Molecular determinants of response to pemetrexed

As more agents become available for cancer treatment, the costs of treatment both to the patient in terms of side effects and quality of life, and to the health service in terms of financial burden, need to be considered. Biomarkers are required which can select patients who will derive benefit from treatments. Although effective patient selection is possible for some of the newer "targeted" agents, predicting which patients will benefit from conventional cytotoxic agents remains a challenge. These agents play an important role in cancer management, often at the cost of significant toxicity. The purpose of this work was to study tumour levels of potential molecular determinants of response to pemetrexed, a multitargeted antifolate, and, using clinical correlative data, to identify useful predictive markers for clinical outcome. The underlying hypothesis was that ovarian tumours, 90% of which highly express folate receptor alpha (FR alpha), a high affinity low capacity folate transporter known to bind pemetrexed, may efficiently import pemetrexed and hence show enhanced sensitivity to the drug. Expression levels of two other folate transporters, the reduced folate carrier (RFC) and the recently identified proton coupled transporter,and of three of the intracellular targets of pemetrexed, folyl-polyglutamate synthetase (FPGS), thymidylate synthase (TS) and glycinamide formyl transferase (GARFT) were also measured. During the course of this work new evidence emerged that pemetrexed import was largely mediated via RFC and PCFT rather than FR alpha and a phase 11study of pemetrexed in ovarian cancer showed disappointing response rates. My studies demonstrated that FR alpha mRNA did not relate to protein expression in the majority of ovarian tumours and cell line work showed that FR alpha was highly responsive to environmental change. The methods optimized in ovarian cancer tumour samples were subsequently employed to measure circulating cell free TS mRNA in patients treated with pemetrexed and lapatinib. Data from this study suggests that plasma TS levels have potential as a non-invasive biomarker in this group of patients, but larger confirmatory studies are required.