In vivo therapy of malignant melanoma by means of antagonists of αv integrins

Abstract

Integrin alphavbeta3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of alphavbeta3. In this report, we characterize the activities of 2 antagonists of alphavbeta3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate-attached cells in vitro. In vivo, alphavbeta3 antagonists behaved as anti-tumor drugs in a dose- and time-dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing alphavbeta3 as xenografts but did not affect the alphavbeta3-negative (although alphav integrin-positive) tumors. This demonstrated that alphavbeta3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine alphavbeta3, the effect is due only to the direct anti-tumor activity and not to the well-known anti-angiogenic activity of alphav-integrin antagonists. Taken together, our results confirm the essential role of alphavbeta3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of alphav-integrin antagonists for the treatment of such tumors.

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

“…22 In concordance with our data, Mitjans et al 23 recently reported that the pan-␣v monoclonal antibody 17E6 and an RGD peptide detached M21 melanoma cells from vitronectin and that only ␣v␤3-expressing melanoma growth was inhibited by this antibody. Similarly, Chatterjee et al 24 reported that a cyclic RGD peptide, similar to ours, induced cell death in the ␣v␤3-expressing brain tumor cells U87MG and U373MG when cells were grown in tissue culture as monolayers or as spheroids, but it had no effect on U251 cells, which lack expression of ␣v␤3.…”

Integrin αvβ3‐targeted cancer therapy

“…17E6 can strongly perturb cell attachment mediated by α v integrins and inhibit cell attachment to α v ligands such as vitronectin and fibronectin. Using a panel of six human melanomas and five carcinomas, 17E6 efficiently blocked the in vivo tumor growth of integrin α v β 3 -positive xenografts but did not affect the α v β 3 -negative xenografts [Mitjans et al, 2000;Mitjans et al, 1995]. Given that mAb 17E6 also does not recognize murine α v β 3 , the anti-tumor effect is likely due to the direct antitumor activity, and not to the anti-host vasculature activity in the mouse model.…”

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

“…Cilengitide has demonstrated preclinical single-agent anti-tumor activity against melanoma [96] and orthotopic brain tumor xenografts [36,71], which may be due to apoptosis induced by tumor cell detachment [71]. Recent preclinical work has focused on the clinical observation that MGMT methylated tumors tend to respond positively to cilengitide combined with XRT/TMZ compared to MGMT unmethylated tumors [43].…”