Τίτλος:
Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. © 2014, American Association for the Advancement of Science. All rights reserved.
Συγγραφείς:
Wan, X.
Corn, P.G.
Yang, J.
Palanisamy, N.
Starbuck, M.W.
Efstathiou, E.
Li-Ning Tapia, E.M.
Zurita, A.J.
Aparicio, A.
Ravoori, M.K.
Vazquez, E.S.
Robinson, D.R.
Wu, Y.-M.
Cao, X.
Iyer, M.K.
McKeehan, W.
Kundra, V.
Wang, F.
Troncoso, P.
Chinnaiyan, A.M.
Logothetis, C.J.
Navone, N.M.
Περιοδικό:
Science Translational Medicine
Εκδότης:
American Association for the Advancement of Science
Λέξεις-κλειδιά:
dovitinib; fibroblast growth factor; fibroblast growth factor receptor 1; prostate specific antigen; 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; antineoplastic agent; benzimidazole derivative; fibroblast growth factor 2; fibroblast growth factor receptor 1; quinolone derivative, animal experiment; animal model; antiangiogenic activity; antineoplastic activity; Article; bone metastasis; bone quality; bone scintiscanning; cancer cell; castration resistant prostate cancer; cell interaction; controlled study; drug megadose; drug targeting; human; human cell; low drug dose; lymph node; lymph node size; molecular interaction; mouse; musculoskeletal system parameters; nonhuman; osteoblast; positive feedback; prostate cancer; protein blood level; protein expression; receptor blocking; signal transduction; stroma cell; tumor microenvironment; tumor volume; animal; apoptosis; bone; Bone Neoplasms; disease model; drug effects; drug screening; gene expression regulation; genetics; male; metabolism; Neovascularization, Pathologic; pathology; Prostatic Neoplasms; secondary; stroma cell; tumor cell line; vascularization, Animals; Antineoplastic Agents; Apoptosis; Benzimidazoles; Bone and Bones; Bone Neoplasms; Cell Line, Tumor; Disease Models, Animal; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Neovascularization, Pathologic; Osteoblasts; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Quinolones; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Stromal Cells; Tumor Microenvironment; Xenograft Model Antitumor Assays
DOI:
10.1126/scitranslmed.3009332
