EXPERIMENTAL CANCER CHRONOTHERAPEUTICS

 

Our laboratory studies the interactions between the circadian timing system and, cancerogenesis and anticancer treatment response.


Plurisdiciplinary studies are undertaken within our laboratory to study the interactions betweenthe molecular circadian clock, the cell cycle and the pharmacology of anticancer drugs. We aim to identify the molecular mechanisms driving tumor progression and antitumor agent chronotoxicity/chronoefficacy. Our global research project address conceptual, technical and methodological barriers to allow for the personalisation of cancer chronotherapeutics (Figure 1).

 

Figure 1 : Algorithm to optimize cancer chronotherapy, based on chronotolerability. The objective is to prevent drug toxicities and associated circadian disruption which may favor tumor progression.

 

1) Influence of the circadian timing system on cell cycle, cell death and anticancer drug response.  Our laboratory develops innovative in vitro and in vivo experimental models to investigate the disrutption and the reinforcement of all components of the circadian timing system which induces temporal variations in cell cycle, apaptosis, DNA repair, drug metabolims and activity.

 

Figure 2 : Disruption of the molecular circadian clock in cancer. The cellular clock is composed of approximately 15 genes interconnected in regulatory loops (left panel) which interact with most pathways deregulated in cancer cells (right panel).

Experimental investigations involve the manipulation of food intake or light-dark cycles over the 24h span, the administration of anticancer drugs, and/or the use of genetically modified cell lines or animals holding mutations or knock downs of specific clock genes.

The first circadian transcriptomics study in xenografted mice demonstrated that meal timing slowed down tumor growth though the circadian entrainement over 24h of approximately 400 genes involved in cell cycle, cellular metabolism or immunity (Figure 3). This circadian reprogramming of the tumor transcriptome is linked to an amplification of the body temperature rhythms and of other physiological rhythms of the host.

Figure 3 : Experimental circadian reprogramming of the transcriptome of pancreatic cancer by meal timing.

2) Influence of cancer and anticancer drugs on the circadian timing system.

Cancer progression alters both the coordination between cellular clocks and their control on intracellular pathways including cell cycle machinery. Several drugs, such as seliciclib, are able to induce circadian rhythms in tumors which were initially not rhythmic. This new pharmacological property of seliciclib is associated with a better antitumor efficacy of the drug and results from the inhibition in tumor cells of the casein kinase Iδ/ε, an enzyme which regulates the period of the cellular clock.

 

Figure 4 : Hypothetical scheme of synergistic activity of seliciclib (roscovitine), cell cycle and the cellular circadian clock.

Seliciclib, and other anticancer drugs, induce a diruption of the physiology and the molecular mechanisms of the circadian timing system when administered at the circadain times of worst tolerability. Circadian coordination could then contribute to pharmacological drug effects and its alteration could lead to severe toxicities.

 

 

CONTACT US

Unité INSERM U935

Campus du CNRS

Bâtiment A, 3ème étage
7 rue Guy Moquet
94801 Villejuif cedex
France
  • +33 (0)1 49 58 34 81

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