Investigating the emergence of circadian clock-mediated therapeutic windows in the cell cycle of cancer cells

Abstract

The circadian cycle is an approximately 24-hour cycle of physiological and biochemical processes in organisms. At a cellular level, the circadian clock comprises core clock genes showing oscillatory expression with a period of nearly 24 hrs These genes directly regulate cell cycle checkpoints. The clock-cell cycle coupling is crucial to cancer therapy since it has been shown that the maximum tolerated dose and the treatment outcome in cancer chemotherapy and radiotherapy differ depending on the dosage time. Chronotherapy is an emerging cancer therapy scheme wherein patients are administered therapy based on their circadian cycles. However, a proper understanding of the coupling of the clock to the cell cycle in different cancer cells and the effect of therapy on these oscillators is needed before we can apply chronotherapy on a large scale. In my thesis, I developed an agent-based four-compartment simulation based on the stochastic molecular clock and cell cycle gene dynamics, which can simulate cell proliferation and recapitulate physically realistic cell cycle phase durations. I further introduced a modified Linear-Quadratic (LQ) model that describes the dose and cell cycle phase-dependent effect of radiation on cells. I use HCT116 cells to experimentally show that clock coupling to the cell cycle can lead to a roughly 25.8 hr oscillation in the G1 proportion. Using the radiation simulation, I show that circadian coupling to cell cycles opens a therapeutic window wherein we can target specific cell types at their most sensitive cell cycle phase. The radiation model further suggests that daily dosing would not be an optimal therapy scheme due to post-radiation cell cycle arrest. We can use the radiation model to understand the effect of irradiating cells at different times, allowing us to develop an optimal sequential chronotherapy scheme for cancer.