Project 459021

Despite many advances in cancer treatment, it is challenging to selectively kill cancer without harming normal tissue. Cancer cells have high levels of DNA damage, relying on DNA repair to survive. This creates a therapeutic opportunity, as these cells become dependent on particular pathways, which can be selectively targeted. This works very well in theory, and in lab simulations, however few of these treatments ever reach the clinic. One reason for this may be that it is impossible to inhibit 100% of the DNA repair proteins in a patient. One notable exception is the success of PARP inhibitors, which were discovered to use a strategy called protein trapping. These drugs target the PARP repair protein as it binds to the site of a lesion, trapping it to the DNA. This not only prevents the damaged DNA from being repaired, but also blocks the activity of uninhibited PARP and alternative pathways that the tumor cell may use to repair the damage. Therefore, with only partial protein inhibition we can still kill cancer cells. My project aims to replicate this clinically proven strategy for the next generation of cancer targets. WRN is a DNA repair protein which is required for the survival of cancers with microsatellite instability. This is common in colorectal, gastric and endometrial cancers. To identify promising regions for protein trapping, I will create mutations in WRN to model the binding of an inhibitor to that site. I will create libraries of these mutations using the latest advances in CRISPR-Cas9 gene editing technology. Once I have identified and characterized promising sites, our collaborators will use computer algorithms to find inhibitors in compound libraries which I will test for WRN trapping. These molecules will serve as the foundation for new cancer treatments, improving quality of life for patients and families. By creating a pipeline to identify protein trapping molecules, we will help bridge the gap between theoretical and clinical realities.