Critical Role Of The Bone Microenvironment In Cancer Metastases - Treating Bone Metastases In Prostate Cancer Patients

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 26 Oct 2009 - 3:00 PDT

email to a friend   printer friendly   opinions  

UroToday.com - Most men with advanced, hormone refractory prostate cancer have metastases which occur preferentially in the skeleton (1). Why is this bad? Bone metastases are incurable and cause skeletal-related events (SREs) that contribute substantial morbidity: fractures, nerve compression, and severe bone pain. The linked article describes the basic mechanisms that drive bone metastases in a variety of solid tumors. The take-home lesson is that bone itself offers an important target for treatment.

What treatments are available?

Although prostate cancer causes mostly osteoblastic lesions, bone resorption by these metastases is very active. It can be inhibited by drugs such as the approved bisphosphonate, zoledronic acid. Two newer classes of anti-resorptive drugs developed for use in osteoporosis are performing well in Phase III clinical trials: small molecule inhibitors of cathepsin K and the monoclonal antibody denosumab against RANK ligand (2). These agents act on bone cells rather than tumor, are effective palliation against all types of skeletal metastases, but have not been found to decrease tumor burden or improve survival in patients.

Can osteoblastic responses also be targeted?

Current clinical trials with endothelin A receptor antagonists are aimed at blocking bone responses to prostate-secreted endothelin (3). Again, the drug may act on bone cells to inhibit tumor growth indirectly (4). Preliminary reports suggest that one of the antagonists may significantly increase overall survival (3). Other drugs aimed at osteoblasts are less far along in preclinical development. We have recently reviewed the development of new treatments for prostate cancer bone metastases (5).

Might standard treatments make bone metastases worse?

Many cancer treatments cause bone loss, including cytotoxic chemotherapies and sex steroid suppression (6,7). Patients with skeletal metastases due to breast and prostate cancers have multi-year survivals, putting them at continuing risk for SREs from therapy-induced bone loss, which is currently under-treated. An additional concern is that high bone turnover could attract tumor cells to the skeleton and stimulate metastases. This has been shown in animal models of breast cancer (8). The HSP90 inhibitor 17-AAG stimulates bone resorption by direct actions on osteoclasts and in animal models makes bone metastases worse, a side effect preventable with available drugs (9). Basic scientists remain dissatisfied with animal models of skeletal metastases, which mimic only a few of the many steps in the natural history of metastatic disease, but this is one of many cases where they prove their worth in preclinical drug development.

Future directions:

Anti-angiogenic therapies have been stymied by the ability of tumors to circumvent inhibitors of angiogenic factors. A better approach appears to be normalization of the tumor vasculature (10). The bone microenvironment provides prostate cancers a fertile location to grow by causing pathological bone responses. If we knew how to normalize the bone, the skeleton might provide a much less hospitable site for prostate cancers metastases. However, we do not know how to define 'normal' for bone, much less make it so. A goal closer to realization is to overcome the resistance to chemotherapy that the bone microenvironment provides. For example, inhibiting bone turnover increases sensitivity of prostate cancer to killing by a kinase inhibitor or paclitaxel in animal models (11).

References

1. Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, Abbruzzese JL. Metastatic patterns in adenocarcinoma. Cancer. 2006 Apr 1;106(7):1624-33.

2. Deal C. Potential new drug targets for osteoporosis. Nat Clin Pract Rheumatol. 2009 Jan;5(1):20-7.

3. James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T, Phung D, Dawson NA. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol. 2009 May;55(5):1112-23.

4. Yin JJ, Mohammad KS, Käkönen SM, Harris S, Wu-Wong JR, Wessale JL, Padley RJ, Garrett IR, Chirgwin JM, Guise TA. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10954-9.

5. Mohammad KS, Fournier PG, Guise TA, Chirgwin JM. Agents Targeting Prostate Cancer Bone Metastasis. Anticancer Agents Med Chem. 2009, Epub ahead of print.

6. Smith MR. Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6315s-6319s.

7. Gralow JR, Biermann JS, Farooki A, Fornier MN, Gagel RF, Kumar RN, Shapiro CL, Shields A, Smith MR, Srinivas S, Van Poznak CH. NCCN Task Force Report: Bone Health in Cancer Care. J Natl Compr Canc Netw. 2009 Jun;7 Suppl 3:S1-S32.

8. Zheng Y, Zhou H, Fong-Yee C, Modzelewski JR, Seibel MJ, Dunstan CR. Bone resorption increases tumour growth in a mouse model of osteosclerotic breast cancer metastasis. Clin Exp Metastasis. 2008;25(5):559-67.

9. Yano A, Tsutsumi S, Soga S, Lee MJ, Trepel J, Osada H, Neckers L. Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15541-6.

10. Fukumura D, Jain RK. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem. 2007 Jul 1;101(4):937-49.

11. 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.

Written by Sandra Casimiro, PhD, and John Chirgwin, PhD as part of Beyond the Abstract on UroToday.com.

UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice. To access the latest urology news releases from UroToday, go to: www.urotoday.com

Copyright © 2009 - UroToday

• Additional
• References
• Citations