Cancer remains one of the leading causes of death in the Western world, and while chemotherapy has provided a major improvement in survival for a wide array of malignant diseases lethality remains high in most cancers and side-effects are severe, and include developmental impairment, when used in childhood malignancies, infertility as well as damage to non-malignant tissues with resulting diminished quality of life for a large proportion of survivors.
Recently, the realization that several tumour types contain rare populations of cancer stem cells (CSCs), which are capable of reforming the tumour upon transplantation while their progeny are not, have opened the possibility of using CSCs as targets for directed molecular therapies that could lead to improved tumour eradication as well as reduced side effects of treatment. The goal of the present project is to perform a thorough characterization of AML, cALL and breast cancer CSCs, as well as a systematic comparison of these with their normal stem cell and progenitor counterparts using gene profiling, to identify putative molecular targets in CSCs.
In parallel, we will use mouse genetic modelling to obtain information about genes regulated by oncogenic changes in stem- and progenitor cell populations. Directly oncoprotein-regulated CSC targets will be validated in vitro and, where relevant, in vivo. Finally, we will screen small molecule libraries for compounds that antagonize leukemogenic oncoproteins in efficient zebrafish models. These compounds will be tested for activity in mammalian assays, screened against the putative targets identified by gene profiling, and used to affinity-purify additional interacting proteins.
The final outcome will be a set of identified and validated CSC molecular targets, and a corresponding collection of small molecule inhibitors with activity against the effects of leukemogenic oncoproteins on hematopoietic stem cell/progenitor populations.
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