Abstract 1468: Antagonism of platelet-derived growth factor receptor-α as a potential therapeutic for prostate cancer bone metastases

Abstract

Abstract Prostate adenocarcinoma is the second leading cause of cancer death among men, due primarily to the fact that the majority of prostate cancers will eventually spread to the skeleton. Metastatic dissemination requires a complex series of coordinated events that result in cells that escape from the primary tumor into the circulation and eventually colonize distant organs. The ability of disseminated cancer cells to evolve into metastases of clinically significant size depends strongly on their compatibility with, and ability to utilize, this new micro-environment. We previously showed that bone-metastatic prostate cancer cells exposed to human bone marrow respond by activation of cell survival pathways, such as PI3K/Akt., and that these events are mediated by the alpha-receptor for platelet-derived growth factor (PDGFRα). We also have shown that prophylactic antagonism of this receptor using IMC-3G3, a monoclonal, humanized antibody currently in phase II trials, was able to significantly reduce tumor burden in an in vivo model of skeletal metastasis. Here we show that IMC-3G3 can be used in a curative manner to reduce the growth of previously established skeletal lesions. In addition, we have successfully combined this antibody with zoledronic acid, a bisphosphonate commonly used to treat skeletal metastases, with encouraging results. Interestingly, treatment with a monoclonal antibody targeting only host PDGFRα failed to show any significant difference over saline treated mice. Lastly, we sought to dissect the mechanism by which PDGFRα may exert its role within the bone microenvironment. We provide evidence that soluble components of human bone marrow can activate PDGFRα through a mechanism that does not require the canonical binding of PDGF ligand(s) to the receptor. To establish the relevance of this phenomenon in vivo, we employed a PDGFRα mutant lacking the extracellular ligand-binding domain. Our studies show that this truncated PDGFRα was able to restore bone-metastatic potential of prostate cancer cells as effectively as the full-length form of the receptor. In addition, we have found that expression of PDGFRα, and its related signaling events, results in the regulation of a specific set of genes that we believe may aid in the survival and growth of metastatic prostate cancer cells within the bone. Studies to understand the contribution of several of these putative bone metastatic genes are currently underway in our laboratory. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1468.