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Beyond the Abstract - Bisphosphonate anticancer activity in prostate cancer and other genitourinary cancers, by Fred Saad, MD

BERKELEY, CA (UroToday.com) - Anticancer therapies have traditionally been targeted directly against cancer cell growth.

However, newer treatment strategies also target the microenvironment that supports metastatic cancer cell growth. Because the bone microenvironment can act as a metastatic niche, bone-targeted agents may be a viable anticancer therapy option.

Bisphosphonates (BPs) are the standard of care for maintaining bone health in patients with bone metastases from solid tumors, such as prostate cancer (PC), or with bone lesions from multiple myeloma.1 Bone metastases develop in 65% to 75% of patients with advanced PC and in 20% to 40% of patients with other advanced genitourinary (GU) cancers.2 Metastatic bone disease disrupts normal bone homeostasis between bone resorption and bone formation, causing weakening of the skeleton.2 As a result, bone metastases often lead to skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, radiation therapy to bone, and hypercalcemia of malignancy.2 All BPs are antiresorptive agents that block pathologic bone resorption by inducing osteoclast apoptosis. Later-generation, nitrogen-containing BPs (NBPs) also inhibit osteoclast activation and function.3,4 Therefore, BPs reduce the tumor burden in bone and interrupt the vicious cycle of increased osteolysis coupled with increased tumor growth.5

In addition to the established use of BPs for the treatment of metastatic bone disease, emerging evidence supports their anticancer activity. A potential mechanism for cancer cells metastasizing to bone is thought to occur via the “seed and soil” hypothesis.6,7 In this mechanism, circulating tumor cells (CTCs) may act as “seeds” for subsequent local and distant relapse in supportive “soil,” and the sites of future tumor growth can be the primary tumor site (tumor “self-seeding”) or distant metastases.5,7 However, CTCs often adhere to the bone marrow microenvironment to become disseminated tumor cells (DTCs) because the bone marrow microenvironment provides a secure niche for tumor cells to survive for prolonged periods of time and allows them to evade the cytotoxic effects of systemic anticancer therapy.5,8-10 Furthermore, CTCs and DTCs have been associated with an increased risk of recurrence and distant metastases in patients with PC.11-13

Rendering the bone marrow microenvironment less suitable for the growth of DTCs is a potential mechanism that may contribute to the observed anticancer activity of BPs.14 Nitrogen-containing BPs inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway required for the posttranslational modification and function of small guanosine triphosphatases (GTPases), such as ras, rho, and rac, that play a key role in cell proliferation and survival.15 As pyrophosphate analogues, BPs are integrated into an intracellular adenosine triphosphate (ATP) analogue that can promote cellular apoptosis directly.15 Thus, NBPs interfere with multiple cellular functions required for the bone-resorbing activity and survival of osteoclasts. These same cellular functions also may be involved in cancer cell growth,16 providing another potential mechanism of action for the observed anticancer activity of BPs. Indeed, preclinical evidence using mouse models suggests that BPs can decrease the tumor burden in bone in an osteoclast-independent manner.17 Moreover, BPs may target several steps involved in the metastatic process, including tumor cell growth, migration, adhesion to extracellular matrix, extravasation into distant tissues, angiogenesis, and avoidance of immune surveillance.5,14

Zoledronic acid (ZOL), a third-generation NBP, is currently recommended for reducing the risk of skeletal morbidity in patients with bone metastases from castration-resistant PC and other GU cancers, such as renal cell carcinoma and bladder cancer.1,18 Preclinical and emerging clinical evidence suggests a potential anticancer role for BPs, especially ZOL, in this setting.19-31 Indeed, clinical studies indicate that ZOL can normalize bone marker levels (a potential measure of skeletal disease burden),19,20,32,33 which may improve survival in patients with aggressive bone disease from prostate and other GU cancers, supporting a broader therapeutic role for ZOL in GU malignancies.

In view of its established role and safety profile in the bone metastases setting, it is likely that a potential additional anticancer benefit from ZOL may be achieved without increased toxicity for patients. Therefore, bone-directed therapies such as ZOL represent an important component in the therapeutic repertoire to prevent cancer recurrence. Ongoing studies are investigating bone-targeted agents for the prevention of bone metastases in patients with PC and other GU malignancies, and results of these studies will help refine the role of these agents.

