BACKGROUND: The major cause of death in prostate cancer (PCa) cases is due to distant metastatic lesions, with the bone being the most prevalent site for secondary colonization.
Utilization of small molecule inhibitors to treat bone metastatic PCa have had limited success either as monotherapies or in combination with other chemotherapeutics due to intolerable toxicities. In the current study, we developed a clinically relevant in vivo intraosseous tumor model overexpressing the platelet-derived growth factor D (PDGF D) to test the efficacy of a newly characterized vascular endothelial growth factor receptor (VEGFR)/PDGFR inhibitor, cediranib (also called AZD2171).
METHODS: An intratibial-injection model was established utilizing DU145 cells with or without increased PDGF D expression. Tumor-bearing mice were treated by daily gavage administration of cediranib and/or weekly i.p. injection of docetaxel for 7 weeks. Tibiae were monitored by in vivo/ex vivo X-rays and histomorphometry analysis was performed to estimate tumor volume and tumor-associated trabecular bone growth.
RESULTS: Cediranib reduced intraosseous growth of prostate tumors as well as tumor-associated bone responses. When compared to the standard chemotherapeutic agent docetaxel, cediranib exhibited a stronger inhibition of tumor-associated bone response. The efficacy of cediranib was further enhanced when the drug was co-administered with docetaxel. Importantly, the therapeutic benefits of cediranib and docetaxel are more prominent in intraosseous prostate tumors overexpressing PDGF D.
CONCLUSION: These novel findings support the utilization of cediranib, either alone or in combination with docetaxel, to treat bone metastatic PCa exhibiting PDGF D expression.
Written by:
Najy AJ, Jung YS, Won JJ, Conley-Lacomb MK, Saliganan A, Kim CJ, Heath E, Cher ML, Bonfil RD, Kim HR. Are you the author?
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Reference: Prostate. 2011 Dec 27.
doi: 10.1002/pros.22481. [Epub ahead of print]
PubMed Abstract
PMID: 22213159
UroToday.com Investigational Urology Section
