Precision Therapy to Target Pancreatic Ductal Adenocarcinoma

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

GOAL A (completed)- MSLN is the target of many therapeutics being tested in clinical trials but little is understood about the effect of MSLN on PDAC aggressiveness and therapeutic resistance. We have previously found that loss of MSLN impairs the ability of PDAC to colonize the peritoneum and cause metastasis there. MSLN loss from cancer cells impaired the establishment of blood vessels to the new tumor deposits. In FY24and25, we published our data investigating the role of shed MSLN in pancreatic cancer peritoneal metastasis. We found that membrane-bound mesothelin causes tumor cell clustering that enhances metastasis and that high concentration of shed MSLN can disrupt this pro-tumorigenic behavior. Importantly, this and other previous work was performed with human PDAC cell lines using immune-suppressed mice as hosts. GOAL B (ongoing)- MSLN-targeted therapeutics are typically antibody-based and large molecule therapeutics penetrate poorly into PDAC. To address this, we are collaborating to develop new formats MSLN-targeted therapeutics. First, we are developing a MSLN-targeted nanoboady drug conjugate (NDC) in collaboration Mitchell Ho (NCI/ LMB) and extramural chemist Goncalo Bernardes (Cambridge). Secondly, in collaboration with Serguei Kozlov (NCI/ CAPR) we have developed KPC GEMM mice with human MSLN knock-in so that human-MSLN-targeted therapeutics can be tested for tumor penetration in a gold standard autochthonous model with stroma, blood vessels, and tumor density that closely resembles that seen in human patients. Thirdly, we are investigating stromal modulating agents such as However, MSLN is now known to interact with macrophages in the immune system. In collaboration with Serguei Kozlov (NCI/CAPR), we developed immune-competent PDAC models with MSLN loss to better understand the role of MSLN in the presence of a complete and active immune system. We are currently writing up a manuscript about these models.