title: Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling.
abstract: Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Nguyen
authors.forename: Nazanin
authors.initials: N
authors.lastname: Ruppender
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.forename: Lisha G
authors.initials: LG
authors.lastname: Brown
authors.forename: Ted S
authors.initials: TS
authors.lastname: Gross
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Frauke
authors.initials: F
authors.lastname: Schimmoller
authors.forename: Dana T
authors.initials: DT
authors.lastname: Aftab
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology* / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D000813:Anilides; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; C000588866:KDR protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2