Cancer Research - Europa

EPITRON
Epigenetic treatment
of neoplastic disease
34
Summary
Chromatin is epigenetically modifi ed to regulate gene
expression. Upstream signals induce complex patterns of
enzyme-catalysed modifi cations of DNA and histones,
key protein components of chromatin. These epigenetic
modifi cations create docking sites and form a code that
specifi es transient or permanent (and heritable) patterns
of genome function. In addition, epigenetic enzymes
modify the activity of major transcription factors. Emerging
evidence causally links altered epigenetic functions
to oncogenesis, and suggests that chromatin regulators
and upstream pathways are critical targets for developing
novel anti-cancer drugs (epi-drugs). EPITRON will
defi ne and validate the concept of ‘epigenetic cancer
treatment’ from the molecular mechanism(s) to animal
models reproducing human cancers. EPITRON will establish
a programme from drug target exploration and drug
development to preclinical validation in vitro, ex vivo and
in vivo. Epi-drugs are amongst the most important novel
drugs that have been generated to treat cancer, as can be
concluded already from the existing results obtained with
HDACi’s, some of which performed very well in phase I
and phase II clinical trials. EPITRON is unique in its eff orts
to strengthen European biomedical and pharmaceutical
competitiveness. It fosters an exchange of biomedical
knowledge, technology and materials among European
laboratories, provides opportunities for education and
training – and creates jobs.
Problem
Keywords | Epigenetic | apoptosis | diff erentiation |
Elucidating the ‘signatures’ of cancer cells is one of the four
so-called ‘extraordinary opportunities for immediate investment’
defi ned by the National Cancer Institute of the United
States of America. These four priorities (defi ning the signatures
of cancer cells, cancer genetics, preclinical models of
cancer and imaging technologies) were selected as top priorities
to receive privileged attention and funding. Thus the
EPITRON project aims to contribute at multiple levels to the
defi nition of epigenetic signatures of cancer.
Aim
The overall goal of EPITRON is to validate and extend the
concept of ‘epigenetic therapy’ of cancer. For this a pipeline
will be established, which extends from the analysis of epigenetic
(de)regulation in cancer to the study and generation
of epi-drugs in a multiplicity of in vitro, ex vivo and in vivo
mouse models. We will develop and use mouse models that
accurately reproduce the human disease. The particular
goals of EPITRON are:
• to study the epigenetics of cancer cells (with a focus on
leukaemia, breast and colon cancer), and defi ne the
mechanisms of (cancer selective) action of epi-drugs;
• to establish the basis of the cancer-selectivity of TRAIL/
TRAIL receptor action;
• to identify novel epi-drug targets;
• to synthesise novel epi-drugs with increased effi cacy/
tumour selectivity;
• to validate epi-drug target therapy of cancer in vitro
(primary normal and tumour cells), ex vivo (leukaemic
blasts vs. normal progenitors) and in vivo (mouse models
which accurately reproduce human cancer; the focus
will be on APL/AML but also solid cancer models will be
used or established).
Taken together, EPITRON will not only provide information
about epigenetic modifi cation imposed upon cancer cells,
validate existing and generate novel epi-drugs, but most
importantly engage upon a major challenge of cancer therapy
by devising treatments that kill cancer, but not normal cells.
Expected results
To validate and extend the concept of ‘epigenetic cancer
therapy’, EPITRON will follow six axes of research, focused
on preclinical models.
• Mechanisms of anti-leukaemic action of epigenetic
drugs. We will defi ne the anti-leukaemogenic potential
and the corresponding mechanistic basis of existing epigenetic
drugs used alone or in combination, and in
combination with other signalling drugs, such as nuclear
receptor ligands. The impact of chromatin modifi cation
(DNA, histones) that correlates with tumourigenesis and
underlying recognition principles will be studied.
• Oncofusion genetic and epigenetic programmes. We will
use cell lines, patients’ blasts and mouse models to
understand the altered gene programming due to the
oncogenic fusion protein(s).
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME