Targeting Organelle pH Homeostasis in Pancreatic Cancer
Abstract
Fiscal Year 2022 Pancreatic Cancer Research Program (FY22 PCARP) Focus Areas to be Addressed in the Proposed Research: (i) Our work will impact the understanding of the relationship between oncogenic signaling and the tumor microenvironment that drives therapeutic response, and (ii) our work will impact new drug development targeted toward cancer sensitivity and resistance mechanisms. Innovative Aspects of the Proposed Research Project: Pancreatic cancer cells are exquisitely sensitive to changes in their internal pH. If a cancer cell becomes too acidic or too basic, this disrupts almost every molecular pathway involved in tumor growth, leading to cancer cell death. We recently discovered that pancreatic cancer cells regulate their internal pH through a protein called NHE7. This protein acts to maintain pH balance and, importantly, it only functions in cancer cells and not in normal cells. This specificity to tumors means that NHE7 represents a protein that we can try to stop in cancer cells while leaving the normal cells of the body unharmed. To find new drugs that might block pH balance in pancreatic cancer, we used a drug discovery approach. We took advantage of the state-of-the-art molecular testing capabilities that we have in-house and checked thousands of drugs for an effect on the pH of the pancreatic cancer cells. We identified a drug called IMD-0354, which blocks a molecular switch that is critical to pancreatic cancer progression. We show in this application that IMD-0354 disrupts pH balance in pancreatic tumor cells and causes cell death specifically in the cancer cells, leaving normal cells unaffected. We are excited about this new discovery because it means that we might be able to develop IMD-0354 or a similar drug as a therapeutic approach for pancreatic cancer. Impact of the Proposed Research Project on the Field of Pancreatic Cancer Research: We have two specific goals for this application that will impact the field of pancreatic cancer research. The first goal is to understand how IMD-0354 disrupts pH balance in pancreatic cancer cells. To fully examine whether IMD-0354 can be used as a therapy in pancreatic cancer, we need to have a better understanding of how it works from a molecular perspective. To do this, we will use genetic approaches in cells from pancreatic cancer patients and test how IMD-0354 leads to an acidic internal cellular pH that specifically kills the cancer cells. Our second goal is to find out whether IMD-0354 can stop tumor growth in an animal model of pancreatic cancer. To test this, we will surgically transfer cancer cells directly into the pancreases of mice and then treat the animals with IMD-0354. We will measure tumor growth, as well as the lifespan of the mice. Using these animal models, we will also test whether IMD-0354 treatment can improve chemotherapy or immunotherapy. Impact of the Proposed Research Project on Pancreatic Cancer Patients: While IMD-0354 and similar drugs have been studied in sicknesses like non-alcoholic fatty liver disease, they have never been tested in pancreatic cancer. Our findings show for the first time that IMD-0354 can kill pancreatic cancer cells, leaving normal cells healthy. We are very encouraged by these results and plan to find out whether IMD-0354 can be used to control the growth of pancreatic tumors. If successful, our work could set the stage for the clinical usage of IMD-0354 or similar drugs in pancreatic cancer. This has the potential to have immediate impact for patients since IMD-0354 and related molecules have been used in the clinical setting for other diseases, such as eye degeneration. This means that it would be relatively straightforward to test whether repurposing these drugs for pancreatic cancer has any benefit to clinical outcomes for patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310795
Entities
People
- Cosimo Commisso
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army