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

Aleksandra Filipović; Ylenia Lombardo; 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

doi:10.1007/s10549-014-3119-z

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

Aleksandra Filipović^*, Ylenia Lombardo, 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

21 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 language	English
Pages (from-to)	455-462
Number of pages	8
Journal	Breast Cancer Research and Treatment
Volume	148
Issue number	2
DOIs	https://doi.org/10.1007/s10549-014-3119-z
Publication status	Published - 7 Nov 2014

Keywords

Breast cancer
Monoclonal antibodies
Nicastrin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10549-014-3119-z

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Filipović, A., Lombardo, Y., Fronato, M., Abrahams, J., Aboagye, E., Nguyen, Q. D., d’Aqua, B. B., Ridley, A., Green, A., Rahka, E., Ellis, I., Recchi, C., Przulj, N., Sarajlić, A., Alattia, J. R., Fraering, P., Deonarain, M., & 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

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

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.",

keywords = "Breast cancer, Monoclonal antibodies, Nicastrin",

author = "Aleksandra Filipovi{\'c} and Ylenia Lombardo and Monica Fronato and Joel Abrahams and Eric Aboagye and Nguyen, {Quang De} and d{\textquoteright}Aqua, {Barbara Borda} and Anne Ridley and Andrew Green and Emad Rahka and Ian Ellis and Chiara Recchi and Natasa Przulj and Anida Sarajli{\'c} and Alattia, {Jean Rene} and Patrick Fraering and Mahendra Deonarain and Coombes, {R. Charles}",

year = "2014",

month = nov,

day = "7",

doi = "10.1007/s10549-014-3119-z",

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Filipović, A, Lombardo, Y, Fronato, M, Abrahams, J, Aboagye, E, Nguyen, QD, d’Aqua, BB, Ridley, A, Green, A, Rahka, E, Ellis, I, Recchi, C, Przulj, N, Sarajlić, A, Alattia, JR, Fraering, P, Deonarain, M & Coombes, RC 2014, 'Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells', Breast Cancer Research and Treatment, vol. 148, no. 2, pp. 455-462. https://doi.org/10.1007/s10549-014-3119-z

TY - JOUR

T1 - Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells

AU - Filipović, Aleksandra

AU - Lombardo, Ylenia

AU - Fronato, Monica

AU - Abrahams, Joel

AU - Aboagye, Eric

AU - Nguyen, Quang De

AU - d’Aqua, Barbara Borda

AU - Ridley, Anne

AU - Green, Andrew

AU - Rahka, Emad

AU - Ellis, Ian

AU - Recchi, Chiara

AU - Przulj, Natasa

AU - Sarajlić, Anida

AU - Alattia, Jean Rene

AU - Fraering, Patrick

AU - Deonarain, Mahendra

AU - Coombes, R. Charles

PY - 2014/11/7

Y1 - 2014/11/7

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Monoclonal antibodies

KW - Nicastrin

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U2 - 10.1007/s10549-014-3119-z

DO - 10.1007/s10549-014-3119-z

M3 - Article

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AN - SCOPUS:84911977124

SN - 0167-6806

VL - 148

SP - 455

EP - 462

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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