypes associated with increased risk of MTX-induced toxicity or with reduced MTX sensitivity and unfavourable prognosis are consequently low. For these reasons, all evidence reported so far needs further validation in larger patients series.

• Polymorphisms affecting genes involved in the MTX and folate pathways can mediate the drug-induced toxicity, but further investigations and functional analyses are needed before this body of information can effectively be transfered into clinical practice.

This box summarizes key points contained in the article.

Acknowledgments

The Authors’ studies cited in this review were supported by grants from the Italian Association for Cancer Research (Associazione Italiana per la Ricerca sul Cancro, A.I.R.C.; grants to Massimo Serra) and Istituto Ortopedico Rizzoli (5 x mille contributions to the Rizzoli Institute).

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.