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

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

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)455-62
Number of pages8
JournalBreast Cancer Research and Treatment
Volume148
Issue number2
DOIs
Publication statusPublished - Nov 2014

Keywords

  • Amyloid Precursor Protein Secretases
  • Animals
  • Antibodies, Monoclonal
  • Apoptosis
  • Blotting, Western
  • Cell Movement
  • Cell Proliferation
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Triple Negative Breast Neoplasms
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Journal Article
  • Research Support, Non-U.S. Gov't

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