ABSTRACT
The prevailing new strategy for rationally targeted cancer treatment is aimed at the development of target-selective “smart” drugs on the basis of characterized mechanisms of action. The connection between Notch signaling, carcinogenesis and angiogenesis, as well as its crosstalk with many oncogenic signaling pathways suggest that Notch signaling may be such a candidate for multi-target drugs. The major therapeutic targets in the Notch pathway are the Notch receptors, in which GSIs prevent the generation of the oncogenic NICD and suppress the Notch activity (Shih Ie and Wang 2007; Imbimbo 2008). Gamma-secretase is a large membrane-integral multisubunit protease complex, which is essential for Notch receptor activation (Bergmans and De Strooper 2010). Rasul et al (Rasul et al. 2009) tested the effects of three different GSIs in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines, but had a minimal effect on the non-malignant breast lines. GSI1 treatment resulted in a marked decrease in g-secretase activity and down-regulation of the Notch signaling pathway with no effects on expression of the g-secretase components or ligands. In a recent
report (Efferson et al. 2010), the authors observed that inhibition of the Notch pathway with a GSI decreased both the Notch and mTOR/Akt pathways. Antitumor activity resulting from GSI treatment was associated with decreased cell proliferation as measured by Ki67 and decreased expression of glucose transporter Glut1 (Efferson et al. 2010). GSI effects are much higher in HER2/neu-positive cell lines where HER2 is amplified and/or over-expressed (ZR-75-1 and MDA-MB-453) compared with HER2negative cells (MCF-7 and MDA-MB-231) that lack ERbB2 amplification and show low HER2 expression (Lee et al. 2008; Rizzo et al. 2008b; Rasul et al. 2009). Since HER2 can influence the activity of Notch (Chen et al. 1997) and inhibition of HER2 via trastuzumab can activate Notch signaling (Osipo et al. 2008), it will be important to consider GSI as a monotherapy or in combination with trastuzumab or lapatinib in HER2 breast cancer patients. Although several GSIs have been developed into clinical trials (Shih Ie and Wang 2007), GSIs fail to distinguish individual Notch receptors. In addition, GSIs inhibit other signaling pathways (Beel and Sanders 2008) and cause intestinal toxicity (van Es et al. 2005), probably attributable to dual inhibition of Notch1 and Notch2 (Riccio et al. 2008). Very recently, Wu et al (Wu et al. 2010) utilized phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Their results showed that inhibition of either receptor alone reduces or avoids toxicity, demonstrating a clear advantage over pan-Notch inhibitors.
