Preclinical quantitative imaging (QI) and mouse tumor models bridge the gap between the discovery of new therapeutic targets and the ultimate proof of their efficacy in cancer patients. The Penn Quantitative MRI Resource for Pancreatic Cancer aims to standardize quantitative imaging methods optimized for biologically relevant mouse models to accelerate the development of novel therapies for pancreatic ductal adenocarcinoma (PDA). PDA is featured by a dense stroma, which constitutes a unique tumor microenvironment that resists drug penetration and is immune suppressive. Successful stroma-directed interventions can be a vital part of effective PDA management. Although several stroma-directed drugs are being examined in the clinic, QI markers are not available for evaluating stroma responses in mice or patients. We have identified translational motion sensitive MRI markers which can detect changes of the tumor microenvironment, and we propose to examine their utility for stroma-directed interventions. However the preclinical imaging techniques are suboptimal for studying orthotopic tumors in locations susceptible to respiratory/cardiac motion such as the pancreas. Importantly, the motion-robust imaging must be achieved simultaneously with adequate temporal resolution required by the dynamic imaging protocol, the spatial resolution required to resolve the small size targets. Our prior success in the development and optimization of preclinical and clinical MRI methodology provides a roadmap to accomplish the mission of optimizing the preclinical motion-sensitive MRI techniques to match the advanced clinical benchmarks. Our Resource will leverage the substantial institutional resources including the Mouse Hospital of PENN Pancreatic Cancer Center, which provides the genetically engineered mouse (GEM) models of PDA credentialed for studying stroma-directed interventions. The strong collaboration with our industrial partner has led to the design of a co-clinical trial that includes a prospective phase-II clinical trial and a preclinical trial, where the utility of QI markers will be tested in both patients and mice responding to the same treatment of an investigational stromal drug. A multi-expertise team and an Advisory committee will join force to achieve the technical transformation, conduct the co-clinical trial and build the Resource web-portal to disseminate all workflow documents, research tools and QA/QC phantoms and to share the novel data content.
High quality and reproducible quantitative imaging markers applicable to realistic mouse models are important for testing new treatment modalities for the pancreatic cancer. By applying the state-of-the-art optimization methods, we will enable the preclinical MRI techniques that are sensitive to changes of the tumor microenvironment to study mice bearing spontaneous pancreatic cancer. We will build a Resource web portal to share all the data, the technical know-how and workflow documents with the research community.
| Cao, Jianbo; Pickup, Stephen; Clendenin, Cynthia et al. (2018) Dynamic contrast-enhanced MRI detects responses to stroma-directed therapy in mouse models of pancreatic ductal adenocarcinoma. Clin Cancer Res : |
