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Development of Notch Pathway Inhibitors for Cancer Therapy

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Breast Cancer Metastasis and Drug Resistance

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Abstract

Notch signaling is an evolutionarily conserved cell-signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. A series of pre-clinical studies using primarily small molecule inhibitors of γ-secretase have demonstrated anti-tumor effects. Phase I trials have identified a reasonable safety profile for these agents, especially with intermittent administration. Mechanism-based combinations specific for individual indications are being investigated. Several other classes of Notch inhibitors are being developed. In this review, we describe the basics of Notch signaling, the role of Notch in normal and cancer stem cells; finally we describe opportunity and challenges in the development of Notch inhibitors as novel targeted agents for cancer patients.

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Abbreviations

NIC :

Notch intracellular domain

NEC :

Notch extracellular domain

NTM :

Notch transmembrane domain

EGF:

Epidermal growth factor

NEDD4:

Neural precursor cell expressed developmentally down-regulated 4

HES1-5:

Hairy/enhancer of split family 1-5

GSK3b:

Glycogen synthase kinase 3 beta

T-ALL:

T cell acute lymphoblastic leukemia

GSI:

Gamma secretase inhibitors

DLL 1, 3, 4:

Delta-like 1, 3, 4

OFUT1:

O-Fucosyltransferase 1

MAML1:

Mastermind-like 1

PS1:

Presenilin 1

CSC:

Cancer stem cells

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Acknowledgments

This work was financially support by NCIAG. We thank Dr. Christian R. Gomez for his critical review and comments on the manuscript.

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  1. Cancer Institute, University of Mississippi, 2500 N. State Street, Guyton 2 Building Suite G751-5, Jackson, 39216, Mississippi, MS, USA

    Ingrid Espinoza & Lucio Miele

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  2. Lucio Miele
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Correspondence to Lucio Miele .

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  1. School of Medicine, Karmanos Cancer Institute, Wayne State University, John R Street 4100, Detroit, 48201, Michigan, USA

    Aamir Ahmad

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Espinoza, I., Miele, L. (2013). Development of Notch Pathway Inhibitors for Cancer Therapy. In: Ahmad, A. (eds) Breast Cancer Metastasis and Drug Resistance. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5647-6_17

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