Exploring DNA damage response pathways as targets for cancer therapy

Project Summary: It is well established that defects in DNA damage response (DDR) pathways accelerate tumorigenesis. Significant efforts have been devoted to target defective DDR pathways to improve outcome for cancer patients. These efforts led to the FDA’s approval of PARP inhibitors for the treatment of cancers carrying BRCA1/2 mutations and also the approval of immunotherapy for cancers with mismatch repair deficiency. Moreover, many inhibitors targeting DNA repair and/or cell cycle checkpoints have also entered clinical trials. Thus, there is an urgent need to understand how to effectively use these existing and new therapies for cancer treatment. We now know that targeting DDR pathways and/or DDR defects not only affect intrinsic tumor proliferation, but also change tumor-microenvironment interactions. Thus, we are expanding our DDR studies from in vitro to in vivo settings. In this project, we will determine mechanistically how several essential DDR genes/proteins control cell proliferation and DNA damage repair. We plan to establish separation of function mutations to further elucidate the key roles of these DDR genes and pathways both in vitro and in vivo. Additionally, we will investigate DDR defects in cancer therapy in vivo. Our recent success with in vivo CRISPR screens provides us an opportunity to explore avenues to target DDR pathways and DDR defects for cancer treatment in vivo. We anticipate that knowledge gained from these studies will help us design better treatment strategies for cancer patients.