Final Report Summary - DIRECT (Disabling Radiotherapy resistance in Cancer Treatment)
It is well recognized that biological heterogeneity within tumors is a key driver of cancer progression and a cause of treatment failure in patients. Tumor heterogeneity is caused by stochastic mutations in tumor subpopulations as well as the response to changes in the tumor microenvironment including limitations in nutrients and oxygen (hypoxia) availability. Tumor Hypoxia is strongly associated with poor outcome and response to treatment in patients and a high priority clinical target. The clinical value of drugs targeting hypoxia, however, has been limited so far. Mounting evidence shows that that cancer stem cells are part of the hypoxic tumor niche to promote tumor resistance and that NOTCH signaling -a stem cell pathway- is of key importance. Drugs targeting the NOTCH pathway are in clinical trials but their application thus far has been limited due to the adverse dose-limiting side-effects in normal tissues. Limiting the activity of highly potent NOTCH drugs to hypoxic tumor areas would overcome such limitations and provide a higher chance of treatment success. To achieve this new mechanistic insight and methodologies are required for the identification and of therapy-resistant populations and their elimination to prevent tumor recurrence. In this project, we have therefore developed genetically encoded sensors that enable labeling and tracing of hypoxic cells in tumors at the single cell level using intravital imaging. The outcome of these studies will be to identify a window of opportunity to best combine hypoxia targeting drugs with other treatments to improve survival and quality of living. We have also functionalized clinically approved-but failed- g-secretase inhibitors with hypoxia-activated triggers to limit their activity under normal physiological oxygen conditions. We created two lead compounds which only inhibit Notch activity under hypoxia. These compounds will now be tested for their ability to block Notch signaling in tumors. If successful such stem cell functional drugs could be used at high and sustained doses because normal tissue effects are attenuated.