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Targeting pH Homeostasis as a Therapeutic Approach for Pancreatic Cancer

Institution: Sanford Burnham Prebys Medical Discovery Institute
Investigator(s): Koen Galenkamp,
Award Cycle: 2019 (Cycle 30) Grant #: T30FT0952 Award: $195,450
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Tobacco use accounts for 20% of the cases of pancreatic cancer, which only has an 8% five-year survival rate and is rapidly becoming the second-leading cause of cancer-related deaths in the US. This extremely poor prognosis underscores the need to develop novel treatment strategies that improve the survival of pancreatic cancer patients, since treating pancreatic cancer with current therapeutic approaches has proven difficult and ineffective. Tumor cells grow faster than normal cells and increase their nutrient consumption to sustain this abnormality. This hypermetabolic state causes the production of acids that need to be transported out of the cancer cells in order to maintain a balanced pH, a process called pH homeostasis. Tobacco is thought to increase the production of acids, making this pH balance particularly important in tobacco-related cancers. Since avoiding accumulation of acids within the cell is crucial for cancer cell survival, impeding the transport of acid out of the cell could prove an effective therapeutic approach. By mining pancreatic cancer patient datasets, I identified a pH-regulating protein that is increased in pancreatic cancer patients and correlates with reduced patient survival. My preliminary experiments show that pancreatic cancer cells require this protein to maintain pH balance and reducing the activity of this protein efficiently kills cancer cells, resulting in a complete loss of tumor formation in mice. Interestingly, removal of this protein from normal cells has no effect, suggesting that this protein’s function might be tumor-specific, making it an excellent candidate as a therapeutic target. In the proposed study, I will define the mechanisms through which this protein regulates tumor pH and the effects of tobacco on this balance, thereby advancing the knowledge in the field of tumor pH homeostasis. By using animal models that mimic human pancreatic cancer, I propose to test whether removing this pH regulator causes tumors to shrink. Altogether, I aim to increase our understanding of its role in pancreatic cancer and validate the possibility that it can be targeted to develop a novel therapeutic modality. This work could pave the way for near-future drug development studies aimed towards improving clinical outcomes for tobacco-related cancer patients.