Our laboratory has designed an innovative strategy for curative purposes associating chronotherapies and surgical resection of metastasis of colorectal cancers. Two clinical trials in metastatic colorectal cancer patients revealed that the chronomodulated administration scheme designed by our laboratory was better tolerated in men compared to women (2006, Giacchetti et al J Clin Oncol ; 2007, Lévi et al. ADDR ). To further study sex specificity, the unit has gathered a database of ~1400 patientsregistered in European clinical trials, and corrdinates several European projects which integrate the role of sex in chronotherapeutics.

Our laboratory propose a global vision of the circadian timing system, as an interface with the environment and the main physiological systems of the organism such as metabolism or cell proliferation. This allows the identification of circadian biomarkers informing on the dynamics of the circadian timing system and of the physiological functions it governs over time (Figure 1).


Figure 1 :  Relation between the circadian timing system and physiological biomarkers utilized to optimize and personalize chronomodulated infusion scheme in cancer patients (Lévi et al., 2011).


Thus, the disruption of the rest-activity rhythm, a biomarker of the circadian coordination is associated withhigher incidence of severe drug toxicities, lower drug antitumor efficacy and survival of cancer patients (Figure 2).


 Figure 2 : Rest-activity rhythms recorded during 3 days by a wrist actimeter worn by 3 metastatic colorectal cancer patients (Mormont et al., 2000 ; Innominato et al, 2009 ).



Several important discoveries in the last decades in the field of colorectal cancer research have resulted from the synergy between our chronotherapy clinical unit and other research teams, including:


- In 1990,  the proof of a secure use of oxaliplatin (Eloxatine) administered in a chonomodulated manner according to biological rhythms. Oxaliplatin was previsouly considered as too toxic to be further developped for the clinic.

- In 1992, the discovery of the activity of oxalipaltin against colorectal cancers, in particular in association with 5-Fluorouracile/ folic acid. It was the chronomodulated administration of those three molecules which constituted the first proof of efficacy of this drug combination, which is nowadays the gold standard for the treatment of digestive cancers.

-In 1997, the demonstration that chronotherapy of those three molecules was up to 5-fold less toxic and twice more efficient compared to constant perfusion in metastatic colorectal patients.

- In 1999, the first demonstration of the curability of metastatic colorectal cancer though a new medical/surgical strategy combining the reduction of the metastasis volume by chronomodulated chemotherapies and a subsequent surgical resection.  No colorectal cancer patients with inoperable metastasis survived after 3 years before this strategy.

- In 2008, the first demonstration of antitumor efficacy of hepatic intra-arterial administration of chronomodulated chemotherapies against inoperable metastasis of colorectal cancers which were resistant to conventional chemotherapies. Those results initiated the OPTILIV European protocol coordonated by our Laboratory.


Other discoveries initiated research projects in our research teams:

- Existence of circadian disruption circadienne in 25-30% of metastatic colorectal cancer patients, which was associated with a poorer quality of life and survival (Mormont et al., Clin Cancer Res, 2000 ; Innominato et al., Cancer Res, 2009)

- Differences of toxicity and efficacy of chronotherapies according to the patients' sex (Giacchetti et al., 2012).

- Potentiation of the efficacy of chronotherapies by targeted molecules such as antibodies agaisnt the Epidermal Growth Factor Receptors (EGFR).

- Need to minimize chemotherapies toxicities in order to optimize their efficacy. This principle is opposite to the conventional chemotherapy paradigm (Innominato et al, 2011 Chronobiology Int, 2012 Int J Cancer, 2013 Cancer).


Unité INSERM U935

Campus du CNRS

Bâtiment A, 3ème étage
7 rue Guy Moquet
94801 Villejuif cedex
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