Download mol cancer med

MOL CANCER MED
Developing molecular medicines
for cancer in the post-genome era
Keywords
Therapy, genome, telomerase,
diagnosis, drugs
Summary
(A) Normal human skin
(B) organotypic culture of the immortal HaCat skin keratinocytes
The cellular immortality enzyme telomerase (one
Both are co-stained with an antibody against hTERT (red nuclear staining) and an antibody decorating the
of the most promising universal cancer markers)
basement membrane (green staining). All nuclei are counterstained with DAPI (in blue)
and associated telomere maintenance mechanisms represent novel anti-cancer targets of
enormous therapeutic and diagnostic potential. In
MOL CANCER MED, a multinational EU translational cancer research MOL CANCER MED is focused on a single group of highly promising
consortium has been established, in which expert cancer geneticists anti-cancer targets associated with telomerase and telomere mainand molecular biologists will interact with prominent pharmacologists, tenance. Repression of telomerase in the somatic tissues of humans,
clinicians and pathologists to develop these exciting new cellular targets and probably other long-lived mammals, appears to have evolved as
into measurable pre-clinical advances, within a four-year time-frame.
a powerful protective barrier against cancer. Immortalisation in vitro
of normal human cells that lack telomerase involves the reactivation
The project has been structured into three, highly interactive areas of telomerase or, rarely, an alternative (ALT) mechanism for maintainof activity, involving the fundamental evaluation and pre-clinical valida- ing telomeres. It is clear that telomerase is obligatory for continuous
tion of: (i) telomerase as a target for cancer treatment and diagnosis tumour cell proliferation, clonal evolution and malignant progression.
based on new molecular knowledge about its expression and func- Because telomerase is found in around 90% of human cancers and is
tion, (ii) associated downstream telomere maintenance mechanisms as essential for the continued proliferation (and clonal evolution) of canadditional targets for novel drug design, and (iii) new anti-cancer drugs cer cells, it represents one of the most exciting anti-cancer targets thus
based on these targets. The consortium will bring to bear diverse and far discovered. Results with a variety of telomerase inhibitory strategies
complementary technological know-how of considerable power to in human cancer cells have confirmed that its functional inactivation
deliver the above primary objectives. Effective management will maxi- results in progressive telomere shortening, leading to growth arrest
mise synergies across MOL CANCER MED in order to produce genu- and/or cell death through apoptosis. Promising candidate small moline improvements in the design of new treatments that promise to be ecule inhibitors are beginning to emerge that will form the basis for
active against a broad spectrum of common human malignancies.
anti-telomerase drug development. MOL CANCER MED is based on
successful Framework 5 research concerned with establishing the value
of the cellular immortality enzyme telomerase as an anti-cancer target
(Project: QLG-1999-01341; TACIT) and represents an expansion and
Problem
elaboration of this. TACIT yielded results that have triggered new transCancer is a leading cause of death in the western world, second only to lational research with clearly defined clinical applications. To this set of
cardiovascular disease, and is therefore a European public health prob- activities have been added carefully selected new EU research teams,
lem of overwhelming human and economic significance. The incidence notably in the area of drug development.
of cancer is set to increase substantially with demographic and possibly environmental influences playing a part. However, there is now an
improved molecular understanding of the key genetic, biochemical and
cellular changes leading to cancer, in significant part due to the efforts
of diverse groups of world-class EU-based scientists. With the completion of the human genome sequence imminent, it is now timely to
initiate a major European coordinated effort to translate fundamental
scientific knowledge about cancer into safer, more effective, therapies
and improved early diagnostic procedures.
Cancer research
138
Aim
Expected results
1. Novel anti-cancer drug targets and diagnostic methodologies derived
from advances in: (i) the understanding and definition of biochemical
response pathways underpinning the telomere checkpoint for somatic
cell proliferation, (ii) the identification and molecular/functional characterisation of natural mechanisms of telomerase repression and
cell self-renewal (including hTERT repressor genes and chromatin
remodelling factors) in normal human cells and their dysregulation
in human cancers, and (iii) understanding the mechanisms of action
and pharmacological activity of existing small molecule telomerase
inhibitors (eg BIBR1532), and (iv) establishment of the precise roles
of telomere aggregates and telomere-length-independent functions
of telomerase in human cancer.
