High grade astrocytomas represent the most common brain malignancies with limited therapeutic options available and proven association with generally poor clinical outcomes. Improved understanding of disease etiology thus represents a promising avenue for developing innovative diagnostic and therapeutic strategies. The project encompases a broad set of collaborative efforts among CAPR (Dr. Van Dyke's Preclinical Research Center), UNC (Dr. Ryan Miller's lab) and ISB (Dr. Leroy Hood's lab) to characterize molecular signatures and pathways underlying the astrocytomagenesis process and to identify promising early prognostic markers of cancerous transformation as well as response to therapeutic treatment. To this end, the project leverages the advantages of inducible disease initiation in the mouse, the ability to perturb and/or monitor the carcinogenesis process, and the extensive power of unbiased systems biology approach. A variety of state-of-the-art molecular technologies will monitor genome, transcriptome, proteome, and metabolom dynamics in tissues and blood serum as the disease progresses. Where possible, a cross-species data analysis will be exploited to determine the relevance of findings to human disease. During the past year, CAPR scientists developed and optimized breeding approaches to maintain the colony of one-of-a-kind inducible genetic model for high-grade astrocytoma and glioblastoma. The model features a complex genetic setup that mingles several mutant alleles to render dysfunctional pRb/p105/p130, K-ras, and PTEN/Akt pathways alone or in different combinations. The required set of assays to rapidly identify individual animals with desired allelic combinations has been designed and validates, along with multiple histology-, molecular biology-, and in vivo imaging-based clinically relevant endpoints to monitor disease progression stage. To exemplify, an upgraded approach allowing simultaneous imaging of multiple animals by MRI modality has been adopted by CAPR making feasible multiple longitudinal imaging sessions of the entire experimental cohort. In another line of experiment, the Preclinical Evaluation group of CAPR has developed a complementary orthotopic intracranial xenograft modelling strategy employing either human glioma cell lines or primary AA/GBM cells isolated from de novo tumor bearing animals and minimally maintained under in vitro culturing conditions. These orthotopic models have been utilized thus far in several collaborative PK/PD projects aimed at bioavailability studies in brain tissue for nanotechnology compounds and drug candidates identified through high-throughput in vitro screening strategies (e.g. Schweinfurthins, in intramural CCR collaboration with Dr. Karlyne Reilly or international collaboration with CGMH, Taiwan, to evaluate ultrasound-assiated drug delivery strategy).
|Van Dyke, Terry (2010) Finding the tumor copycat: approximating a human cancer. Nat Med 16:976-7|
|Walrath, Jessica C; Hawes, Jessica J; Van Dyke, Terry et al. (2010) Genetically engineered mouse models in cancer research. Adv Cancer Res 106:113-64|