Folylpoly-Glutamate Synthetase Expression Is Associated with Tumor Response and Outcome from Pemetrexed-Based Chemotherapy in Malignant Pleural Mesothelioma

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Folylpoly-Glutamate Synthetase Expression Is Associated with Tumor Response and Outcome from Pemetrexed-Based Chemotherapy in Malignant Pleural Mesothelioma Daniel C. Christoph, MD, PhD, Bernadette Reyna Asuncion, MD, Celine Mascaux, MD, PhD, Cindy Tran, BSc, Xian Lu, PhD, Murry W. Wynes, PhD, Thomas C. Gauler, MD, Jeremias Wohlschlaeger, MD, Dirk Theegarten, MD, Volker Neumann, PhD, Rodrigo Hepp, MD, Stefan Welter, MD, Georgios Stamatis, MD, Andrea Tannapfel, MD, Martin Schuler, MD, Wilfried E. Eberhardt, MD, Fred R. Hirsch, MDPhD Journal of Thoracic Oncology Volume 7, Issue 9, Pages 1440-1448 (September 2012) DOI: 10.1097/JTO.0b013e318260deaa Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Pemetrexed's mechanism of action: After transfer into cells, pemetrexed undergoes polyglutamylation. Both the nonglutamated and as the polyglutamated forms are able to inhibit DHFR, GARFT, and TS. Figure according to36. AMP, adenosine monophosphate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FPGS, folylpoly-γ-glutamate synthetase; GARFT, glycinamide ribonucleotide formyltransferase; GGH, gamma-glutamyl hydrolase; Gln, glutamine; GMP, guanosine monophosphate; IMP, inosine monophosphate; PCFT, proton-coupled folate transporter; PPRP, phosphoribosyl pyrophosphate; RFC, reduced folate carrier; THF, tetrahydrofolate; TS, thymidylate synthase. Journal of Thoracic Oncology 2012 7, 1440-1448DOI: (10.1097/JTO.0b013e318260deaa) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 A to H, Examples of IHC for FPGS and TS in MPM samples with different protein expressions. A to D, IHC with an antibody against FPGS: (A) hepatocellular carcinoma was used as positive control; (B) weakly stained MPM sample (H-score of 90); (C) moderately stained MPM sample (H-score of 170); and (D) strongly stained MPM sample (H-score of 290). E to -H, IHC with an antibody against TS (dilution 1:10); (E) colorectal carcinoma was used as positive control; (F) weakly stained MPM sample (H-score of 90); (G) moderately stained MPM sample (H-score of 170); and (H) strongly stained MPM sample (H-score of 290). Magnification 1:400. IHC, immunohistochemistry; FPGS, folylpoly-γ-glutamate synthetase; TS, thymidylate synthase; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2012 7, 1440-1448DOI: (10.1097/JTO.0b013e318260deaa) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 A to D, Associations between protein expression of FPGS and (A) PFS or (B) OS; associations between protein expression of TS and (C) PFS or (D) OS. FPGS, folylpoly-γ-glutamate synthetase; PFS, progression-free survival; H-Score, Hybrid-Score; OS, overall survival; TS, thymidylate synthase; IMIG, International Mesothelioma Interest Group; HR, hazard ratio; CI, confidence interval. Journal of Thoracic Oncology 2012 7, 1440-1448DOI: (10.1097/JTO.0b013e318260deaa) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions