Targeting Cancer-Associated Fibroblasts with Recently Approved HIF2𝛼 Inhibitor, Belzutifan, in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a formidable cancer with low survival rates, influenced by a hypoxic tumor microenvironment rich in cancer-associated fibroblasts (CAFs) which contribute to tumor progression and therapeutic resistance. This paper proposes a novel approach to PDAC treatment by identifying the effects of HIF2a inhibition. Leveraging Belzutifan, an FDA-approved HIF2a inhibitor, this paper aims to assess the mechanism by which Belzutifan can effectively target myofibroblastic CAFs in the PDAC tumor stroma. By conducting a literature review and integrating findings from preliminary in vitro experiments using PDAC organoid/immune/CAF cell co-cultures, I aim to explore the changes in gene expression and signaling pathways. This will include assessing the impact on immune cell recruitment and activation through advanced molecular techniques. The findings are anticipated to advance our comprehension of PDAC pathophysiology and highlight potential therapeutic avenues, offering a promising shift in PDAC treatment strategies.