Abstract A067: Identifying and targeting FOLFIRINOX resistance mechanisms to improve outcomes in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 12%. More than 80% of PDAC patients cannot undergo potentially curative surgical resection due to the presentation of advanced, metastatic disease, and are instead offered systemic chemotherapy regimens to which resistance is rapidly acquired. FOLFIRINOX chemotherapy offers an 11.1-month median survival compared to 6.8 months with Gemcitabine. Rapid onset of resistance to FOLFIRINOX, coupled with the lack of alternative targeted therapies, ultimately results in patients succumbing to the disease. My project aims to identify mechanisms by which PDAC cells acquire resistance to FOLFIRINOX treatment and investigate interventions aimed at enhancing and/or reinstating FOLFIRINOX sensitivity. Our lab has propagated distinct patient derived xenografts (PDXs) from the Avner Australian Pancreatic Cancer Matrix Atlas (APMA) and I have exposed them to 11 - 15 rounds of FOLFIRINOX (or vehicle control) in vivo to reflect the clinical management of PDAC. Additionally, intrapancreatic orthotopic tumors derived from cells from the KPC mouse model (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) have received 5 - 6 rounds of FOLFIRINOX (or vehicle control). These tumors will undergo quantitative data-independent acquisition mass spectrometry proteomic analysis and RNA sequencing transcriptomic analysis (RNAseq) to reveal resistance pathways and/or proteins operating in the chronically treated tumors and the surrounding pancreatic tumor microenvironment. Additionally, we have developed and cultured matched treatment naïve and FOLFIRINOX-treated patient-derived cell lines (PDCLs) and mouse cell lines from the PDX and KPC-derived tumors. These lines will allow us to validate future targets via gene knockdown and/or pharmacological intervention. 3D assays, such as our organotypic matrix models, will be performed to assess the metastatic potential of cancer cells and their response to FOLFIRINOX in vitro. Furthermore, subcutaneous and orthotopic (intrapancreatic) models coupled with intravital (in vivo) imaging and biosensor technology will allow us to assess targeting in live tumors and metastatic sites in real time. It is the hope that this research will lead to the identification of proteins or protein pathways which can be manipulated in order to re-sensitize tumors to FOLFIRINOX chemotherapy. Citation Format: Victoria Tyma, Ying-Fei Liew, Alice Tran, Anna Howell, Shona Ritchie, Avner Australian Pancreatic Cancer Matrix Atlas, Australian Pancreatic Genome Initiative, Thomas Cox, Marina Pajic, David Herrmann, Brooke Pereira, Paul Timpson, Katie Gordon. Identifying and targeting FOLFIRINOX resistance mechanisms to improve outcomes in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A067.