NHE7 as a Novel Drug Target in Pancreatic Cancer
Abstract
Pancreatic cancer is poised to be the second leading cause of cancer death in the U.S. by 2020, and with a 5-year relative survival rate of just 7%, this disease has the highest death rate among the most commonly diagnosed cancers. These staggering statistics underscore the need for new therapeutic strategies that offer significant improvement in clinical outcome. By specifically designing scientific studies geared towards identifying drug targets that cause or sustain pancreatic cancer, we can move closer to devising new treatment modalities for this horrible disease. In general, cancer arises due to mutations in specific genes that lead to uncontrolled cell growth. Mutations in a gene known as KRAS are thought to initiate pancreatic cancer and have been found in nearly all documented cases of this disease. One of the outcomes of a KRAS mutation is that cells begin to internalize large volumes of their surrounding fluid, a process called macropinocytosis, and we have recently reported that tumors use this process to capture and ingest circulating proteins, which are then degraded to provide the much-needed nutrients that the tumors use to fuel their growth. We have found that blocking this nutrient uptake pathway results in a reduction in tumor growth; therefore, finding new ways to modulate this pathway represents a novel approach to the treatment of pancreatic cancer. We have discovered that a new player in this process is a gene called NHE7. NHE7 controls macropinocytosis and tumor nutrition through its activity as a pH regulator. Without pH regulation, tumor cells lose their ability to balance their acidity and undergo programmed cell death as a result. We have found that depleting NHE7 from pancreatic cancer cells leads to a reduction in tumor cell growth. Moreover, using "big data" approaches, we have found that not only is NHE7 expressed much higher in pancreatic tumors relative to normal pancreas, but also patients with the highest levels of NHE7 have a dramatically reduced lifespan and worse prognoses. Together, these data mean that drug inhibitors specific to NHE7 could be utilized as a treatment paradigm and that NHE7 might be a prognostic indicator for pancreatic cancer. In this proposal, we aim to establish that NHE7 depletion from pancreatic cancer tumors leads to a reduction in tumor growth, and we will explore the development of an NHE7 inhibitor that could be employed clinically. As an expert in the field of pancreatic cancer, Dr. Commisso s research has direct relevance to the Pancreatic Cancer topic area. Dr. Commisso is 100% committed to a career in pancreatic cancer and his goal is to become a researcher at the forefront of innovation in this field. This Career Development Award will allow Dr. Commisso the opportunity to advance his career in cancer research by aiding him to achieve his scientific goals, which are centered on conducting cutting-edge, impactful scientific research that will lead to new ways of tackling pancreatic cancer. The activities set out in his career development plan have been strategically selected in order to meet these goals, while fostering and supporting a high level of productivity. The applicability of the proposed research will be in the near-term development of novel therapeutic drugs for cancer, especially pancreatic cancer. In addition to pancreatic tumors, macropinocytosis is also prevalent in lung, colon, bladder, and breast tumors; therefore, our work could be of benefit to many different cancer patients. My laboratory s expertise is in the understanding of how tumors scavenge circulating protein and turn it into metabolic fuel to grow, and our primary efforts are to pinpoint specific drug targets within the macropinocytosis pathway that could be inhibited in order to starve tumors of these nutrients. By developing drugs that target pH regulation, we should be able to block the tumor s ability to obtain nutrients from an otherwise harmless protei
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710316
Entities
People
- Cosimo Commisso
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army