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Country of origin: Italy

Summary

An Italian University research laboratory has developed an invention, in which the expression of Notch receptors in human tissue samples of Hepatocellular Carcinoma (HCC) and adjacent HCC-free tissue has been explored. This invention can be very useful in the treatment of HCC, which ranks fifth in frequency worldwide among all human cancer and causes 1 million deaths annually. They are looking for license agreement and industrial development.

Full description

Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide among all human cancer and causes 1 million deaths annually. Despite many promising treatment options, which include surgical resection, alcohol or radiofrequency ablation, chemoembolization, and liver transplantation, long-term prognosis remains poor in patients with advanced disease.

At present, embolization is the most widely used primary treatment for non resectable HCC and has been the most-used therapy for patients awaiting liver donation for the prevention of HCC progression that might preclude transplantation. Embolization agents are usually administered together with selective intra-arterial cytotoxic agents, among them doxorubicin is most frequently used. Although this regimen significantly delays tumour progression and vascular invasion, this approach only achieves a partial response in patients.

Despite the recent development of new treatment modalities, the need to discover therapeutic molecules to overcome resistance to chemotherapeutic agents of HCC is still urgent. Notch receptors are implicated in proliferation, differentiation and apoptosis. Because of increasing evidence that the Notch signalling pathway is abnormally deregulated in human cancer, Notch receptors are potential targets for selective killing malignant cells.

In the present invention, the expression of Notch receptors in human tissue samples of HCC and adjacent HCC-free tissue has been explored and the physiological effects of ablating Notch3 expression by shRNA in HepG2 cells have been assessed. It has been found that Notch3 is selectively expressed in HCC but not in surrounding HCC-free tissue. Consistent with a previous study on HCC cell lines that showed that Notch1 over expression inhibits cellular growth through p21 up regulation, the authors of the present invention found that loss of Notch1 expression by targeted shRNA knockdown greatly reduced p21 protein expression by immunoblot analysis. However, contrary to what would be expected based on prior art and other results obtained for the Notch1 receptor in HCC, it was surprisingly found that inhibition of Notch3 activity by targeted shRNA or by anti-Notch3 antibodies, did not alter HepG2 growth rates. In this context, cell growth parameters were assessed one week post-infection by propidium iodide staining in conjunction with flow cytometry. The results obtained showed that Notch3 knock-down in HepG2 cells caused the accumulation of phosphorylated p53 and repression of p21 with no apparent effect on cellular growth or viability. Thus contrary to Notch1, Notch3 does not appear to contribute to the proliferation of human HCC, at least in this in vitro context. Remarkably, the mortality of HepG2 cells stably expressing Notch3 shRNAs (in comparison to a luciferase shRNA negative control) doubled and tripled in response to doxorubicin (or other molecules used for cancer therapy) treatments of 6 and 24 hours respectively, as revealed by trypan blue dye exclusion. On the other hand, Notch1 ablation had no demonstrable effect on their drug induced apoptosis. Notch3 expression, hence, functions at least in part as a specific positive effector of multi-drug resistance by preventing the activation of p53-dependent apoptosis and, as a consequence, engenders HCC with resistance to chemotherapeutics or other environmental stresses.

Innovative Aspects

Specific positive effector of multi-drug resistance by preventing the activation of p53- dependent apoptosis;
Engenders HCC with resistance to chemotherapeutics or other environmental stresses.

Partner expertise sought:

- Type of partner sought:Industry

- Specific area of activity of the partner:Health, Pharmaceutical

- Task to be performed by the partner sought:Industrial

Listed under: Medicine/healthcare/veterinary \ Biotech, Pharma and Cosmetics

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Key dates Profile created on: 01 February 2010 Closing date: 07 January 2011

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