Animal models are an essential step in the discovery process and provide critical support for further establishing the therapeutic and averse effect profile of a novel compound prior to advancement to in vivo toxicological screening and early phase clinical studies. CNPD3 investigators have considerable expertise in models of cancer as well as CNS diseases, including pain, drug addiction, and cognitive function.
Patient-Derived Xenograft (PDX) Models.
Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies for cancer. Critical aspects of cancer responsible for its highly lethal nature, such as the development of local invasion and distant metastasis, remain underrepresented in preclinical models of cancer. The purpose of our work is to develop a more representative personalized model of cancer that recapitulates key aspects of the human disease. In an effort to develop more reliable preclinical models, we established a patient-derived xenograft (PDX) model. Comparisons to established commercially available cancer cell lines alone, patient-derived tumor xenografts retain the extremely important heterogeneous and rich stromal background which contributes to tumor progression and contributes to systemic disease of most solid cancers. Along with the importance of cross-talk within patient-derived primary cancer cells and human stromal cells in the tumor, the actual site of tumor implantation (subcutaneous versus orthotopic) is also critical toward recapitulating cancer’s local and systemic effects which are commonly observed in our cancer patient population. Orthotopically implanted PDX-derived tumors consistently incorporated into the murine parenchyma or tumor origin, metastasized and induced muscle wasting (cancer cachexia) directly proportional to the size of the tumor, which is consistent with the syndromes noted in patients with cancer. Such data suggests that orthotopic implantation of patient-derived tumors with intact tumor microenvironment allow for systemic profiles that empty along the portal systemic circulation and contribute to features of more representative cancer-associated symptoms missing from prior preclinical models. The orthotopic implantation technique with patient-derived tumors allow for retention of the heterogeneous nature of human cancer. We demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human cancer. A correlative preclinical model of cancer is necessary to fully understand the possible mechanisms contribute to cancer syndromes and overall patient survival.
Genetic and Other Models of Cancer.
A number of rodent tumorigenesis models have been employed to 1) identify and develop natural product-based cancer chemopreventive agents; 2) determine the active component(s) and dissect the mechanism of action; and 3) develop surrogate biomarkers to facilitate clinical translation. For example, for lung tumorigenesis, a tobacco specific nitrosamine (NNK) and a polyaromatic hydrocarbon (BaP) have been utilized individually or in combination to induce lung tumorigenesis in A/J mouse model and in F344 rat model. For prostate tumorigenesis, the transgenic adenocarcinoma mouse prostate (TRAMP) model has been used which does not need carcinogen induction. For colorectal tumorigenesis, a dimethylhydrazine-based Wistar rat model animal model has been established as well. Mutant KRAS and other models are also available for testing in collaboration with the UF Health Cancer Center.
Studies are conducted in state-of-the-science equipment obtained from leading commercial vendors (MedAssociates, Coulbourn, San Diego) and managed by personnel with considerable expertise in programming and engineering, which offers creative, cutting-edge options to meet diverse needs. Work in both rats and mice provides a translational element, the flexibility to integrate PK and PD analyses, and the ability to genetically mutate targets that are not otherwise accessible with current pharmacological tools. The genetic approaches include whole body protein knockouts/knockins, as well as conditional protein knockouts/knockins offering both spatial (specific anatomical areas and specific types of cells) and temporal specificity (activated at any stage of development). Sophisticated pharmacological analyses including dose-response and quantitative analyses of drug interactions in the whole animal provides critical insight into mechanism of action in vivo, thereby extending information generated during earlier in vitro pharmacological stages of assessment. In addition to the focus on drug addiction and pain, assays are being expanded into mood disorders, including stress, anxiety and depression, as well as learning and memory, and cognitive performance.