This consortium represents a multi-disciplinary team effort to launch an integrated program focused on model development/refinement, cancer gene discovery, preclinical experimental therapeutics and technology development. The model development initiative will seek to develop and characterize models that recapitulate two fundamental aspects of cancer in humans - epithelial cancer predisposition and episodic chromosomal instability - by engineering mice that experience transient telomere dysfunction and subsequent telomerase activation in the evolution of colorectal cancer and squamous cell carcinoma of the skin. In addition, a model of pancreatic ductal adenocarcinoma will be developed in which we attempt to ascertain whether telomere-linked chromosomal instability and compromised telomere checkpoints serve as a general mechanisms driving age-dependent epithelial carcinogenesis. In the cancer gene discovery area, we will conduct a comprehensive comparative oncogenomic analysis of human and mouse epithelial cancers (specifically colon, skin and pancreas) by taking advantage of powerful gene-specific array-CGH and informatics platforms. These comparative oncogenomic studies will not only serve to validate these models but also carry the potential to identify common and distinct molecular themes in human and murine carcinoma development. In therapeutics program, inducible oncogene melanoma models will be used to identify genetic resistance elements capable of replacing activated RAS, BRAF or AKT function in established tumors. Both genomic and forward genetic screens are proposed. Finally, an important mission will be technology development in the areas of genomics, informatics, imaging and nanoteclmology. Specifically, the team will develop the oligo-based CGH platform and develop of informatics tools for crossspecies genomic comparisons. The imaging component will feature several experiments such as the application of novel reagents to visualize the dynamic vascular changes occurring in regressing tumors as well as hypoxia-induced reporters capable to monitoring oxygen status in growing and regressing tumors. Finally, nanosensors will be developed that are capable to detecting telomerase activity and quantifying telomere reserves.
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