The broad, long-term goal of the proposed research career is to develop in silico models of deoxynucleotide metabolism that will facilitate drug and radiation dose time course optimizations in the treatment of mismatch repair defective (MMR-) malignancies. The five-year goal of this research plan is to build a model of ionizing radiation (IR) damage driven iododeoxyuridine (IdUrd) incorporation into the DNA of quiescent cells as a model of the quiescent state of tumor stem cells; IdUrd radiosensitization is proportional to IdUrd-DNA and MMR- cells retain IdUrd-DNA longer than MMR+ cells. Using isogenic RKO cell lines that differ only in MMR competence, a mathematical model of deoxynucleotide metabolism will be developed to predict which time courses of IdUrd, leucovorin, ralitrexed, and 5'-amino-5-deoxythymidine maximize differences in IdUrd-DNA between MMR- cells and MMR+ cells over some post IR time interval; predicting when this time interval occurs could then be used to time a second dose of IR to exploit the IdUrd-DNA differences. The hypothesis is that such a model of deoxynucleotide metabolism can indeed be built and experimentally validated. ? ? The Specific Aims of this research are: (1) to develop a literature-based mathematical model of the folate-purine-pyrimidine system and use it to form a baseline prediction of IdUrd incorporation into DNA; (2) to further develop this model incrementally through a continuous cycle of wet-lab experimental validations of theoretical predictions followed by dry-lab model modifications and new predictions, beginning with single agents and proceeding to more complicated multi-drug scenarios with increasing cycles; and (3) to develop an interface and rigid programming format that will allow automatic conversions of source implementations of deoxynucleotide metabolism in R (an open source, object-oriented statistical programming environment that carries the advantage of Bioconductor tools) to Systems Biology Markup Language. Achievement of Aim 3 will broaden public use of the current model. Achievement of all three Specific Aims will provide building blocks for subsequent translational cancer research studies. These studies will include Dr. Timothy J. Kinsella's chemoradiation studies of an IdUrd prodrug, IPdR, against MMR defective malignancies, and likely the studies of others, since the folate-purine-pyrimidine system holds a very central position in anti-cancer drug development. ? ?
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