title: Placental growth factor and soluble c-kit receptor dynamics characterize the cytokine signature of imatinib in prostate cancer and bone metastases.
abstract: To assess the hypothesis that the dynamics of plasma angiogenic and inflammatory cytokines after docetaxel chemotherapy with or without the c-kit/abl/platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate for prostate cancer are associated with outcome, the kinetics of 17 plasma cytokines before versus after chemotherapy were assessed and associations with progression-free survival (PFS) examined. After adjusting for multiple tests, significantly different declines in placental growth factor (PIGF), soluble vascular endothelial growth factor receptor-1 (VEGFR1), VEGF, and soluble c-kit were observed with docetaxel plus imatinib (n=41) compared to docetaxel alone (n=47). Based on a piecewise linear regression model for change in concentration of each cytokine as a function of the probability of change in p-PDGFR in vivo, only the dynamics of PIGF (P<0.0001) and soluble c-kit (P<0.0001) differed with imatinib therapy. In a Bayesian log-normal regression model for PFS, a rise in human matrix metalloproteinase 9 after docetaxel alone associated with a longer PFS. Distinct plasma angiogenic cytokines are modified by imatinib and partitioned by in vivo p-PDGFR dynamics after docetaxel chemotherapy for metastatic prostate cancer. Plasma PIGF and soluble c-kit kinetics are candidate biomarkers of imatinib effect. The predictive value of human matrix metalloproteinase 9 kinetics for docetaxel efficacy requires prospective validation.
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. pmathew@tuftsmedicalcenter.org
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D001549:Benzamides; D054316:Biomarkers, Pharmacological; C000608036:PGF protein, human; D010879:Piperazines; D011257:Pregnancy Proteins; D011743:Pyrimidines; D043823:Taxoids; D000072483:Placenta Growth Factor; D000077143:Docetaxel; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit