Targeting Notch in oncology: the path forward

Abstract

Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.

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Fig. 1: Overview of Notch signalling, therapeutic targets and pharmacological agents.
Fig. 2: Intratumoural heterogeneity of Notch function.
Fig. 3: Notch roles in tumour angiogenesis.
Fig. 4: Ligand-independent Notch activation by the TCR and its modulation by adenosine in T cells.
Fig. 5: Notch-mediated crosstalk between BLBCCs and TAMs.

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Acknowledgements

The authors wish to acknowledge the support of the U.S. National Cancer Institute (grant CA-P01-166009) and the Cancer Crusaders Foundation (L.M.).

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Glossary

Epithelial–mesenchymal

(EMT). A phenotypic switch, which can be reversible, whereby epithelial cancer cells acquire mesenchymal characteristics, including motility, and potentially stem-like characteristics.

Cancer stem cells

(CSCs). Generally small populations of cells in malignancies that have stem-like characteristics: expression of embryonic or tissue stem cell markers, ability to divide symmetrically or asymmetrically, and resistance to chemotherapy and radiation.

Adenosine

A nucleoside resulting from the enzymatic hydrolysis of extracellular ATP by nucleoside triphosphate diphosphohydrolase 1 (also known as CD39), nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and ecto-5′ nucleotidase (also known as CD73).

Myeloid-derived suppressor cells

(MDSCs). These include two main subtypes of immature myeloid cells (polymorphonuclear MDSCs and monocytic MDSCs), which are released from the bone marrow and migrate to the tumour microenvironment, where they suppress tumour immunity through a variety of mechanisms.

Chimeric antigen receptor

(CAR). A recombinant transmembrane receptor designed to bind specific antigens and activate transduced patient T cells.

BiTE

(Bispecific T cell engager). A recombinant bispecific antibody that uses one antigen-binding site to engage a tumour-selective antigen and an anti-CD3 antigen-binding site to non-specifically activate the T cell receptor of tumour-infiltrating lymphocytes.

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Majumder, S., Crabtree, J.S., Golde, T.E. et al. Targeting Notch in oncology: the path forward. Nat Rev Drug Discov 20, 125–144 (2021). https://doi.org/10.1038/s41573-020-00091-3

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