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Abstract
Understanding the therapeutic effect of drug dose and scheduling is critical to inform the design and implementation of clinical trials. The increasing complexity of both mono, and particularly combination therapies presents a substantial challenge in the clinical stages of drug development for oncology. Using a systems pharmacology approach, we have extended an existing PK-PD model of tumor growth with a mechanistic model of the cell cycle, enabling simulation of mono and combination treatment with the ATR inhibitor AZD6738 and ionizing radiation. Using AZD6738, we have developed multi-parametric cell based assays measuring DNA damage and cell cycle transition, providing quantitative data suitable for model calibration. Our in vitro calibrated cell cycle model is predictive of tumor growth observed in in vivo mouse xenograft studies. The model is being used for phase I clinical trial designs for AZD6738, with the aim of improving patient care through quantitative dose and scheduling prediction.
Highlights
The DDR pathway enables eukaryotic cells to repair DNA damage occurring in response to a variety of endogenous and exogenous sources[18]
The model represents the transition of a population of cells through the G1, S and G2/M phases with additional DNA damaged states for replication stress and ionizing radiation (IR) induced damage for the relevant cell cycle phase (Fig. 1)
Replication stress is modeled as an alternative S phase (“S damaged”) with transition back into the cell cycle simulating repair, a reaction which is inhibited by the addition of drug, simulating the mode of action of AZD6738
Summary
The DDR pathway enables eukaryotic cells to repair DNA damage occurring in response to a variety of endogenous and exogenous sources[18]. Inhibition of DNA damage detection can lead to cell cycle arrest or mitotic spindle catastrophe[19,30]. The former occurs upon stalling of the replication fork, the latter if checkpoints are dysfunctional because of, e.g. mutations[31]. AZD6738 is a selective inhibitor of ATR16,32 and it is hypothesized that application as therapy in an ATM deficient setting will result in deficiency in both DDR pathways, inhibiting DNA damage signaling resulting in cell death if damage is sufficiently high, and abrogation of the G2/M checkpoint with consequent genomic instability during mitosis (mitotic spindle catastrophe)[16,18,19]. The LoVo cell line is ATM pathway deficient due to mutation in MRE11, preventing formation of the MRN complex and subsequent recruitment of ATM to sites of DNA damage to initiate repair[34]
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