Abstract 4121: Folate pathway in malignant pleural mesothelioma (MPM): Novel therapeutic opportunities due to folate receptor alpha overexpression
Authors: Nunez Maria Ines , Suraokar Milind , Behrens Carmen , Woods Denise M. , Lin Heather , Lee Jack , Mehran Reza J. , Franklin Wilbur , Tsao Anne , Wistuba Ignacio Ivan 
Published: August 2014

Abstract
Background. The folate pathway is active in several cancers including malignant pleural mesothelioma (MPM). Membrane receptors folate receptor alpha (FRα), reduced folate carrier 1 (RFC1), proton coupled folate transporter (PCFT) and the enzyme thymidylate synthase (TS) regulate intra-cellular uptake of folate molecules and antifolate drugs. Due to the documented overexpression of folate markers in MPM they arise as potential targets for novel specific therapies with humanized monoclonal anti-FRα antibody and also to antifolate chemotherapy with pemetrexed.
Material and Methods. We studied 79 surgically resected MPM (43 epithelioid, 28 biphasic and 13 sarcomatoid histology types). Protein expression of FRα, RFC1, PCFT and TS was examined by immunohistochemistry (IHC) in FFPE tissues placed in tissue microarray platform and results correlated to clinical-pathologic characteristics. Gene expression and DNA copy number changes of the FRα gene (FOLR1) were examined in 53 mesothelioma tumors using Affymetrix U133 Plus 2.0 microarray's and Illumina HumanOmni1-Quad v1.0 chips, respectively. The expression microarray data was analyzed in the GeneSpring GX 11 software (Agilent technologies Inc.) while DNA copy number changes were detected using the Nexus 5.0 software (BioDiscovery Inc.).
Results. MPM frequently showed protein over-expression of FRα, RFC1 and PCFT. Nuclear TS expression positively correlated (P&lt;0.043) with cytoplasmic TS and membrane RFC1. Patients with T1/T2 tumor had significantly (P=0.038) higher levels of membrane FRα, compared to patients with T3/T4 tumors. Epitheloid MPM had the highest level of cytoplasmic PCFT (P=0.005) among the three histological types, while patients with sarcomatoid histology had the lowest. In the multivariate analysis, with adjustment of gender, N and M stage, Patients who expressed any nuclear TS (score &gt;0) had a lower hazard ratio than those who did not (HR=0.309; 95%CI 0.159, 0.601; P=0.0005). Patients with any level (score &gt;0) of cytoplasmic PCFT had lower hazard ratio than those with absence of the marker (HR=0.539; 95%CI 0.306, 0.952; P=0.0332). Our gene expression data analysis on 53 mesothelioma tumors showed greater than 2-fold increase in the FOLR1 and 3-fold increase in the TYMS messenger RNA levels compared to paired normal tissue. Additionally, at least 7 of these tumors show increased gene copy number at the FOLR1 locus (Ch11q 13.4).
Conclusions. Folate membrane transporters (FRα, RFC1, PCFT) and the enzyme TS are frequently over expressed in MPM tumor tissues, and PCFT and TS are associated with tumors’ clinico-pathological features. The high level of expression of FRα in MPM supports the rational use of potential utilization of humanized monoclonal anti-FRα antibody and also standard antifolate chemotherapy in this disease. Supported by grant US DoD W81XWH-07-1-0306, ASCO CDA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4121. doi:10.1158/1538-7445.AM2011-4121