Targeting the {alpha} receptor for platelet-derived growth factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis.
OBJECTIVE
Platelet-derived growth factor α (PDGFRα) is highly expressed in primary prostate cancer and associated skeletal metastases. Here, we tested whether targeting this receptor could impair metastatic colonization and progression, as well as prolong survival, either as primary or as combination therapy.


METHODS
We used a preclinical animal model of metastasis in which PC3-ML human prostate cancer cells are inoculated directly in the blood circulation. First, the humanized, monoclonal antibody IMC-3G3 was administered to mice bearing established skeletal metastases. Second, we targeted the stromal PDGFRα with IMC-1E10, an antibody specific for the murine receptor. Third, IMC-3G3 and the bisphosphonate zoledronic acid (ZA), administered separately or in combination, were tested on the progression of skeletal lesions and overall survival. In addition, the ability of IMC-3G3 and ZA to impair initial colonization of the bone marrow by prostate cancer cells was investigated.


RESULTS
The blockade of PDGFRα on prostate cancer cells by IMC-3G3 reduces the size of established skeletal metastases, whereas the IMC-1E10 antibody directed against the stromal PDGFRα fails to inhibit metastatic progression. IMC-3G3 and ZA, either separately or in combination, significantly slow tumor growth and seem to prolong survival. Lastly, the blockade of PDGFRα by IMC-3G3 inhibits the initial phase of bone colonization, whereas ZA is ineffective at this stage.


CONCLUSIONS
This study presents compelling evidence that targeting PDGFRα with IMC-3G3 delays the progression of early metastatic foci and reduces the size of more established lesions. In addition, IMC-3G3, either alone or in combination with ZA, prolongs survival in animal models.
Russell
Mike R
MR
Departments of Pharmacology and Physiology, Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
Liu
Qingxin
Q
Fatatis
Alessandro
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000517:prevention & control / Q000556:secondary*; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000008:administration & dosage; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D041681:NIH 3T3 Cells; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D000911:Antibodies, Monoclonal; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020796:Receptor, Platelet-Derived Growth Factor alpha; C000589393:olaratumab