In this proposal, we use genetic and proteomic approaches to address the fundamental mechanism of how the membrane-bound KRAS regulates the deubiquitylating enzyme USP7 promoting DNA repair. In Aim 1, we will utilize genetically engineered cell lines to study the KRAS-USP7 axis associated with therapy resistance. We will determine the downstream effectors of the KRAS pathway that regulate USP7 transcription and specifically test whether this network controls a known USP7 transcription factor (FOXO6). Aim 2 will investigate the effects of targeting USP7 in combination with radiation therapy to induce synthetic lethality in KRAS mutant PDAC. We will utilize an innovative in vivo MRI-guided 3D-conformal radiotherapy regimen to simulate the clinical applicability of RT for increased selective tumor sensitization. We will also test for GI toxicity with this combination to ensure the safety of this approach. These studies will provide mechanistic insight into how KRAS and USP7 coordinate DNA repair and provide translational targets to combine with current genotoxic strategies. The execution of this award will propel my independent physician-scientist career, strengthening my credentials in translational sciences and propelling the practice of targeted therapies for the effective treatment of resistant pancreatic cancer.

1. ASTRO-CSDG-23-1037280-01-CDP

2023-07-01

2027-06-30