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Nucleoside analogs in combination with Nodal, SHH or mTOR inhibitors for eliminating epithelial cancer stem cells (CSC)

Epithelial cancers are among the most

frequent causes of death. Especially pancreatic carcinomas are characterized by early metastatic spread and a pronounced resistance to chemotherapy and radiation. Despite extensive

research activities in the field of tumor biology, there has hardly been any substantial progress within the past decades regarding therapeutic success. The introduction of the chemotherapeutic agent gemcitabine improved clinical response by reducing pain and loss of weight. As the median 5-year survival rate (1-4%) and the median survival time (5 months) are very low, the prognosis of patients with pancreatic cancer has remained poor. During the last years, it has been shown that stem cells play a decisive role in the development and progression of cancer and that distinct populations of cells with stem cell properties may be essential for the development and perpetuation of various human cancers, including pancreatic cancer, colon cancer, lung cancer, breast cancer and brain tumor. Unfortunately, conventional therapy using chemotherapy or radiation seems to have little to no effect on cancer stem cells (CSC). If a tumor is depleted of CSC, it will lose its exclusive source for growth promotion and metastasis and will eventually degrade due to the limited self-renewal capacity and life span of more differentiated tumor cells. The current inventions are based on combination therapies of nucleoside analogs with inhibitors of either the Nodal/Activin pathway or the mTOR / hedgehog pathway and show a remarkable capacity to eliminate cancer stem cells and to subsequently inhibit pancreatic cancer.

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