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

Abstract

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.

Quantitative analysis of the effects of iododeoxyuridine and ionising radiation treatment on the cell cycle dynamics of DNA mismatch repair deficient human colorectal cancer cells

“…These data contribute to our overall strategy of developing effective patient specific treatment strategies using comprehensive IUdR–IR models to optimise the IUdR‐mediated radiosensitisation of MMR− (damage tolerant) human cancers while minimising IUdR and/or IUdR + IR effects on proliferating dose‐limiting normal (MMR+) cells/tissues (e.g. bone marrow, GI epithelium) [5, 11, 12, 14].…”

“…We have also shown that cell cycle dynamics are different in MMR+ against MMR− cells with and without IUdR treatment [13]. Using synchronised isogenic MMR+ and MMR− cell populations, we developed a synchronous probabilistic cell cycle model to study the effects of IUdR on cell cycle dynamics with the aim of developing optimal IUdR dosing strategies that maximise therapeutic gain [13, 14].…”

Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers

“…The MMR process is modeled as a stochastic hybrid system that incorporates both the continuous and discrete dynamic behaviors of MMR (Figure 4), as published in the Proceedings of the IEEE/NIH BISTI Life Science Systems and Applications Workshop, 2007 (Gurkan et al, 2007b). As indicated above, the MMR process involves a finite number of sub-processes, each involving biochemical dynamics for recognition, excision, and repair.…”

“…Our current plan is to further develop these probabilistic models of IUdR ± IR interactions using data derived from in vivo systems of HCT116 (and other) human tumor cell lines as xenografts in athymic mice which will also allow for assessment of treatment effects (toxicities) on normal tissues (which are MMR + ) to calculate a therapeutic index (Gurkan et al, 2007b). …”

“…To better understand the dynamics involved in our observed biochemical and molecular differential MMR processing of 6-TG (Figure 1 ) vs. IUdR (Figure 2 ) damage, as well as IR damage (Figure 3 ), we are applying dynamic systems methods to develop an in silico model of MMR. The MMR process is modeled as a stochastic hybrid system that incorporates both the continuous and discrete dynamic behaviors of MMR (Figure 4 ), as published in the Proceedings of the IEEE/NIH BISTI Life Science Systems and Applications Workshop, 2007 (Gurkan et al, 2007b ). As indicated above, the MMR process involves a finite number of sub-processes, each involving biochemical dynamics for recognition, excision, and repair.…”