Agents Targeting Prostate Cancer Bone Metastasis

Main Category: Prostate / Prostate Cancer
Also Included In: Cancer / Oncology;  Bones / Orthopedics
Article Date: 29 Dec 2009 - 0:00 PDT

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UroToday.com - Advanced prostate cancers regularly metastasize to the skeleton, and better treatments are needed to decrease morbidity and increase survival in men with end-stage disease. Metastatic prostate cancer cells alter the bone microenvironment in two ways:

1) they stimulate formation of disorganized new bone with poor biomechanical quality;

2) they stimulate bone remodeling by activating osteoclasts.

These two steps offer unique adjuvant targets to supplement conventional anti-tumor therapies. Drugs against osteoclasts include classes of anti-resorptive agents developed against osteoporosis. In addition to the approved bisphophonates, inhibitors are in Phase III trials against osteoclast-selective targets cathepsin K and RANK ligand. Pathological bone in osteoblastic lesions may be caused by prostate-secreted endothelin-1, whose actions are blocked by endothelin receptor antagonists in Phase III trials. The status of these drugs is reviewed in the linked title article. Bone metastases provide a novel paradigm for cancer treatment: adjuvant therapy aimed at the metastatic microenvironment (rather than the tumor itself) can reduce tumor burden and decrease morbidity and mortality. Such therapy can increase the efficacy of conventional cytotoxic agents to kill tumor within bone (1,2), where it is otherwise resistant to treatment. The next step beyond the abstract is to develop more adjuvant therapies that target the microenvironment. The agents described above were developed for non-cancer indications: anti-resorptives for osteoporosis and endothelin antagonists for pulmonary hypertension. They were easily tested in animal models and rapidly brought to clinical trials, since their pharmacokinetics and safety profiles were known. How will we go about testing new mechanisms? For example, the authors have preliminary data that the tumor-secreted peptide adrenomedullin might be a good target for adjuvant therapy, but there are no drugs ready to test in laboratory animals, which is also a slow and expensive approach. Direct anti-tumor drugs are first tested against growth of tumor cells in vitro, but bone metastases do not form in vitro. It would be risky to develop drugs in vitro to find out that the drug target was not important in vivo.

Better assays for proof-of-principal testing of new molecular targets are needed. A recent paper shows that prostate cancer cells can be grown together with mouse skull fragments (3). The bone pieces contain all of the major bone cell types and mineralized matrix (4), which is a major storage site of immobilized insulin-like growth factors, transforming growth factor beta and more. The bone microenvironment may be reproduced with greater fidelity than by co-culturing cell lines, although this approach is being actively developed (5). We can look forward to improvements in screening adjuvant agents aimed at the bone microenvironment using such assay systems. Ex vivo screening can provide the proof-of-principal to justify development of drugs that are effective in animal models and can safely be brought through the clinical trial process. A major remaining challenge is the pain caused by tumor in bone, where some of the causal peptides (endothelin, adrenomedullin) are nociceptive transmitters. Pain and its alleviation presently can only be studied in patients or in complex animal models (6).

References:

1) Kim SJ, Uehara H, Yazici S, He J, Langley RR, Mathew P, Fan D, Fidler IJ. Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer. Cancer Res. 2005 May 1;65(9):3707-15.

2) Brubaker KD, Brown LG, Vessella RL, Corey E. Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment. BMC Cancer. 2006 Jan 17;6:15.

3) Nordstrand A, Nilsson J, Tieva A, Wikström P, Lerner UH, Widmark A. Establishment and validation of an in vitro co-culture model to study the interactions between bone and prostate cancer cells. Clin Exp Metastasis. 2009 Sep 1. [Epub ahead of print]

4) Mohammad KS, Chirgwin JM, Guise TA. Assessing new bone formation in neonatal calvarial organ cultures. Methods Mol Biol. 2008;455:37-50.

5) Mastro AM, Vogler EA. A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. Cancer Res. 2009 May 15;69(10):4097-100.

6) Bove SE, Flatters SJ, Inglis JJ, Mantyh PW. New advances in musculoskeletal pain. Brain Res Rev. 2009 Apr;60(1):187-201.

Written by Khalid S. Mohammad, MD, PhD, and John M. Chirgwin, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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