Systemic IMMunological determinants of tumor evolution and therapy response in BRCA-mutated pancreatic cancer
Patients with pancreatic ductal adenocarcinoma (PDAC) are in dire need of early detection biomarkers and effective treatments. While advanced tumors have been well-described, the changes occurring in tumor initiation remain ill-defined. Moreover, the organismal-level effects of cancer-predisposing factors on the systemic immune environment and their impact on disease progression and therapy response remain unexplored. We hypothesize that an in-depth study of the reciprocal interactions between local mechanisms of tumorigenesis and the host’s systemic immunity will uncover mechanisms, noninvasive biomarkers and actionable targets to improve early detection and treatment of PDAC in patients at high risk. SIMMBAP integrates clinical investigators, cancer biologists and computational scientists seeking to expose actionable changes in circulating immune cells and circulating tumor DNA (ctDNA), focusing on well-defined high-risk populations or PDAC patients harboring germline pathogenic variants in BRCA1/2. We will integrate ctDNA analyses, single-cell multiomics and clinical datasets using state-of-the-art computational tools to chart the systemic pre-cancer landscape in individuals at risk of PDAC (Aim 1). Expanding these analyses to baseline and post-treatment blood and tissue samples from patients with advanced PDAC, the project will nominate tumor-intrinsic and systemic immune/inflammatory traits associated with tumor evolution and therapy response (Aim 2). These candidates will be functionally probed using mouse models and organoid systems that mimic the pathogenesis of gBRCA-PDAC (Aim 3). Through this multidisciplinary approach, SIMMBAP will produce an atlas of systemic molecular and immunological patterns associated with cancer predisposition, expose actionable mechanisms licensing PDAC initiation and therapy resistance, and uncover new immune biomarkers and therapeutic targets that pave the way to novel early diagnosis and interception strategies.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.