Integrins as therapeutic targets

As previously discussed, integrins have been shown to mediate tumour progression, tumour cell metastasis and EMT in both in vitro and in vivo models. Thus, these preclinical studies have suggested that integrins could be a novel therapeutic target to prevent cancer progression, including prostate cancer. Currently, studies have been focused on targeting integrin avp3 in breast cancer, ovarian cancer and prostate cancer. Integrin avp3 is likely to be a good cancer angiogenesis target because it is highly expressed on tumour-associated new blood vessels and the surface of most epithelial tumours cells.

There are currently antibody-type inhibitors (LM609, MEDI-522, CNTO95, c7E3, 17E6) or peptide-type inhibitors (Cilengitide, ATN-161) under investigation. However, here only inhibitors that have been tested specifically on prostate cancer models will be reviewed. MEDI-522 is a humanized monoclonal antibody specific for integrin avp3 and a phase I dose escalation trial was conducted in 25 individuals with a variety of metastatic solid tumours which included, breast, colorectal, melanoma, non-small cell lung cancer, ocular mel anoma, renal, sarcoma and prostate cancers [70]. Participants in the trial were treated on a daily basis with dosages ranging from 2 to 10 mg/kg/wk, intravenously. Treatment showed a possible effect on tumour perfusion with an increase in mean transit time of blood through target tumour lesions after 8 weeks. There were no significant toxicities observed in the treated individuals, with only mild constitutional and gastrointestinal symptoms observed. Only two individuals with metastatic renal cancer remained on treatment and showed prolonged stable disease for 1 or 2 years, respectively, suggesting MEDI-522 may have clinical activity in metastatic renal cancer. Currently, a phase II, randomized, open-label, two-arm, multicenter study of MEDI-522 in combination with docetaxel (an anti-mitotic, standard chemotherapy drug), prednisone (a glucocorticoid prodrug), and zolendronic acid (a bi-sphosphonate) in individuals with metastatic androgen-independent prostate cancer has just been completed. However, the results of the trial have not been documented yet.

CNTO95 is a fully human antibody that recognizes the integrin av. It binds to both integrin avp3 and avp5 [71]. CNTO95 was found to inhibit adhesion and migration of HUVECs (human umbilical vein endothelial) and A375.S2 (human melanoma) cells on vitronectin, fibrinogen, gelatin and fibrin, which are ligands for integrin avp3 and avp5. In an in vivo study, CNTO95 inhibited the growth of human melanoma tumours in nude mice by approximately 80% and reduced final tumour weight by 99%, thus suggesting it has antitumour effects. A phase I clinical study was conducted in 24 individuals with a variety of advanced solid tumours. However, there were no individuals with prostate cancer included in this study. CNTO95, administered intravenously, was generally well tolerated with no adverse side effects. Individuals with ovarian cancer showed a prolonged stable disease with CNTO95 treatment and a 9 month partial response was observed in one individual with angiosarco-ma. Interestingly, the partial response was observed in an individual with tumour expressing integrin avp1 and not avp3, suggesting a broad specificity for integrin av. Currently, a phase II study of CNTO95 in combination with docetaxel for the first-line treatment of individuals with metastatic hormone refractory prostate cancer has been completed, although the results have yet to be documented.

Cilengitide is a cyclic peptide that is a potent and selective inhibitor of integrin avp3 and avp5 mediated cell adhesion. In a phase I study, Cilengitide was administrated as a continuous infusion in 4 week cycles at doses of 1, 2, 4, 8, 12, 18, 27, and 40mg/h in 25 individuals with a variety of solid tumours including prostate cancer. This study showed that Cilengi-tide was generally well tolerated as a continuous infusion and only mild side effects were observed. However, the variable dose did not affect tumour size. This lack of dose-response could be because the lowest dose was as effective as the highest dose. Interestingly, two phase II studies on Cilengitide were conducted by the same research team [72, 73]. In the earlier study, Cilengitide was administrated at 500 mg and 2000 mg, intravenously twice weekly in 44 asymptomatic individuals with metastatic castrate resistant prostate cancer (CRPC) [72]. The treatment was randomized and well tolerated and at the endpoint at 6 months, 9% of participants treated with 500 mg Cilengitide and 23% of participants treated with 2000 mg Cilengitide showed no tumour progression, suggesting better outcomes with the higher dose. The majority of the participants showed stable disease for 9 months. In the second phase II study, Cilengitide was adminitrated at 2000 mg, intravenously twice weekly until toxicity or progression in individuals with non-metastatic CRPC [73]. This treatment was well tolerated although two grade three toxicities (atrial fibrillation) were observed. In addition, Cilengitide showed no detectable clinical activity in this study.

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