BACKGROUND: Malignant mesothelioma is a highly aggressive tumor arising from mesothelial-lined surfaces, most often in the pleura cavities. Antifolates belong to the most effective cytotoxic drugs for malignant pleural mesothelioma (MPM) treatment. Pemetrexed is an antifolate inhibiting different folate pathway genes (thymidylate synthase [TS], dihydrofolate reductase, glycinamide ribonucleotide formyltransferase [GARFT], and aminoimidazole carboxamide ribonucleotide formyltransferase, [AICARFT]). Increased activity of pemetrexed occurs by folylpolyglutamate synthetase (FPGS), intracellular transport by reduced folate carrier (RFC). The aim of the study was to explore potential correlations between TS, GARFT, AICARFT, RFC, and FPGS levels in MPM and associations with clinical benefit from pemetrexed treatment. METHODS: Samples from 63 patients were tested using immunohistochemistry (IHC) and quantitative polymerase chain reaction(qPCR) for expression levels of TS, GARFT, AICARFT, RFC, and FPGS. Clinical data were evaluated to determine associations between efficacy of pemetrexed and enzyme expression levels. Evaluation of expression levels was done through TaqMan-based qPCR, and IHC was evaluated semiquantitatively by using the H-score. RESULTS: qPCR analysis showed no difference in expression pattern of GARFT and AICARFT. IHC analysis revealed a heterogeneous staining pattern for all the enzymes. No significant association was found between TS expression and survival or objective response of the tumors after pemetrexed treatment. FPGS (p = 0.0111) and RFC (p = 0.0088) mRNA expression levels were strongly associated with overall survival in these patients. CONCLUSIONS: Our results reveal that in pemetrexed-treated MPMs TS expression levels have no influence on patient outcome. Furthermore, GARFT and AICARFT were homogeneously expressed in the patient samples. Folate uptake mechanisms by RFC and activation by FPGS were associated with clinical benefit from pemetrexed treatment.
BACKGROUND:Malignant mesothelioma is a highly aggressive tumor arising from mesothelial-lined surfaces, most often in the pleura cavities. Antifolates belong to the most effective cytotoxic drugs for malignant pleural mesothelioma (MPM) treatment. Pemetrexed is an antifolate inhibiting different folate pathway genes (thymidylate synthase [TS], dihydrofolate reductase, glycinamide ribonucleotide formyltransferase [GARFT], and aminoimidazole carboxamide ribonucleotide formyltransferase, [AICARFT]). Increased activity of pemetrexed occurs by folylpolyglutamate synthetase (FPGS), intracellular transport by reduced folate carrier (RFC). The aim of the study was to explore potential correlations between TS, GARFT, AICARFT, RFC, and FPGS levels in MPM and associations with clinical benefit from pemetrexed treatment. METHODS: Samples from 63 patients were tested using immunohistochemistry (IHC) and quantitative polymerase chain reaction(qPCR) for expression levels of TS, GARFT, AICARFT, RFC, and FPGS. Clinical data were evaluated to determine associations between efficacy of pemetrexed and enzyme expression levels. Evaluation of expression levels was done through TaqMan-based qPCR, and IHC was evaluated semiquantitatively by using the H-score. RESULTS: qPCR analysis showed no difference in expression pattern of GARFT and AICARFT. IHC analysis revealed a heterogeneous staining pattern for all the enzymes. No significant association was found between TS expression and survival or objective response of the tumors after pemetrexed treatment. FPGS (p = 0.0111) and RFC (p = 0.0088) mRNA expression levels were strongly associated with overall survival in these patients. CONCLUSIONS: Our results reveal that in pemetrexed-treated MPMs TS expression levels have no influence on patient outcome. Furthermore, GARFT and AICARFT were homogeneously expressed in the patient samples. Folate uptake mechanisms by RFC and activation by FPGS were associated with clinical benefit from pemetrexed treatment.
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Authors: E Giovannetti; P A Zucali; Y G Assaraf; N Funel; M Gemelli; M Stark; E Thunnissen; Z Hou; I B Muller; E A Struys; M Perrino; G Jansen; L H Matherly; G J Peters Journal: Ann Oncol Date: 2017-11-01 Impact factor: 32.976
Authors: R F H Walter; F D Mairinger; S Ting; C Vollbrecht; T Mairinger; D Theegarten; D C Christoph; K W Schmid; J Wohlschlaeger Journal: Br J Cancer Date: 2015-02-10 Impact factor: 7.640
Authors: Robert Fred Henry Walter; Claudia Vollbrecht; Robert Werner; Jeremias Wohlschlaeger; Daniel Christian Christoph; Kurt Werner Schmid; Fabian Dominik Mairinger Journal: Oncotarget Date: 2016-04-05
Authors: Fabian Dominik Mairinger; Claudia Vollbrecht; Elena Flom; Daniel Christian Christoph; Kurt-Werner Schmid; Jens Kollmeier; Helmut Hans Popper; Thomas Mairinger; Robert Fred Henry Walter Journal: Oncotarget Date: 2017-06-06
Authors: Fabian D Mairinger; Jan Schmeller; Sabrina Borchert; Michael Wessolly; Elena Mairinger; Jens Kollmeier; Thomas Hager; Thomas Mairinger; Daniel C Christoph; Robert F H Walter; Wilfried E E Eberhardt; Till Plönes; Jeremias Wohlschlaeger; Bharat Jasani; Kurt Werner Schmid; Agnes Bankfalvi Journal: Oncotarget Date: 2018-04-27
Authors: Robert F H Walter; Robert Werner; Michael Wessolly; Elena Mairinger; Sabrina Borchert; Jan Schmeller; Jens Kollmeier; Thomas Mairinger; Thomas Hager; Agnes Bankfalvi; Daniel C Christoph; Wilfried E E Eberhardt; Till Plönes; Clemens Aigner; Kurt W Schmid; Jeremias Wohlschlaeger; Fabian D Mairinger Journal: J Oncol Date: 2018-07-17 Impact factor: 4.375
Authors: Giovanna Li Petri; Btissame El Hassouni; Rocco Sciarrillo; Niccola Funel; Giulia Mantini; Eveline A Zeeuw van der Laan; Stella Cascioferro; Amir Avan; Paolo Andrea Zucali; Nadia Zaffaroni; Tonny Lagerweij; Barbara Parrino; Kees Smid; Marcello Deraco; Carlotta Granchi; Alicja Braczko; Ryszard T Smolenski; Larry H Matherly; Gerrit Jansen; Yehuda G Assaraf; Patrizia Diana; Jacqueline Cloos; Godefridus J Peters; Filippo Minutolo; Elisa Giovannetti Journal: Br J Cancer Date: 2020-06-04 Impact factor: 7.640