Anne S Tsao1, Heather Lin2, Brett W Carter3, J Jack Lee2, David Rice4, Ara Vaporcyan4, Steven Swisher4, Reza Mehran4, John Heymach5, Monique Nilsson5, Youhong Fan5, Maria Nunez5, Lixia Diao6, Jing Wang6, Junya Fujimoto7, Ignacio I Wistuba7, Waun Ki Hong5. 1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Electronic address: astsao@mdanderson.org. 2. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 3. Department of Diagnostic Radiology Thoracic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 4. Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 5. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 6. Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 7. Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Abstract
INTRODUCTION: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. METHODS: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419. RESULTS: For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5-110), and the median posttreatment score was 41.9 (interquartile range 4.2-60) (p = 0.004). A decrease in p-SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p-SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. CONCLUSIONS: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.
INTRODUCTION: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. METHODS: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419. RESULTS: For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5-110), and the median posttreatment score was 41.9 (interquartile range 4.2-60) (p = 0.004). A decrease in p-SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p-SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. CONCLUSIONS: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.
Authors: Runzhe Chen; Won-Chul Lee; Anne S Tsao; Jianjun Zhang; Junya Fujimoto; Jun Li; Xin Hu; Reza Mehran; David Rice; Stephen G Swisher; Boris Sepesi; Hai T Tran; Chi-Wan Chow; Latasha D Little; Curtis Gumbs; Cara Haymaker; John V Heymach; Ignacio I Wistuba; J Jack Lee; P Andrew Futreal; Jianhua Zhang; Alexandre Reuben Journal: Clin Cancer Res Date: 2020-08-14 Impact factor: 12.531
Authors: Luca Hegedüs; Kata D Szücs; Matthias Kudla; Julian Heidenreich; Verena Jendrossek; Samuel Peña-Llopis; Tamas Garay; Andras Czirok; Clemens Aigner; Till Plönes; Silvia Vega-Rubin-de-Celis; Balazs Hegedüs Journal: Front Cell Dev Biol Date: 2022-03-22
Authors: Hely Ollila; Juuso Paajanen; Henrik Wolff; Ilkka Ilonen; Eva Sutinen; Katja Välimäki; Arne Östman; Sisko Anttila; Eeva Kettunen; Jari Räsänen; Olli Kallioniemi; Marjukka Myllärniemi; Mikko I Mäyränpää; Teijo Pellinen Journal: J Pathol Clin Res Date: 2021-05-06