EDITORIAL

Bone disease in prostate cancerajco_1281 3..4

Adnan NAGRIAL and Lisa HORVATHSydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia

Despite advances in therapy, prostate cancer remains thethird most common cause of cancer death in the devel-oped world. Advanced prostate cancer results in thedeath of >2 500 men in Australia each year. The majorityof men have bone-predominant disease with only ~20%developing visceral metastases.1 Bone metastases area cause of significant morbidity with complications,including pain and fractures, often resulting in hospitali-sation. In previous studies, the rates of skeletal relatedevents were as high as 49% in a 24 month period,2

predominantly due to metastatic bone disease and to alesser extent androgen deprivation induced osteoporosis.

Normal bone physiology is usually tightly regulatedbut becomes disrupted in malignant disease. The inter-action of tumour cells and osteoblasts/osteoclasts iscritical to the pathophysiology of bone metastases.Although prostate cancer metastases have classicallybeen classified as an osteoblastic phenotype, evidencenow suggests that osteoclastic activity is critical to mor-bidity and survival.3 Bone resorption requires the attach-ment of osteoclasts, to the bone mineralised matrixthrough numerous mechanisms including integrins.

Bisphosphonates, in particular Zoledronic acid, areroutinely used to prevent skeletal complications in menwith bone metastases from hormone-refractory prostatecancer. Zoledronic acid decreases bone resorption andreduces the incidence of skeletal related events from49% to 38%,2 but do not have an effect on diseaseprogression. This continues to be a disappointment inthe management of bone disease in prostate cancer, espe-cially considering that a recent study in early breastcancer patients showed that the addition of ZoledronicAcid to endocrine treatment results in a relative reduc-tion of 36% in the risk of disease progression.4

Integrins are a class of transmembrane receptors forextracellular matrix proteins which play a key role incell survival, proliferation, migration and activation ofgrowth factor receptors. Furthermore, integrins areessential for endothelial cell migration, proliferation,and survival during the process of angiogenesis. Deregu-

lation of integrin function has been associated withtumour progression and metastasis in melanoma, breastand prostate cancer.5 Several integrins have been impli-cated in primary prostate tumour growth and metasta-sis, however, avb3 has been specifically associated withthe development of bone metastases. McCabe et al.demonstrated that avb3 integrin activation on prostatecancer cells is essential for the recognition of key bone-specific matrix proteins and regulates not only prostatecancer cell growth but also tumour-induced bonegrowth.6 avb3 integrin expression in prostate cancer celllines and xenografts has also been associated withincreased angiogenesis both alone and in combinationwith avb5 integrin.5

In this edition of the journal, Rosenthal et al. reporton a novel inhibitor of the avb3 integrin receptor,MK-0429.7 In this study, the authors evaluated thesafety and tolerability of MK-0429 and assessed theeffect on bone turnover by measuring the ratio ofurinary cross-linked N-telopeptides of Type 1 collagento creatinine (uNTx). The drug appears to be well tol-erated at both the 200 mg and 1600 mg doses withgrade 1/2 nausea being the most common side effect.Despite the small patient numbers and short treatmentperiod, there was a modest but significant decrease inthe uNTx at both dose levels suggesting decreased boneresorption. Although there was an increase in PSA levelsin both study groups over the 4 weeks, very little can beread into this as the timeframe was limited.

Several other therapeutics have been developed totarget prometastatic and proangiogenic integrins. Cilen-gitide, a small molecule inhibitor of avb3 and avb5 inte-grins, has demonstrated tolerability and evidence ofactivity as both a single agent8 and in combination withtemozolomide in glioblastoma.9 It is now being evalu-ated in two phase II trials in hormone-refractory pros-tate cancer.10 The NCI6735 study is assessing Cilengitideat a dose of 2000 mg twice weekly in non-metastatichormone-refractory prostate cancer, while the NCI6372study is a randomised study evaluating Cilengitide doses

Asia–Pacific Journal of Clinical Oncology 2010; 6: 3–4 doi:10.1111/j.1743-7563.2010.01281.x

