A conceptual modeling framework for the study of DNA mismatch repair pathway to improve therapeutic gain in cancer treatment

摘要

The DNA mismatch repair pathway is an important repair mechanism in the cell that ensures genomic stability. Mismatch repair deficiencies are shown to be associated with certain hereditary forms of cancer as well as many sporadic cancers. The loss of mismatch repair also leads to resistance to chemotherapeutic agents and other types of DNA stress including ionizing radiation. An alternative treatment strategy for mismatch repair deficient cancers is the use of iododeoxyuridine and ionizing radiation together to generate cytotoxicity that will eventually lead to cell death. There are measurable differences in the cell cycle dynamics for mismatch repair proficient and deficient cells with and without treatment using iododeoxyuridine. A finite-state probabilistic cell cycle model is developed to study the effects of iododeoxyuridine on the cell cycle dynamics. We discuss how these models can be used to maximize therapeutic gain through the design of optimal dosing strategies of iododeoxyuridine and optimal timing of the ionizing radiation treatment. We introduce a conceptual hybrid modeling framework to study the dynamics of mismatch repair pathway in order to be able to manipulate the pathway to improve therapeutic gain. We also discuss the experimental data that are required to support the modeling framework.