Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have few effective therapeutic options available. Most patients quickly develop resistance to current therapies and progress to metastatic disease which is universally lethal. Current treatments for PDAC include chemotherapy combination of 5- fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel. To study the tumorspecific chemotherapy response, we established a robust 3D culture method to propagate patient-derived organoids (PDOs) ex-vivo and demonstrated that these models recapitulate the genomic and transcriptomic hallmarks of the disease. Importantly, we found that PDO-response to chemotherapy mimics patient-response. This pharmacotyping method allowed us to identify both chemosensitive and chemoresistant patient models. We find that gene expression regulating metabolic pathways are dramatically and specifically rewired in the sensitive and resistant PDOs. Importantly metabolic rewiring is a hallmark of cancer and PDAC and has been shown to promote resistance phenotype in patients and laboratory models. We therefore hypothesize that PDOs will have distinct metabolic profile associated with chemosensitivity and chemoresistance. The tumor microenvironment (TME) of PDAC contributes to the drug resistance phenotype observed in patients. Specifically, PDAC cells promote a metabolic rewiring in cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) which in turn contributes to chemoresistance. Furthermore, we and others have shown that chemoresistance-associated CAFs can reprogramed cancer cells to become more resistant to treatment therefore the cell-cell signaling that promotes and maintains chemoresistance is complex and involved both cancer intrinsic and extrinsic mechanisms. Here we hypothesize that chemoresistance in PDAC is associated with metabolic rewiring in the cancer cells which promotes survival and alters the stromal microenvironment to further enhance metabolic resistance to chemotherapy.

Project Narrative: Acquired resistance to therapy contributes to poor survival outcomes in cancer patients. The primary objective of this U54 application is to establish a successful and self-sustaining ARTNet Center for Pancreatic Cancer (ACPC) to explore novel mechanisms and combination therapies to target acquired resistance in pancreatic cancer. We will collaborate and work closely with other ARTNet centers, coordinating center, and the National Cancer Institute to provide novel mechanistic insights and translational opportunities to target therapy resistance with the long-term goal of improving overall patient survival.