The objective of the proposed planning activity, and the broad, long-term goal of our proposed Case Integrative Cancer Biology Program (ICBP), is to develop a fully integrated interdisciplinary team of systems scientists and cancer biologists that can address the complex biological problem of cancer using systems approaches. This effort is being built on a cancer research forte at the Case School of Medicine and pioneering research in systems theory and mathematical control in the Case School of Engineering. The scope of this work is composed of five integrated projects that include research, data and model sharing, and educational activities. The projects will produce a predictive in silico model of deoxynucleotide metabolism that will facilitate drug and radiation dose time course optimizations in future therapies of mismatch repair defective (MMR-) malignancies. The projects will investigate two basic approaches for selectively killing MMR defective cells. In one approach (Project 1), cells that are MMR defective due to either methylation silencing or genetic mutations are targeted;in the other approach (Project 2), only methylation silenced MMR defective cells are targeted. In both approaches, the strategy is to preferentially accumulate drug into DNA of MMR defective cells. In the first approach, IdUrd accumulates preferentially in the DNA of MMR defective cells and after an appropriate amount of incorporation, cells are exposed to radiation to selectively kill MMR- cells. In the second approach, FdCyd is first used to load FdUrd selectively into the DNA of cells MMR defective due to methylation, and after sufficient loading, dH4Urd (an inhibitor of cytidine deaminase) is then used to redirect FdCyd into DNA where it acts as a demethylating agent that reverses MMR competence and thus creates a catastrophic spike of DNA double strand breaks (DSBs). Through an iterative process that involves model development and systems analysis, experimentation and data collection, model testing and validation, and a detailed study of coordination and control between the salvage and de novo deoxynucleotide synthesis pathways (Project 3), we will produce a deoxynucleotide metabolism model in R and make it publicly available in both R and Systems Biology Markup Language (Project 4). To educate oncologists and engineers, we will develop a graduate level course sequence in Integrative Cancer Biology (Project 5). Accomplishing these projects will produce building blocks needed for subsequent translational cancer research studies. At the completion of this three-year project, we will have developed a strong interdisciplinary team that will be capable of advancing the study of cancer as a problem of complex biological systems.
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