Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 11%. More than 80% of PDAC patients cannot undergo potentially curative surgical resection due to the presentation of advanced, metastatic disease, and are instead offered standard-of-care chemotherapy regimens to which resistance is rapidly acquired. Standard-of-care FOLFIRINOX combination chemotherapy, which is a regimen of three chemotherapy drugs, Oxaliplatin, Irinotecan and Fluorouracil with Calcium Leucovorin, offers an 11.6-month median increase in survival. Rapid onset of resistance to this chemotherapy regimen, coupled with the lack of alternative targeted therapies, ultimately results in patients succumbing to the disease.
Our lab has propagated distinct patient derived xenografts (PDXs) from the Avner Australian Pancreatic Cancer Matrix Atlas (APMA) and have exposed them to 11 -15 rounds of FOLFIRINOX (or vehicle control) in vivo to reflect clinical management of the disease. Once ready, these tumours will undergo downstream quantitative tandem liquid chromatography mass spectrometry (LC-MS/MS) proteomic analysis and RNAseq transcriptomic analysis to reveal resistance pathways and/or proteins operating in the chronically treated tumours and the surrounding pancreatic tumour microenvironment.
Further to this, we have developed and cultured matched treatment naïve and FOLFIRINOX-treated patient-derived cell lines (PDCLs) from the PDX tumours. These lines will allow us to validate future targets via gene knockdown and/or pharmacological intervention using a range of in vitro and in vivo models. We will use 3D-organotypic matrix models to assess cancer cell invasion and response to FOLFIRINOX in vitro. Furthermore, subcutaneous and orthotopic (intrapancreatic) PDCL models coupled with intravital (in vivo) imaging and biosensor technology will allow us to assess targeting in live tumours 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-sensitise tumours to FOLFIRINOX chemotherapy.