Inhibition of the alpha receptor for platelet-derived growth factor as a potential therapeutic in bone metastatic prostate cancer

Michael R. Russell

doi:10.17918/00004619

Prostate adenocarcinoma is the second leading cause of cancer death among men, due primarily to the fact that the majority of prostate cancers will inevitably spread to the skeleton. Metastatic dissemination requires a complex series of coordinated events that result in cells escaping from the primary tumor into the circulation and eventually colonizing a distant organ. The ability of these cells to develop into metastases of clinically relevant size depends strongly on their compatibility with, and ability to utilize, the new microenvironment. Previous evidence demonstrated that bone-metastatic prostate cancer cells exposed to human bone marrow aspirates respond through activation of cell survival pathways, such as PI3K/Akt, and these events are mediated by the alpha-receptor for platelet-derived growth factor (PDGFR[alpha]). To date, there is a growing body of evidence to implicate PDGFR[alpha] signaling in the establishment of prostate cancer skeletal metastases. The research presented here employed a mouse model of disseminated prostate cancer and established that although late-stage skeletal tumors were able to utilize the bone microenvironment through osteoclast-mediated bone resorption, the small foci observed in early-stage metastases were unable to do so. It was subsequently determined that prostate cancer cells expressing high levels of PDGFR[alpha] could progress during the early stages of skeletal dissemination, whereas cells expressing lower levels or lacking this receptor fail to survive after extravasation in the bone marrow. Non-metastatic prostate cancer cells were able to acquire bone-metastatic potential upon ectopic over-expression of PDGFR[alpha], however, and functional blockade of human PDGFR[alpha] (utilizing a novel humanized monoclonal antibody) significantly impaired the growth of early skeletal metastases. In addition, treatment of established tumor foci with this antibody reduced the size of metastatic skeletal lesions and its combined use with zoledronic acid, a bisphosphonate, significantly prolonged survival in our mouse model. The experiments presented in this dissertation also sought to determine the mechanism(s) by which PDGFR[alpha] is activated independently of PDGF ligand(s), following exposure to human bone marrow aspirates. It was discovered that soluble components of human bone marrow activate PDGFR[alpha] in a manner independent of canonical PDGF ligand binding. In particular, dimerization of PDGFR[alpha] monomers is not induced by human bone marrow, but this does not prevent both receptor phosphorylation and downstream signaling from occurring. The relevance of this phenomenon was established in vivo, by employing a PDGFR[alpha] mutant lacking the extracellular ligand-binding domain. It was found that this truncated PDGFR[alpha] was able to restore the bone-metastatic potential of prostate cancer cells as effectively as the full-length form of the receptor. Finally, the studies presented here also reveal that expression of PDGFR[alpha] regulates a subset of genes that may also be involved in the metastatic progression of prostate carcinoma. In conclusion, these findings strongly implicate PDGFR[alpha] in the bone tropism of prostate cancer. The accumulated evidence provides a solid rationale for therapeutic strategies aimed at targeting this receptor to prevent or contain bone metastatic complications in patients affected by prostate adenocarcinoma.

Inhibition of the alpha receptor for platelet-derived growth factor as a potential therapeutic in bone metastatic prostate cancer

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Inhibition of the alpha receptor for platelet-derived growth factor as a potential therapeutic in bone metastatic prostate cancer

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