Abstract
Abstract Background: In order to investigate mechanisms of resistance to angiogenesis inhibitors, Notch and Delta-like 4 ligand (DLL4) expression was correlated with response and survival in a series of bevacizumab treated advanced colon cancer patients. DLL4-mediated Notch signalling has recently emerged as an attractive target for angiogenesis-based cancer therapies, given that DLL4 is an important component of Notch-mediated stem cell self-renewal and vascular development. DLL4-induced Notch signalling mediates tumour-resistance to anti-VEGF therapy by inducing the formation of large vessels and activating multiple pathways in preclinical models. Method: Notch and DLL4 expression was evaluated by immunohistochemistry (IHC) on 65 primary colon cancer patients enrolled within randomized clinical trials assessing first-line bevacizumab plus chemotherapy. Results: Notch positivity was localized to the cytoplasm of malignant epithelial cells. In all, 10/60 (17%) evaluable primary tumours had a high Notch expression. Five of the 10 cases (50%) with high Notch expression experienced progressive disease compared with 5/49 (10%) Notch negative cases (p=0.008). Median progression-free survival (PFS) was 2.8 months for Notch positive cases compared with 13.07 months for Notch negative cases (p=0.045). Membranous and/or cytoplasmic DLL4 immunoreactivity of tumour vessels was observed in 30/56 (54%) evaluable colon cancers. No correlation was found between DLL4 expression and clinical outcome. Conclusion: Clinical trials investigating the therapeutic efficacy of bevacizumab in colon cancer did not explore the impact of DLL4-Notch pathway on response and clinical outcome. Our results seem to suggest that high Notch expression might be involved in tumour resistance in colon cancer patients treated with bevacizumab. Citation Format: Francesca Negri, Cecilia Bozzetti, Pellegrino Crafa, Costanza Lagrasta, Stefano Cavalli, Giuseppe Pedrazzi, Giorgio Gardini, Ione Tamagnini, Rosa Porzio, Luigi Cavanna, Carlo Paties, Ida Romano, Antonino Musolino, Gianluca Tomasello, Pier Giorgio Petronini, Andrea Ardizzoni. Notch and DLL4 expression in bevacizumab-treated colon cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4646. doi:10.1158/1538-7445.AM2013-4646 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
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