Abstract Pancreatic cancer patients show an extremely poor prognosis, which is at least in part due to poor response to the current standard-of-care chemotherapies. While pancreatic tumors present an inadequate response to chemotherapy, exposure to chemotherapy leads to development of acquired resistance. The response and resistance to chemotherapies are modulated by signaling and metabolic alterations in tumor cells and companion changes in the immune and non-immune stroma. Major advances in (a) understanding signaling responses of cancer cells and stroma to therapy, (b) understanding metabolic adaptations to signaling and environmental stressors, (c) development of novel therapeutic combinations to improve long-term response to current standards-of-care chemotherapies, and (d) coordinating research/translation efforts by NCI leadership, will provide unparalleled advances in targeting/preventing acquired therapy resistance. The ARTNet Center for Pancreatic Cancer (ACPC) intends to achieve these objectives through an integrated research theme that combined investigations into the metabolic and signaling mediators of acquired resistance in tumor cells and stromal remodeling in pancreatic cancer will lead to novel effective therapies to improve the patient prognosis. Research within ACPC will be fostered through sound guidance from leadership, IAC, EAC, ARTNet network and NCI program. The overall goal of the Center is to study innovative hypothesis-driven mechanisms of metabolic and signaling alterations in tumor cells and tumor-stromal metabolic crosstalk that contribute to acquired therapy resistance in pancreatic ductal adenocarcinoma (PDAC). We hypothesize that our unique leadership team, outstanding expertise of project and core leaders, singular set of technological capabilities and resources, operational design, and strong institutional support of the ACPC will drive transformative advances in the acquired therapy resistance field that will be in alignment with the other ARTNet members and NCI’s mission for the program. Providing novel insights into the mechanistic aspects of the signaling and metabolic mechanisms, the proposed basic and translational studies will ultimately drive the development of novel therapeutic combinations that can change the clinical course of cancer therapy. This will be achieved through the following Specific Aims: Aim 1. Investigate novel mechanisms of acquired resistance at the interface of tumor- stromal metabolic cross talk and examine the preclinical efficacy of identified targets to improve the therapeutic response against pancreatic cancer. Aim 2. Provide robust and innovative toolsets and resources to investigate and validated mechanisms of acquired therapy resistance. Aim 3. Facilitate a systems-level mechanistic understanding of acquired therapy resistance mechanisms.

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.