Leveraging the Tumor Microenvironment in Primary and Metastatic Pancreatic Cancer
Abstract
This application addresses the FY22 Pancreatic Cancer Research Program (PCARP) Focus Area Understanding the relationship between oncogenic signaling and the tumor microenvironment that drives drug resistance and therapeutic response. Close to 50,000 people die each year from pancreatic ductal adenocarcinoma (PDAC) in the United States, making it the third most lethal cancer in the country. When PDAC cells spread to other parts of the body (known as metastatic PDAC, ~90% are found in the liver), existing chemotherapies do not work and 97% of patients die within 5 years after diagnosis. The overall goal of this project is to develop new therapies for treating patients with metastatic PDAC. PDAC has limited access to nutrients and oxygen due to dense and fibrotic tissues surrounding the tumor. As a result, PDAC cells alter their metabolism to adapt and survive under a harsh environment. The Initiating PI Winter recently discovered that blocking a key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) with an inhibitor can block metabolic adaptation. Treating PDAC with the inhibitor dramatically decreased cancer cell growth, and PDAC tumors shrunk in mice. As a result, mice with PDAC survived much longer than those that did not receive the inhibitor. Prior clinical studies reveal that metastatic PDAC in the liver prefers another type of metabolism and may be less susceptible to blocking this enzyme, requiring a different treatment approach. Thus, it is important to fully understand how PDAC cells behave both within the pancreas and at metastatic sites. The liver has a unique environment composed of many endothelial cells (ECs), which normally build blood vessels. The Young Investigator Partnering PI Wang found that liver ECs secret factors that communicate with cancer cells in the liver and accelerate cancer growth. These factors also alter cancer metabolism. Liver ECs do so by activating a surface protein HER3 (human epidermal growth factor receptor 3, also known as ErbB3) in PDAC cells, which in turn activates another molecule (AKT) to reprogram PDAC metabolism. Blocking HER3 decreased PDAC cell growth, and switched cancer metabolism back to a primary tumor-like biology that is maximally susceptible to an IDH1 inhibitor. Our proposed studies will help us to understand how liver ECs help PDAC cells to grow and change cancer metabolism, especially in metastatic sites of spread. Moreover, we will leverage these insights to combine two strategies that should cooperate to effectively treat both primary and metastatic PDAC. We will employ state-of-the-art techniques to determine the effects of liver ECs and HER3/IDH1 inhibition on PDAC cell metabolism and survival, and will identify the pathways that drive those effects. We will also determine if combining an anti-HER3 therapy (seribantumab) and an anti-IDH1 (ivosidenib) agent will lead to stronger anti-cancer effects in cell culture conditions. Additionally, we will employ a mouse model that closely replicates PDAC spread in human, to study the effect of anti-HER3 therapy (seribantumab) and anti-IDH1 therapy (ivosidenib), alone or in combination, on both primary and metastatic disease. Impact: Findings from this project will help us to better understand the differences in metabolism between primary and metastatic PDAC, and the key factors regulating these activities. This project will also help us to understand how the liver microenvironment affects the metabolism of metastatic deposits. These pathways can be targeted with drugs that block IDH1 (ivosidenib) and HER3 (seribantumab), and both are safe in patients. Therefore, if successful, this work can be rapidly translated into clinical trials to test a completely new strategy to treat this lethal disease. More importantly, we anticipate that these studies will identify a drug combination that is especially effective against metastatic PDAC. Innovation: This project will determine the antitumor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310656
Entities
People
- Jordan Winter
Organizations
- Case Western Reserve University
- United States Army