 

Acknowledgements:

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Duprane Pedaci Young, PhD, ProEd Communications, Inc., for her medical editorial assistance with this commentary.

Conflict of Interest:

Dr. Fred Saad has served as an advisor and conducted research for Novartis and Amgen.

 

References:

  1. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. 2008;19(3):420-432.
  2. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165-176.
  3. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337-342.
  4. Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000;88(12 ):2961-2978.
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  11. Kollermann J, Weikert S, Schostak M, et al. Prognostic significance of disseminated tumor cells in the bone marrow of prostate cancer patients treated with neoadjuvant hormone treatment. J Clin Oncol. 2008;26(30):4928-4933.
  12. Morgan TM, Lange PH, Porter MP, et al. Disseminated tumor cells in prostate cancer patients after radical prostatectomy and without evidence of disease predicts biochemical recurrence. Clin Cancer Res. 2009;15(2):677-683.
  13. Berg A, Berner A, Lilleby W, et al. Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy. Int J Cancer. 2007;120(8):1603-1609.
  14. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest. 2002;20(suppl 2):45-54.
  15. Fritz G. Targeting the mevalonate pathway for improved anticancer therapy. Curr Cancer Drug Targets. 2009;9(5):626-638.
  16. Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006;12(20 Pt 2):6222s-6230s.
  17. Hirbe AC, Roelofs AJ, Floyd DH, et al. The bisphosphonate zoledronic acid decreases tumor growth in bone in mice with defective osteoclasts. Bone. 2009;44(5):908-916.
  18. Zometa (zoledronic acid) injection [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011. Available from: http://www.pharma.us.novartis.com/product/pi/pdf/Zometa.pdf. (Accessed December 13, 2011).
  19. Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23(22):4925-4935.
  20. Saad F. New research findings on zoledronic acid: survival, pain, and anti-tumour effects. Cancer Treat Rev. 2008;34(2):183-192.
  21. Saad F, Lipton A. Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers. BJU Int. 2005;96(7):964-969.
  22. Zaghloul MS, Boutrus R, El-Hossieny H, Kader YA, El-Attar I, Nazmy M. A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol. 2010;15(4):382-389.
  23. Guise TA. Antitumor effects of bisphosphonates: promising preclinical evidence. Cancer Treat Rev. 2008;34(suppl 1):S19-S24.
  24. Boissier S, Ferreras M, Peyruchaud O, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000;60(11):2949-2954.
  25. Coxon JP, Oades GM, Kirby RS, Colston KW. Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation. BJU Int. 2004;94(1):164-170.
  26. Facchini G, Caraglia M, Morabito A, et al. Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Cancer Biol Ther. 2010;10(6):543-548.
  27. Morgan C, Lewis PD, Jones RM, Bertelli G, Thomas GA, Leonard RC. The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer. Acta Oncol. 2007;46(5):669-677.
  28. Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, Coleman RE, Holen I. Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer. 2005;113(3):364-371.
  29. Soltau J, Zirrgiebel U, Esser N, et al. Antitumoral and antiangiogenic efficacy of bisphosphonates in vitro and in a murine RENCA model. Anticancer Res. 2008;28(2A):933-941.
  30. Ullen A, Schwarz S, Lennartsson L, et al. Zoledronic acid induces caspase-dependent apoptosis in renal cancer cell lines. Scand J Urol Nephrol. 2009;43(2):98-103.
  31. Yuasa T, Sato K, Ashihara E, et al. Intravesical administration of gammadelta T cells successfully prevents the growth of bladder cancer in the murine model. Cancer Immunol Immunother. 2009;58(4):493-502.
  32. Saad F, Abrahamsson PA, Miller K. Preserving bone health in patients with hormone-sensitive prostate cancer: the role of bisphosphonates. BJU Int. 2009;104(11):1573-1579.
  33. Saad F, Lipton A. Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease. Semin Oncol. 2007;34(6 suppl 4):S17-S23.

 

 

Written by:
Fred Saad, MD 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.

 

Address for correspondence:
Fred Saad, MD
Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame,
1560 Rue Sherbrooke East, Montréal, Quebec, Canada PQ H2L 4M1
Phone: +1 514 890 8000
Facsimile: +1 514 412 7620
E-mail:

 

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