Targeting Nuclear Importins in PDAC
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide with a 5-year survival rate of 9%. By 2030, PDAC is projected to become the second leading cause of cancer-related death in the United States. Unfortunately, there is currently no effective treatment for pancreatic cancer. Surgery, radiation therapy, and chemotherapy only mildly extend survival and/or relieve symptoms, but seldom cure. Therefore, there is an urgent need to identify targets and develop new therapeutic strategies against pancreatic cancer. The objective of this proposal is to validate the protein transportation (importin) complex as a therapeutic target in PDAC. We propose the following aims to test our hypothesis. Aim 1: Validation of importins as druggable targets in pancreatic cancer using preclinical mouse models. Aim 2: Establish the role of importins and genetic interactions with YAP (a tumor promoting protein) in pancreatic cancer using genetically engineered mouse models. Aim 3: Elucidate how importins are regulated and underlying mechanisms through which importins contribute to promoting cancer development. Our study is addressing the following research focuses: Understanding precursors, origins, and early progression of pancreatic cancer; new drug development targeted toward cancer sensitivity and resistance mechanisms. Very little is known regarding the biological significance of importins in PDAC. We identified the importins critical role in PDAC cells and preclinical models. The importin inhibitor Ivermectin has long been approved for the treatment of parasitic infections. Our studies strongly support the repositionable use of Ivermectin in PDAC patients. The research is innovative because it seeks, for the first time, to connect importins with PDAC tumorigenesis and potential therapeutic strategy. Outcomes from our proposed research are expected to have an important positive impact because these studies have the strong potential to identify importins as a prognostic marker and therapeutic target for pancreatic cancer. Successful completion of proposed experiments is expected to provide preclinical evidence for evaluation of Ivermectin (approved by the U.S. Food and Drug Administration) in PDAC patients and to initiate a Phase I clinical trial at our cancer center.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210587
Entities
People
- Jixin Dong
Organizations
- United States Army
- University of Nebraska Medical Center