Abstract B060: Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy

Abstract

Abstract Cancer modeling systems can be advantageous in enabling personalized medicine through rapid testing of therapeutic responsiveness. However, modeling systems often fail in these efforts due to 1) inadequately replicating unique patient genetics, 2) inadequately modeling the patient tumor microenvironment (TME), and 3) lack of internal validation references when isolated from clinical drug response data. We have developed a patient-derived models of cancer (PDMC) program for pancreatic cancer that addresses these challenges. By integrating patient cancer modeling and tissue engineering efforts with clinical trial protocols that perform serial tissue biopsies and analyses during treatment, we can make direct assessments of how different modeling systems replicate actual patient outcomes. Clinical trial protocols include tissue biopsies pre- and post- treatment using targeted therapeutics including MEK and PARP inhibitors. The modeling program, meanwhile, includes collecting metadata from pre- and post- treatment biopsies, the banking of patient tissues, cell line and xenograft generation from each biopsy, multiomic comparisons of models to patient tissue, comparisons of therapeutic responsiveness in models, and ultimately tissue re-engineering through bioprinting of tumor cells along with TME components. Whole exome sequencing is used to confirm that genetic alterations are preserved in each model, and we have established models representing a range of human PDAC genomic profiles. This includes common KRAS and TP53 mutations, as well as rare BRCA mutations and KRAS-wild-type tumors with BRAF mutations. Many cancer-associated fibroblast (CAF) lines have also been established through this program. Including patient derived cell lines, CAD lines, endothelial cells, and PBMCs into 3D bioprinted tumors allows us to better model the TME. Assays performed upon bioprinted tissues can then be directly compared to the same assays performed on the patient tumor to assess similarities as well as further obstacles. Ongoing efforts include building a resource of precise and validated PDMCs for diverse pancreatic cancers, and establishing a path forward for improved cancer modeling for the actualization of personalized medicine in PDAC treatment. Citation Format: Alexander C. Smith, John Muschler, Mike Munks, Rosalie C. Sears, Jonathan Brody. Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B060.