Cediranib inhibits both the intraosseous growth of PDGF D-positive prostate cancer cells and the associated bone reaction.
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.


CONCLUSIONS
These novel findings support the utilization of cediranib, either alone or in combination with docetaxel, to treat bone metastatic PCa exhibiting PDGF D expression.
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Abdo J
AJ
Najy
Young Suk
YS
Jung
Joshua J
JJ
Won
M Katie
MK
Conley-LaComb
Allen
A
Saliganan
Chong Jai
CJ
Kim
Elisabeth
E
Heath
Michael L
ML
Cher
R Daniel
RD
Bonfil
Hyeong-Reh Choi
HR
Kim
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011799:Quinazolines / Q000627:therapeutic use*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D007211:Indoles
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D011799:Quinazolines; C427493:PDGFD protein, human; C500926:cediranib; D007211:Indoles