2. An advanced molecular understanding of telomerase regulation at
chromosome ends (eg involving the key telomere-binding proteins
POT1 and hEST1A) and a comprehensive evaluation of such proteins as anti-telomerase drug targets
3. New and effective molecular inhibitors (eg siRNAs, ribozymes and
peptide nucleic acids) of telomerase and telomere maintenance
(targeting hTERT transcription and telomere-related proteins discovered within the MOL CANCER MED consortium) for the
purpose of vasli.
4. Panels of new molecular markers of telomerase repression, telomere maintenance and associated signalling pathways, that can be
developed into precise, rapid assays for use in novel ‘kits’ for early
cancer diagnosis and prognostic evaluation.
5. An understanding of the differential effects of telomerase/telomere
maintenance inhibition on normal human tissues and in cancers
using organotypic in vitro human cell models.
Human telomeres
6. Rational design of libraries of novel small molecule compounds for
screening against new targets, and selection of small molecule antitelomerase/telomere maintenance drug leads active against individual
new targets discovered during the course of MOL CANCER MED.
7. Identification of potential anti-cancer drugs from the above, following biochemical, pharmacological and functional (in vitro and in vivo)
anti-tumour assays.
8. Preclinical exploitation of potential novel cancer drugs through
interface with clinical oncology centres and SMEs.
Translating
The principal aim of MOL CANCER MED is to fully exploit the
results of recent fundamental advances in understanding the role of
telomerase and telomere maintenance mechanisms in human cancer development, in order to achieve genuine clinical benefit (i.e. in
developing both improved diagnostics and anti-cancer therapies). The
principal measurable objectives of the project, over the complete 48
month period, are: (i) to validate further the potential of telomerase
and telomere maintenance systems in cancer therapy and diagnosis,
(ii) to identify novel molecular targets based on telomere structure,
function & stability, that may be of value in treatment and diagnosis of
the common human cancers, (iii) to create a programme of novel small
molecule drug development based initially on recently identified (but
thus far poorly exploited) targets and, later (from month 12 onwards)
exploiting completely new targets identified during the project.
Potential applications
The emphasis of the LIFESCIHEALTH Priority is very firmly placed
upon multidisciplinary translational research, in which fundamental scientific knowledge is harnessed for the specific purpose of generating,
within the timeframe of FP6, reagents, treatments and diagnostics that
are of clinical value. In MOL CANCER MED, a highly focused strategy
will be adopted towards applying molecular genetic knowledge about
the mechanisms underlying the cancer process to the development of
completely new approaches to cancer treatment, eg in bringing molecular biology, cell biology, genomics and target evaluation together with
small molecule drug discovery.
Project website: www.brunel.ac.uk/research/molcancermed/
Acronym: MOL CANCER MED
Project number: LSHC-CT-2004-502943
EC contribution: € 4 000 000
Duration: 48 months
Starting date: 01/10/04
Instrument: IP
Projects funded under the
Sixth Framework Programme
139
Coordinator
Robert Newbold
Brunel University
Uxbridge, United Kingdom
E-mail: [email protected]
Partners
Stephen Neidle
London School of Pharmacy
London, United Kingdom
Jean-Louis Mergny
INSERM
Paris, France
John Mann
Queens University Belfast
Belfast, United Kingdom
Maurizio D’Incalci
Istituto de Richerche Mario Negri
Milan, Italy
Joachim Lingner
ISREC
Epalinges, Switzerland
Kenneth Parkinson
University of Glasgow
Glasgow, United Kingdom
Uwe Martens
Medical University Center Freiburg
Freiburg, Germany
Petra Boukamp
DKFZ
Heidelberg, Germany
Maria Blasco
CNIO
Madrid, Spain
Keith Nicol
University of Glasgow
Glasgow, United Kingdom
Cancer research
140
Nadia Zaffaroni
National Cancer Institute
Milan, Italy
Nedime Serakinci
University of Aarhus
Aarhus, Denmark
Goran Roos
Umeå University
Umeå, Sweden