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Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeting the Lethal Phenotype

Robert D. Loberg, Christopher J. Logothetis, Evan T. Keller, Kenneth J. Pienta

From the University of Michigan, Ann Arbor, MI; and M.D. Anderson Cancer Center, The University of Texas, Houston, TX

Address reprint requests to Kenneth J. Pienta, MD, FACP, Michigan Urology Center, University of Michigan, 7308 CCGC, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0946; e-mail: kpienta{at}umich.edu.

Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell–microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer–bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.

Supported by National Institues of Health Grants No. NCI 2 P50 CA69568-06A1, NIH 1 R01 CA102872, and NIH 1 PO1 CA093900-01A2, and The Prostate Cancer Foundation. K.J.P. is supported by the American Cancer Society as a clinical research professor. C.J.L. is supported by National Institutes of Health Grant No. NCI P50 CA90270.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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