title: Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.
abstract: 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.
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xinhai
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Corn
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. The Rolanette and Berdon Lawrence Bone Disease Program of Texas, Houston, TX 77030, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Starbuck
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. University of Athens Greece School of Medicine, Athens 11528, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Li Ning Tapia
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Elsa M Li-Ning
authors.initials: EM
authors.lastname: Tapia
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Amado J
authors.initials: AJ
authors.lastname: Zurita
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Aparicio
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Ravoori
authors.affiliation: Department of Biological Chemistry, University of Buenos Aires-National Research Council of Argentina (CONICET-IQUIBICEN), Ciudad Autonoma de Buenos Aires C1428EGA, Argentina.
authors.forename: Elba S
authors.initials: ES
authors.lastname: Vazquez
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Robinson
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yi-Mi
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Iyer
authors.affiliation: Center for Cancer and Stem Cell Biology, IBT-Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Wallace
authors.initials: W
authors.lastname: McKeehan
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kundra
authors.affiliation: Center for Cancer and Stem Cell Biology, IBT-Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. nnavone@mdanderson.org.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D015363:Quinolones; D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1