© 2010 Blackwell Publishing Asia Pty Ltd

of 500 mg and 2000 mg dosing of cilengitide in meta-static hormone-refractory prostate cancer. CNTO 95, amonoclonal antibody targeting av integrins, has demon-strated a favourable toxicity profile in conjunction withdocetaxel and prednisone in hormone-refractory pros-tate cancer. A phase II trial is currently evaluating theefficacy of the CNTO 95/docetaxel/prednisone com-bination in metastatic hormone-refractory prostatecancer (NCT00537381). Another monoclonal antibody,MEDI-522, targets avb3 integrin preventing the bindingof ligands such as vitronectin.11 A randomised phase IItrial is currently assessing the efficacy of adding MEDI-522 to docetaxel, prednisone and zoledronic acid in menwith metastatic hormone-refractory prostate cancer(NCT00072930).

Integrin-targeted therapy holds great promise as botha bone-directed therapeutic and an anti-angiogenicagainst tumour growth at all sites of disease. Morbidityfrom bone disease continues to be a major issue incancer management and so there is certainly a need fornew, more effective therapeutics. MK-0429 is a welltolerated drug with some evidence of activity in boneand unlike the other agents is an oral treatment. This iscertainly an advantage compared to the other anti-integrin therapeutics as studies in oncology patientshave shown that patients prefer to receive oral treatmentas long as it is as efficacious.12 We await the results of thephase II trials of all these drugs with interest.

REFERENCES

1 Coleman RE. Skeletal complications of malignancy.Cancer 1997; 80: 1588–94.

2 Saad F, Gleason DM, Murray R et al. Long-termefficacy of zoledronic acid for the prevention of skeletalcomplications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96:879–82.

3 Guise TA, Mohammed K, Clines G et al. Basic mechanismsresponsible for osteolytic and osteoblastic bone metastases.Clin Cancer Res 2006; 12: 6213s–16.

4 Gnant M, Mlineritsch B, Schippinger W et al. Endocrinetherapy plus zoledronic acid in premenopausal breastcancer. N Engl J Med 2009; 360: 679–91.

5 Goel HL, Li JN, Kogan SP, Languino LR. Integrins inprostate cancer progression. Endocr Relat Cancer 2008;15: 657–64.

6 McCabe NP, De S, Vasanji A, Brainard J, Byzova TV.Prostate cancer specific integrin avb3 modulates bonemetastatic growth and tissue remodeling. Oncogene 2007;26: 6238–43.

7 Rosenthal MA, Davidson P, Rolland F et al. Evaluation ofthe safety, pharmacokinetics and treatment effects of anavb3 integrin inhibitor on bone turnover and disease activ-ity in men with hormone-refractory prostate cancerand bone metastases, Asia–Pacific J Clin Oncol 2010; 6:42–8.

8 Reardon D, Fink K, Nabors B et al. Phase IIa trial ofcilengitide (EMD121974) single-agent therapy in patientswith recurrent glioblastoma: EMD 121974-009, Am SocClin Oncol 2007. Vol. 25.

9 Stupp R, Goldbrunner R, Neyns B et al. Phase I/IIa trial ofcilengitide (EMD121974) and temozolomide with con-comitant radiotherpy, followed by temozolomide and cilen-gitide maintenance therapy in patients with newlydiagnosed glioblastoma, Am Soc Clin Oncol 2007. Vol. 25.

10 Beekman KW, Colevas AD, Cooney K et al. Phase IIevaluations of cilengitide in asymptomatic patients withandrogen-independent prostate cancer: scientific rationaleand study design. Clin Genitourin Cancer 2006; 4: 299–302.

11 McNeel DG, Eickhoff J, Lee FT et al. Phase I trial of amonoclonal antibody specific for alphavbeta3 integrin(MEDI-522) in patients with advanced maligancies, includ-ing an assessment of effect on tumor perfusion. Clin CancerRes 2005; 11: 7851–60.

12 Liu G, Franssen E, Fitch MI, Warner E. Patient preferencesfor oral versus intravenous palliative chemotherapy. J ClinOncol 1997; 15: 110–15.

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© 2010 Blackwell Publishing Asia Pty Ltd Asia–Pac J Clin Oncol 2010; 6: 3–4