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DIRECT Report Summary

Project ID: 617060
Funded under: FP7-IDEAS-ERC
Country: Netherlands

Mid-Term Report Summary - DIRECT (Disabling Radiotherapy resistance in Cancer Treatment)

Owing to an imbalance in oxygen and nutrient supply and demand most human tumors contain areas of low oxygen (Hypoxia). Oncogene activation and oxygen fluctuations cause the activation Hypoxia Inducible transcription Factors (HIF1,2,3) which is associated with aggressive tumor growth and treatment resistance. Therefore tumor hypoxia/HIF proteins maybe a tumor-selective therapeutic target. To study the role of HIF proteins during tumor growth and treatment response we generated tumor cell types lacking HIF1, HIF2 or both proteins. We studied the behavior of these cells under low nutrient and oxygen conditions and found distinct roles for HIF family proteins under stress conditions and changes in their catabolic and anabolic metabolism. To identify hypoxic tumor cells in vivo we generated a hypoxia inducible fluorescent reporter that irreversible marks hypoxic tumor cells. In vivo models are underway. The NOTCH stem cell pathway is frequently implicated in human tumors and NOTCH signaling is important in the survival of hypoxic tumor cells. We have developed novel chemistry to target NOTCH inhibitors specifically to hypoxic tumors and obtained 1 candidate compound that is highly potent and hypoxia selective. Further studies are needed to ensure that these drugs are active in tumors but not in normal tissues.

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