Abstract IA-008: The KPC model has helped advance pancreatic cancer therapy: Disagree

Pancreatic cancer researchers have grappled with the difficulty of reproducing the complex tumor microenvironment which holds the key to improving therapeutic treatments for the disease. For decades, murine models of the disease have underpinned all clinically-relevant pancreatic cancer research and indeed, the transgenic KPC mouse model has been touted as our closest in vivo model to human disease; reproducing disease progression from early PanIN lesions, extensive fibrosis, metastatic spread and chemoresistance. Numerous clinical studies have been initiated based on the work done in this model. However, most of these trials have failed to successfully improve outcomes for pancreatic cancer patients or to even progress beyond phase 2 clinical trials. A/Prof Phillips will argue that the KPC model, while a useful tool to understand pancreatic cancer biology in the laboratory, has had limited clinical impact due to key differences in mouse and human cell biology as well as inherent limitations of the model. Patient-derived 3D tumor models of pancreatic ductal adenocarcinoma (PDAC) have potential to overcome many limitations associated with the KPC model. Human PDAC organoid and whole-tissue explant cultures may hold the key to precision medicine in their ability to predict patient response to existing treatments, to guide translation of new therapies to the clinic in a technique which is both scalable and provides rapid readout 1,2. Furthermore, the ability of the human tumor explant model to retain the multicellular microenvironment of patient tumors provides a powerful tool to study the effects of tumor and stromal targeting agents for pancreatic cancer 3. Coupling this model with the recent explosion of spatial omics techniques also allows us to understand the tumor composition and therapeutic response of individual patient tumors down to the single cell level, negating the need for more homogenous mouse models that require extensive replication and yet make generalized predictions on therapeutic response. Thus, with the advent of these personalized “at-the-bench” 3D human models of pancreatic cancer, perhaps the real question is whether we still require the KPC mouse model? References: 1. Kokkinos, J., Jensen, A., et al., and Phillips, P.A. Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer? Cancers (Basel), 2021. 13(10): p. 2427. 2. Kokkinos, J., Sharbeen, G., et al., and Phillips, P.A., Ex vivo culture of intact human patient derived pancreatic tumor tissue. Sci Rep, 2021. 11(1): p. 1944. 3. Sharbeen, G., McCarroll, J.A., et al., and Phillips, P.A., Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition. Cancer Res, 2021. 81 (13) 3461-3479. Citation Format: Phoebe A Phillips. The KPC model has helped advance pancreatic cancer therapy: Disagree [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-008.