Identifying and characterizing novel inhibitors of ETS transcription factors

The fundamental challenge of cancer research is the discovery of new treatments that eliminate tumours, are minimally toxic and are not susceptible to acquired resistance. The failure of many current approaches stems from acquired resistance by tumour cells resulting from intra-tumour heterogeneity and intrinsic redundancies of signal transduction pathways such that a functioning pathway compensates for the loss of activity of the inhibited/targeted pathway enabling the tumour to escape the effects of the treatment. To overcome this, rather than targeting the upstream components of cell signaling networks (presumed to be druggable), during recent years we developed methodologies for the identification of small molecule inhibitors of transcription factors downstream of these pathways, which were previously regarded as ‘undruggable’ but which ultimately drive the illicit behaviours of tumour cells. ETS transcription factors sit downstream of the central RAF-RAS-MAP kinase pathway, which is indispensable for cell proliferation. Crucially, ETS factors are believed to play a causal role in the development and evolution of the majority of tumour types through chromosomal translocations (e.g. prostate cancer, leukaemia, Ewing’s sarcoma), over expression or aberrant activation (e.g. melanoma, pancreatic cancer). They are also essential for blood vessel sprouting which drives tumour angiogenesis. Targeting ETS factors could therefore represent a ‘kill two birds with one stone’ approach to inhibiting tumour growth. We perform high throughput small molecule screens to identify novel inhibitors of these transcription factors. This approach has yielded unique inhibitors, which will be tested in mouse and zebrafish animal models. State-of-the-art chemical technologies will also be employed to discover new inhibitors (in collaboration with Professor Huib Ovaa).  

Molecular mechanisms governing tissue development

All tissue development and replenishment relies upon the breaking of symmetries i.e. the morphological and operational differentiation of progenitor/stem cells into more specialized cells. One of the main engines driving this process is the Notch signaling pathway. Notch signaling is a ubiquitous signal transduction pathway found in most if not all metazoan cell types characterized to date. It is indispensable for cell differentiation as well as tissue growth, tissue remodeling and apoptosis. Although the canonical Notch signaling pathway is well characterized, accumulating evidence points to the existence of multiple, less well-defined, layers of regulation. By using sprouting angiogenesis (blood vessel formation) as a model system, the aim of our research is to uncover novel dimensions of this pathway, specifically how receptor/ligand interactions and ligand processing determines the strength, the direction and the specificity of the Notch signaling pathway. For this, we combine biochemical and cell-based assays with mathematical modeling (in collaboration with Professor Roeland Merks, Leiden Institute of Mathematics).

In addition to being absolutely necessary for normal development and tissue homeostasis, corruption of Notch signaling has been implicated in numerous diseases including the majority of solid tumors and neurodegenerative disorders such as CADASIL. We will explore how aberrant Notch signaling contributes to cancer and in collaboration with the CADASIL group headed by Dr Saskia Oberstein (Clinical Genetics) and Dr Thom Sharp, we will investigate the molecular basis of Notch receptor mutations underpinning this disease.


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