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Keywords | Tumour cell dissemination | micrometastases | minimal disease | biobanking | genomic profi ling |<br />
microarray analysis | circulating nucleic acids | bioinformatical synopsis |<br />
DISMAL<br />
Molecular Signatures as Diagnostic<br />
and Therapeutic Targets for<br />
Disseminated Epithelial Malignancies<br />
Summary<br />
Disseminated tumour cells (DTC) occur at very low numbers<br />
in the blood and particularly in the bone marrow, and<br />
can be detected using sensitive immunostaining and PCR<br />
methods. However, the sensitivity and specifi city of this<br />
approach need to be improved. Combining the expertise of<br />
11 academic partners with long-term expertise in micrometastasis<br />
research, the DISMAL project will establish an<br />
improved platform for DTC detection with an increased<br />
sensitivity and, in particular, with a greatly improved specificity.<br />
Besides DTC detection, the combination with analysis<br />
of circulating tumour DNA and RNA as well as the expression<br />
profi ling of tumours are being explored to improve the<br />
assessment of minimal disease. We will focus on epithelial<br />
tumours, as they are the most common types of solid<br />
tumours in the EU, investigating the carcinoma types that<br />
display diff erent modes of metastatic spread. Dissemination<br />
via the blood circulation will be analysed using bone<br />
marrow as this is the most important indicator organ epithelial<br />
tumour cells home in on. Using genomic-based<br />
approaches, novel diagnostic target molecules will be identifi<br />
ed on these cells and validated in functional models. We<br />
will complement immunocytochemical DTC detection by<br />
additional genotypic and phenotypic markers relevant for<br />
metastatic progression. To further increase diagnostic precision,<br />
we will analyse whether this improved platform can<br />
be combined with the analysis of tumour characteristics<br />
that were revealed by microarray profi ling, and with evaluation<br />
of circulating tumour-associated DNA or RNA.<br />
Besides the primary focus on improvement of DTC-based<br />
diagnostic platforms, it is important to realise that these<br />
cells are the target cells for any kind of adjuvant systemic<br />
therapy, including chemotherapy and targeted biological<br />
therapies. In innovative DTC models, the effi cacy of<br />
DTC treatment will therefore be analysed and potential<br />
improvements studied. The translation of scientifi c knowledge<br />
into commercial products will be ensured by three<br />
SMEs with unique technological capabilities.<br />
EARLY DETECTION, DIAGNOSIS AND PROGNOSIS<br />
Problem<br />
Investigations during the last decades have shown that the<br />
metastatic cascade is a complex pathobiological process<br />
and highly dependent on the type of tumour. Some tumours,<br />
such as breast cancers, have a proclivity for parallel dissemination<br />
to the haematogenous and lymphatic compartment,<br />
starting in the earliest phases of tumour development.<br />
In other tumour types, such as in head and neck cancer,<br />
this pattern is very diff erent and haematogeneous dissemination<br />
appears to result from metastases in the lymphatic<br />
compartment. For these reasons we selected three tumour<br />
types: one as an extreme example of parallel, independent<br />
dissemination (breast cancer), one as an extreme example<br />
of sequential dissemination (head and neck cancer), and<br />
one intermediate type (colorectal cancer).<br />
Aim<br />
The main objective of the DISMAL-project is to improve the<br />
specifi city and sensitivity of current platforms for DTC<br />
detection in patients with epithelial tumours, the predominant<br />
form of cancer in Europe, whilst also identifying novel<br />
markers at the DNA, RNA or protein level that allows a more<br />
precise detection of DTC with a high risk for metastatic<br />
progression.<br />
The programme will focus on markers associated with haematogenous<br />
dissemination (using bone marrow as the most<br />
well defi ned indicator organ) because these markers have<br />
the potential to become novel targets, not only for diagnostic<br />
purposes but also for therapeutic interventions. The<br />
markers functionally associated with metastatic progression<br />
of DTC are likely to be promising targets for therapy. These<br />
specifi c markers could be further developed as therapeutic<br />
targets in collaboration with SMEs and larger pharmaceutical<br />
industries.<br />
With regard to cancer therapy, two key issues will be<br />
addressed. First, it will be evaluated whether it is possible to<br />
eradicate DTC by an immunotherapeutic approach, optimised<br />
for success in a mouse model. Secondly, we will<br />
investigate whether DTC are susceptible to current systemic<br />
therapies (for example chemotherapy) and develop novel<br />
approaches for their specifi c eradication. Current adjuvant<br />
chemo- or radiation therapy aims at hitting the most overt<br />
property of tumour cells their unrestricted potential to<br />
proliferate. According to our current knowledge, DTC in the<br />
bone marrow are non- or slowly proliferating.<br />
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