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EuroCSC<br />
Targeting <strong>Cancer</strong> Stem Cells for Therapy<br />
Summary<br />
<strong>Cancer</strong> remains one of the leading causes of death in the<br />
western world and, while chemotherapy has provided<br />
a major improvement in survival for a wide array of malignant<br />
diseases, lethality remains high in most cancers and<br />
side-eff ects are severe, including developmental impairment<br />
when used in childhood malignancies, infertility as well as<br />
damage to non-malignant tissues with resulting diminished<br />
quality of life for a large proportion of survivors.<br />
Recently, the realisation that several tumour types contain<br />
rare populations of cancer stem cells (CSCs) which are capable<br />
of reforming the tumour upon transplantation while their<br />
progeny are not, have opened the possibility of using CSCs<br />
as targets for directed molecular therapies that could lead to<br />
improved tumour eradication, as well as reduced side-eff ects<br />
of treatment.<br />
The goal of the present project is to perform a thorough<br />
characterisation of AML, cALL and breast cancer CSCs, as<br />
well as a systematic comparison of these with their normal<br />
stem cell and progenitor counterparts, using gene profi ling<br />
to identify putative molecular targets in CSCs. In parallel, we<br />
will use mouse genetic modelling to obtain information<br />
about genes regulated by oncogenic changes in stem and<br />
progenitor cell populations. Directly oncoprotein-regulated<br />
CSC targets will be validated in vitro and, where relevant,<br />
in vivo. The fi nal outcome will be identifi cation of the nature<br />
and hierarchical position of CSCs in three major cancers, and<br />
a set of identifi ed and validated CSC molecular targets with<br />
activity against the eff ects of leukemogenic oncoproteins on<br />
hematopoietic stem cell/progenitor populations.<br />
38<br />
Keywords | <strong>Cancer</strong> | stem cells | leukaemia | breast cancer |<br />
Problem<br />
Human tumours are currently treated primarily with drugs<br />
with cytotoxic eff ects against proliferating cells. This therapy<br />
is effi cient against cells with the properties of rapidly proliferating<br />
progenitors. However, the realisation that many<br />
tumour types contain malignant cells with stem cell properties,<br />
in that they are able to initiate and sustain a tumour but<br />
proliferate infrequently, provides a potential explanation for<br />
the ability of many tumours to recur even after the eradication<br />
of the bulk tumour mass. The ability to identify and<br />
pharmacologically target these cancer stem cells would signifi<br />
cantly enhance the effi cacy and reduce the side-eff ects<br />
of cancer therapy.<br />
Aim<br />
We will use functional analysis and gene profi ling of purifi ed<br />
human cancer stem cells and genetic modelling in the mouse<br />
to identify molecular targets that may be used to selectively<br />
eradicate or inactivate the malignant stem cells that sustain<br />
tumours. These targets will be validated by knockdown and<br />
genetic ablation in mouse model systems. Finally, we will<br />
initiate the identifi cation of lead compounds with activity<br />
against these targets.<br />
Expected results<br />
We expect to identify and validate target molecules with<br />
activity against cancer stem cells in AML, call and breast<br />
carcinoma.<br />
Potential applications<br />
These results are directly applicable to the development of<br />
drugs targeting human cancer stem cells.<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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