Folate-related biomarkers as predictors of response to pemetrexed therapy

2011

Alexander Steven Whitehead, DPhil

University of Pennsylvania

Philadelphia

Pemetrexed is a chemotherapy drug commonly used for the treatment of non-small cell lung cancer. The drug blocks two proteins called DHFR and TS that cancer cells need to grow. Not all patients respond to pemetrexed. Dr. Alexander Whitehead is studying how changes in the DHFR and TS genes predict response of non-small cell lung cancer patients to pemetrexed.

Research Summary

Folate is a B vitamin that is very important for maintaining health and for protecting against a range of major diseases. It is obtained as ‘natural’ folate from food, in particular leafy green vegetables, or as the synthetic form folic acid from supplements and products made with fortified flour. There are genetic differences in the enzymes that control the way that folate is used inside cells; folate is actually present as multiple forms that support different biochemical processes, and these differences confer different levels of susceptibility to diseases that are associated with low folate and altered folate metabolism. Some of the genetic differences have been linked to lung cancer, and some have recently been linked to good responses to pemetrexed, an anti-folate drug that is used to treat lung cancer. The goal of this project is to define the main folate-related genetic variants AND the relative amounts of the different forms of folate inside cells in patients with lung cancer, and to establish whether any of these factors are over-represented in (i) lung cancer patients compared to healthy individuals, and, even more importantly, in (ii) lung cancer patients who show superior responses to pemetrexed. The project has the potential to identify genetic markers and/or biomarkers that could be used to guide lung cancer chemotherapy.

Technical Abstract

Folate/homocysteine (Hcy) metabolism facilitates the methylation of DNA, proteins and carcinogens; nucleic acid synthesis; and glutathione generation. Dysregulation of folate/Hcy metabolism, due to suboptimal vitamin status and/or functional polymorphisms of key enzymes, is an etiologic feature of some cancers, including lung cancer. Several drugs that target enzymes of folate/Hcy metabolism have become mainstays of cancer chemotherapy, most recently pemetrexed (PMX), which targets dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and is used to treat patients with non-small cell lung cancer (NSCLC). Our primary and secondary hypotheses are that folate/Hcy phenotype, perhaps underpinned by genotype, is a major contributor to (i) clinical response to PMX, and (ii) risk of NSCLC itself. We will use archived and newly acquired samples from PMX-treated NSCLC patients to define pre-treatment and in-treatment folate/Hcy phenotypes using LC-MRM/MS technology that can precisely determine the concentrations and relative proportions of key folates (tetrahydrofolate; 5-methyltetrahydrofolate; 5,10-methenyltetrahydrofolate) and Hcy. Genotypes will be determined for approximately twenty folate-related genes. Biostatistical analyses will be used to establish

whether aspects of folate/Hcy phenotype and/or genotype are prospectively or concurrently associated with time to tumor progression, survival time, toxicity, etc. Case-control analysis of genetic and phenotypic data will also be undertaken to determine whether any genetic and/or biomarker variables predict case status. This project has the potential to identify biomarkers and/or genetic factors that can be used to predict or monitor responses of NSCLC patients to PMX, and may provide the basis for the future deployment of personalized medicine strategies in lung cancer treatment.

Key words

Adenocarcinoma

Biomarker or biomarker testing

Chemotherapy

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Stage IV

Folate-related biomarkers as predictors of response to pemetrexed therapy

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