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Keywords | Circadian | clocks | cell cycle | cancer | chronotherapeutics | drug delivery | dynamic models |<br />
personalized medicine | chronobiology | pharmacology | anticancer drugs | topoisomerase | cyclin dependent kinases |<br />
mouse | patients | transcriptome | proteome | phenome | drug development | systems biology |<br />
TEMPO<br />
Temporal genomics for<br />
tailored chronotherapeutics<br />
Summary<br />
Chronic diseases account for 75 % of the disability-adjusted<br />
years in Europe and cause the premature death of 17 million<br />
people worldwide. Diff erences in aetiology as well as patient<br />
genetic origin, gender, age, lifestyle and biological time<br />
structure account for large variability in individual time<br />
courses of the same disease entity. Patient-tailored therapeutics<br />
is needed to prevent adverse events and improve<br />
overall therapeutic activity.<br />
Rather than using pharmacogenomics for excluding patients<br />
from an active treatment option, TEMPO will combine functional<br />
genomics, proteomics, cell signalling, systems biology<br />
and pharmacokinetics to optimize therapeutic index in<br />
most individual patients. Thus TEMPO will determine 3 to<br />
5 chronotherapeutics schedules with distinct temporal<br />
delivery patterns of the same anticancer drug. Each schedule<br />
is adjusted to a diff erent dynamic class of temporal<br />
genomics and phenomics parameters related to interwoven<br />
circadian and cell division cycles and drug metabolism.<br />
In vivo, in vitro and in silico approaches are integrated<br />
through the multidisciplinary excellence in the consortium.<br />
TEMPO will off er a proof of principle of tailored chronotherapeutics<br />
in mouse models for irinotecan, an active drug<br />
against colorectal cancers, and for seliciclib, currently in<br />
clinical testing. TEMPO will gather the corresponding human<br />
prerequisites and technology for subsequent application to<br />
patients.<br />
Three SMEs play a pivotal role for the impact of TEMPO on<br />
European health, economics and society. Novel and complementary<br />
in silico dynamic models of coordinated clock,<br />
cell cycle and pharmacology pathways will identify new<br />
therapeutic targets and delivery schedules of active molecules,<br />
thus improve drug development processes. New tools<br />
will enable personalized medicine to integrate the time<br />
dimension in routine implementation.<br />
TEMPO will reduce both therapeutic variability and attrition<br />
rates two major impediments for human health and pharmaceutical<br />
industries. However time can diff er between<br />
individuals as a result of genetic polymorphism and lifestyle<br />
diff erences. These determinants can then result in distinct<br />
optimal delivery patterns of cancer medication.<br />
TREATMENT<br />
Problem<br />
Non communicable chronic diseases represent the bulk of<br />
morbidity, disability and premature deaths in Europe and<br />
account for 75 % of the disability-adjusted life years. Among<br />
these, cancer represents the second cause of morbidity and<br />
mortality worldwide. Diff erences in the molecular characteristics<br />
of the tumor cells as well as diff erences in patient<br />
genetic origin, gender, age, lifestyle and circadian rhythms<br />
account for large variability in the time courses of cancer<br />
diseases and treatment response.<br />
TEMPO addresses the control of several key dynamic pathways<br />
in cancer drug metabolism and cellular proliferation by<br />
the circadian timing system. This biological system consists<br />
of a network of molecular clocks that times bodily and cellular<br />
functions along the 24 hours. Chronotherapeutics aim<br />
at the delivery of medications according to the 24-hour<br />
rhythms generated by the patient’s molecular clocks in<br />
order both to prevent adverse events and to improve overall<br />
therapeutic activity.<br />
Aim<br />
The general objective of TEMPO is to design mouse and in<br />
silico models refl ecting diff erent dynamic classes that predict<br />
for distinct optimal chronotherapeutic delivery patterns<br />
of anticancer drugs.<br />
Dynamic classes result from the identifi cation of the most<br />
discriminant parameters refl ecting cell cycle, pharmacology<br />
and physiology determinants that are controlled by the circadian<br />
clock thus impact on the temporal pattern in drug<br />
cytotoxicity. Optimal chronotherapeutic schedule can diff er<br />
in mice from diff erent strains or housed in diff erent environmental<br />
conditions as well as in cancer patients with diff erent<br />
gender and circadian timing status. TEMPO will provide<br />
a classifi cation based on functional genomics, proteomics<br />
and phenomics markers to be selected and validated along<br />
the development of the project.<br />
TEMPO will off er a proof of concept of tailored chronotherapeutics<br />
with a topoisomerase I inhibitor, and, a cyclin-dependent<br />
kinase inhibitor.<br />
The clinical relevance of the dynamic classes established in<br />
mice and in silico will be continuously reassessed along the<br />
development of the project, so as to also identify their counterpart<br />
in patients with corresponding specifi cation of optimal<br />
treatment delivery profi les.<br />
Primary emphasis will be put on the applications of TEMPO<br />
fi ndings to colorectal cancer. This disease aff ects 300 000<br />
new persons in Europe each year and constitutes the second<br />
cause of deaths from cancer in both sexes.<br />
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