Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells

Filipovi?, Aleksandra; Lombardo, Ylenia; Fronato, Monica; Abrahams, Joel; Aboagye, Eric; Nguyen, Quang-De; d�Aqua, Barbara Borda; Ridley, Anne; Green, Andrew; Rahka, Emad; Ellis, Ian; Recchi, Chiara; Przulj, Natasa; Sarajli?, Anida; Alattia, Jean-Rene; Fraering, Patrick; Deonarain, Mahendra; Coombes, R. Charles

Abstract

The goal of targeted cancer therapies is to specifically block oncogenic signalling, thus maximising efficacy, while reducing side-effects to patients. The gamma-secretase (GS) complex is an attractive therapeutic target in haematological malignancies and solid tumours with major pharmaceutical activity to identify optimal inhibitors. Within GS, nicastrin (NCSTN) offers an opportunity for therapeutic intervention using blocking monoclonal antibodies (mAbs). Here we explore the role of anti-nicastrin monoclonal antibodies, which we have developed as specific, multi-faceted inhibitors of proliferation and invasive traits of triple-negative breast cancer cells. We use 3D in vitro proliferation and invasion assays as well as an orthotopic and tail vail injection triple-negative breast cancer in vivo xenograft model systems. RNAScope assessed nicastrin in patient samples. Anti-NCSTN mAb clone-2H6 demonstrated a superior anti-tumour efficacy than clone-10C11 and the RO4929097 small molecule GS inhibitor, acting by inhibiting GS enzymatic activity and Notch signalling in vitro and in vivo. Confirming clinical relevance of nicastrin as a target, we report evidence of increased NCSTN mRNA levels by RNA in situ hybridization (RNAScope) in a large cohort of oestrogen receptor negative breast cancers, conferring independent prognostic significance for disease-free survival, in multivariate analysis. We demonstrate here that targeting NCSTN using specific mAbs may represent a novel mode of treatment for invasive triple-negative breast cancer, for which there are few targeted therapeutic options. Furthermore, we propose that measuring NCSTN in patient samples using RNAScope technology may serve as companion diagnostic for anti-NCSTN therapy in the clinic.

Citation

Filipović, A., Lombardo, Y., Fronato, M., Abrahams, J., Aboagye, E., Nguyen, Q., …Coombes, R. C. (2014). Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells. Breast Cancer Research and Treatment, 148(2), 455-462. https://doi.org/10.1007/s10549-014-3119-z

• Journal Article Type: Article
• Acceptance Date: Aug 27, 2014
• Online Publication Date: Sep 24, 2014
• Publication Date: Nov 30, 2014
• Deposit Date: Oct 17, 2018
• Publicly Available Date: Oct 17, 2018
• Journal: Breast Cancer Research and Treatment
• Print ISSN: 0167-6806
• Electronic ISSN: 1573-7217
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 148
• Issue: 2
• Pages: 455-462
• DOI: https://doi.org/10.1007/s10549-014-3119-z
• Keywords: Nicastrin; Breast cancer; Monoclonal antibodies
• Public URL: https://nottingham-repository.worktribe.com/output/1172178
• Publisher URL: https://link.springer.com/article/10.1007%2Fs10549-014-3119-z