Program > Plenary speakers

Abstract:

Chronotherapeutics aims at improving treatment outcomes through the delivery of medicines according to circadian rhythms. Indeed, xenobiotic metabolism and detoxification, as well as cell cycle events, DNA repair, apoptosis and angiogenesis are rhythmically controlled by the Circadian Timing System (CTS). The CTS is a hierarchical network of molecular clocks in each cell. Most recent progress in dynamic molecular imaging have enabled the tracking of circadian oscillations and their relations with cell cycle or therapeutic activity at single cell level, in cultured cell populations and in freely moving mice. These advances pave the way for modern systems cancer chronotherapeutics, where drug delivery schedules are personalized according to individual CTS characteristics and lifestyle, besides the usual omics.

Molecular clocks generates intracellular circadian oscillations in cell metabolism and division, as a result of interwoven transcription/translation feedback loops involving 15 clock genes. The cellular circadian clocks are coordinated by the suprachiasmatic nuclei (SCN), the main circadian pacemaker in the hypothalamus, which directly or indirectly generates an array of physiological rhythms. The CTS then make the molecular clocks tick in synchrony in the host tissues that can otherwise be damaged by anticancer agents. As a result, circadian timing can modify 2‐ to 10‐fold the tolerability of anticancer medications in experimental models and in cancer patients (Lévi et al. Annu Rev Pharm Toxicol 2010). Improved efficacy is also seen when drugs are given near their respective times of best tolerability. Both experimental and clinical data thus support a unique paradigm for cancer therapy: “the lesser the toxicity, the better the efficacy” (Innominato et al. 2011; Ortiz‐Tudela et al. 2013).

Stochastic and deterministic mathematical models are addressing the three‐way interactions between circadian clocks, cell cycle and drug pharmacodynamics at single cell or cell population levels, while integrative models address the issues of therapeutic optimization at whole body level. Several data‐based chronotherapeutic models not only confirm experimental and clinical chronopharmacology data, but also allow the exploration of many sources of variability, that would otherwise remain hidden (Altinok et al. ADDR 2007, Eur J Pharm Sci 2009; Clairambault 2010; Bernard et al. Plos Comput Biol 2010; Ballesta et al. Plos Comput Biol 2011; Lévi et al. In: Systems Cancer Medicine, 2012; Billy et al. Math Comp Simul 2013). Such “systems chronopharmacology” reveal that optimal cancer chronotherapeutics require circadian entrainment to be robust in healthy cells and weak or disrupted in cancer cells. Indeed host clocks are disrupted whenever anticancer drugs are wrongly dosed or timed (Ahowesso et al. Chronobiology Int 2011). Circadian disruption is deleterious for cancer control, since it accelerates experimental and clinical cancer progression (Filipski et al. JNCI 2002; 2005; Innominato et al Cancer Res 2009) as well as cancerogenesis itself (Filipski et al. Mut Res 2009; Mteyrek et al. In preparation). Experimental and clinical evidence, including a meta‐analysis, further show that female patients displayed more toxicities than males, and could be more prone to treatment‐ induced circadian disruption (Giacchetti et al. JCO 2006, Ann Oncol 2012; Lévi et al. ADDR 2007). In turn circadian disruption appeared as a deleterious effect of wrongly dosed or timed chemotherapy, that predicted for poor quality of life and poor survival (Innominato et al. 2012; Cancer 2013). Moreover a fixed schedule of chronotherapy with oxaliplatin‐5‐fluorouracil‐ leucovorin increased overall survival in men, but not in women with metastatic colorectal cancer in three randomized international trials (Giacchetti et al. Ann Oncol 2012). In this respect, recent experimental systems chronotherapeutics investigation has identified the circadian transcription patterns of clock genes Rev‐erbα and Bmal1 as predictors of optimal internal timing of the anticancer drug irinotecan, despite it ranged over an 8‐h span among 6 mouse categories (Li et al. Submitted).

Therefore non invasive circadian biomarkers such as rest‐activity, temperature and position (Scully et al. Interface Focus 2011; Costa et al. Biostatistics 2013 ; Ortiz‐Tudela et al. Submitted; Roche et al. Submitted) are critical for the modeling of individual patient CTS dynamics in order to personalize timing, amplitude and schedule of chronomodulated drug delivery.

Support: C5SYS project (ANR and ERASysBio+ initiative, an EU ERA‐NET in FP7); CaSYM (FP7) and ARTBC, Hospital P Brousse, Villejuif (France).

Biography:

Francis Lévi received his medical doctorate degree at the University of Paris in 1976. Between 1978 and 1981, he performed postdoctoral research at M.D. Anderson Hospital and Tumor Institute in Houston, then at Chronobiology Laboratories and at the University of Minnesota (Minneapolis) in the USA. He graduated as a Ph.D. in Pharmacology at the University of Paris VI in 1982. He is currently a Research Director at the CNRS. He concurrently developed his research on cancer chronotherapeutics at Paul Brousse hospital, in Villejuif (France) and specialized in medical oncology in 1993. He was visiting professor at Sun Yat Sen University (Guang‐zhou, China). He is active in many scientific societies, and President Elect of the French Society for Chronobiology.

Dr Lévi is a founding member of the National Academy of Technology of France, and a foreign fellow of the National Academy of Science of India. He has lead the team from the French Institute of Health and Medical Research (INSERM) "Biological Rhythms and Cancers" (UMRS776) since 2001. His research unit performs basic, theoretical and clinical research in circadian biology and develops daily applications of research findings to cancer treatment and cancer patient management. He has demonstrated the circadian time dependency of the therapeutic index of anticancer agents in experimental models and identified the rhythms in cell detoxification, proliferation, metabolism and DNA repair as main determinants. The chronotherapeutic concepts led him to pioneer and lead the development of oxaliplatin at preclinical, Phase I, II and III levels. This drug is now the main drug to treat colorectal cancer worldwide. Dr Lévi has been the main investigator of nearly 30 clinical trials, including large international Phase III studies, which he had the initiative of.

Current research focuses on the interactions between the circadian timing system, the cell cycle and drug metabolism and detoxification, and their implications for improving cancer therapy and health‐related quality of life. These ongoing research projects involve cell cultures and mouse models, in silico models and translational and clinical studies, as well as dedicated technology developments.

His collaborative research projects are supported by the European Union in the Systems Biology and Medicine and the e‐health areas (FP7, ERASYSBIO+), the National Agency for Research of France (circadian and cancer biomarkers), the Ile de France and Champagne‐ Ardenne Regions and the French State, and the International Association for Research on Biological Time and Chronotherapy (ARTBC International). This international cooperative group investigates the relevance of biological rhythms for cancer medicine. Dr Lévi is currently the main investigator of OPTILIV, the first European trial of hepatic artery infusions against colorectal cancer metastases (NCT00852228), which he designed in partnership with Merck‐Serono and Pfizer. He has been coordinating or a steering committee member of 5 European projects since 2004 (FP6 or FP7). He has been further coordinating the Domomedicine task force of the National Academy of Technologies of France for the past 6 years.

Dr Lévi has published more than 332 scientific articles in international journals, such as Lancet, British Medical Journal, Nature Medicine, Annual Reviews of Pharmacology and Toxicology, Journal of Clinical Investigation, Journal of Clinical Oncology, Journal of the National Cancer Institute, Cancer Research, Clinical Cancer Research, Annals of Oncology, International Journal of Cancer, Cancer, British Journal of Cancer, Clinical Pharmacology and Therapeutics, PLOS Computational Biology, PLOS One, and Chronobiology international.

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