Transforming the future of cancer treatment Oncology ... - Roche

Notch signaling
pRED
Gamma secretase is a key enzyme in the intramembrane proteolytic processing of several signaling
receptors, including Notch, a cell surface receptor critical in cell fate signaling. 1 The gamma secretase
processing of Notch produces its active form, called intracellular Notch (ICN). 1,2 This protein translocates
to the nucleus and forms part of a large transcription complex that directly alters the expression of key
proliferation- and differentiation-specific genes. 1 Notch’s role in cell fate determination points to
3 potential drivers of efficacies: (1) promotion of cell differentiation, (2) reduction of the cancer stem cell
tumor subpopulation, (3) inhibition of angiogenesis by targeting Notch signaling in tumor endothelial cells. 1
Gamma secretase inhibitor (RG4733)
The gamma secretase inhibitor RG4733 is a potent and selective inhibitor of gamma secretase, inhibiting
Notch signaling in tumor cells. 1 Blocking of Notch signaling produces a slower-growing, less-transformed
phenotype in preclinical cancer models, resulting in significant inhibition of tumor growth in vivo. 1,2
References
ADCs
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Angiogenic signaling
1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
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Apoptosis
1. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2:420-430.
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
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B-cell surface proteins
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2. Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol. 2000;27(6 suppl 12):17-24.
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