Targeting a Novel Pocket on ITGAV
NIH
UNIVERSITY OF CALIFORNIA, SAN DIEGO
Project Summary. Cancer deaths remain at an all-time high in the United States leaving an urgent clinical need to develop novel therapeutic strategies to help patients. The lack of effective treatments is in part due to underlying complexities in cancer that current scientific approaches are just beginning to uncover. Technological advances are rapidly changing the landscape of scientific discovery; for example, the combination of mathematical modeling in tandem with laboratory based validation leading to better combinational therapies to treat cancer. For this reason, I propose training in both with the F99/K00 Predoctoral to Postdoctoral Fellow Transition Award. For the F99 phase, the dissertation research, I will focus on laboratory based research skills to identify and propose a novel therapeutic to treat cancers. In a high level CRISPR screen targeting about 580 genes on the cell surface we found that Integrin Alpha V (ITGAV) is essential for the survival of solid tumors (colon, pancreatic, and breast cancer). To validate ITGAV as the most essential integrin we designed a second layer screen targeting all 26 integrins and found that ITGAV and Integrin Beta 5 (ITGB5) are the only essential integrins in solid tumors. Interestingly, integrins must for an obligate heterodimer between an alpha and a beta subunit of which ITGAV and ITGB5 are one of the known 24. As the more essential pair, ITGAV was probed with a high-density CRISPR tiling scan and we found a small pocket to be essential for ITGAV function and it was amendable to small molecule binding. A structure based analysis found a loop structure of the beta pair of ITGAV interacts with the discovered pocket, leading to our hypothesis that the pocket is essential for the heterodimer stability between ITGAV and its beta pair. Indeed, from a high-throughput screen of 500 small molecules we found one compound that appears to bind in our pocket and disrupt the heterodimer between ITGAV and ITGB5. Further validation of this potential will be the remaining work to be done for the dissertation research and upon completion, will fill an unmet clinical need since no there no FDA approved drugs targeting integrins approved for cancer indications. To further advance the potential to treat cancer I plan to use mathematical modeling approaches to identify novel therapeutic strategies by understanding the complexities of cancer signaling during the K00 phase, the proposed postdoctoral work. To study complex cancer signaling, in collaboration with Dr. Pirrotte, we generated kinase activity scores in cells where ITGAV was knocked out. With this data we can model the effects of signaling as it relates to measurable changes in the cancer cells. Specifically, we will study cell cycle control, which is inhibited with ITGAV loss. Additionally, we can model known inhibitors to common signaling cascades as novel combinational therapeutic strategies. To confirm our model, I will use laboratory based skill developed during the F99 phase. Overall with the training with the F99/K00 award I will gain skills to be able to build mathematical models to study cancer and validate those models with laboratory based skills. This will allow me to become and independent research and leading scientist in translational research. Project Narrative The proposed research aims to fill an unmet clinical need in treating aggressive cancers such as colon, pancreatic, and breast. We found that Integrin Alpha V (ITGAV) is necessary for the survival of these cancers and that a novel pocket on its structure can be targeted with a drug. Additionally, we will investigate the complex signaling controlled by ITGAV to propose combinational therapies and create new therapeutic strategies to treat these cancers.
Other Research-Related