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Notch targeting in cancer

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Notch signalling through its four receptors (Notch1-4) is being extensively studied in the context of its relevance as an evolutionarily conserved pathway involved in cell fate control during pre natal and post natal development, as well as in carcinogenesis. Accumulated evidence suggests that Notch ...

Notch signalling through its four receptors (Notch1-4) is being extensively studied in the context of its relevance as an evolutionarily conserved pathway involved in cell fate control during pre natal and post natal development, as well as in carcinogenesis. Accumulated evidence suggests that Notch inhibition is an attractive strategy for the treatment of haematological malignancies and solid tumours due to the fact that Notch is a key regulator of multiple cancer hallmarks, including cancer stem cell propagation and behaviour, epithelial-to-mesenchymal transition, tumour-stromal cross-talk, tumor angiogenesis and adaptive immune response.

Notch1 activating mutations drive > 50% of T-cell acute lymphoblastic leukemias, and overexpression of Notch receptors in breast, colon, lung, ovarian, prostate, pancreatic cancers correlates with increased risk of metastatic relapse and adverse prognosis. In a subset of breast cancer patients, Notch activating fusion gene (Notch-MAST) confers oncogenic addiction for cell survival.

Furthermore, Notch receptors and ligands, in particular Jagged-1 and Dll-4, are widely expressed in endothelial and perivascular cells. Notch signaling is therefore critical for arterial specification, sprouting angiogenesis, and vessel maturation, and blocking Notch function in tumor vasculature provides a means to suppress tumor growth.
Recent evidence also indicates that angiogenesis regulatory pathways and developmental pathways that control cancer stem cell fate are intimately connected, and that endothelial cells are a key component of the cancer stem cell niche. Understanding how Notch interacts with other factors that control endothelial cell functions and angiogenesis in cancers will pave the way to innovative therapeutic strategies that simultaneously target angiogenesis and cancer stem cells.

In addition to playing a role in cognate cancer cells, Notch mediates changes in the tumor stroma, which affect cancer cell dormancy as well as field cancerization, a condition of major clinical significance linked with multifocal and recurrent tumors.

To achieve these pleiotropic effects, Notch signalling is involved in bidirectional 'cross talk' interactions with multiple other pathways that include candidate therapeutic targets (PI3K/Akt, mTOR, estrogen receptor, HER2, EGFR, VEGFR etc). These interactions are being extensively studied in order to facilitate our ability to design rational combination therapeutic regimens.

Based on the molecular structure of Notch receptors, Notch ligands and Notch activators, a set of Notch pathway inhibitors have now been developed. These include: small molecule gamma-secretase inhibitors, gamma secretase modulators, Notch targeting antibodies, Notch decoys, as well as monoclonal antibodies and probody variants thereof, against Notch ligands. Most of these inhibitors have shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical and biological targeted agents is still under study in different clinical trials. To determine which patients are most likely to benefit from treatment with Notch inhibitors, it will be necessary to develop molecular tests to accurately measure pathway activity in specific tumors. Finally, mechanism-based toxicities are being addressed in preclinical and clinical research.

All these aspects of Notch signalling and targeting will be comprehensively addressed by proposed authors, who are esteemed experts in the field of Notch signalling with extensive experience in basic, translational and clinical research.


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