LEaDing Fellows
LEaDing FellowsThe ‘LEaDing Fellows Postdoc Programme’ is a Horizon2020 Marie Skłodowska-Curie COFUND programme and will provide 90 researchers from all over the world who recently obtained a PhD, with the opportunity to gain two years of work experience. These positions are available in the challenging, internationally acclaimed and multidisciplinary environment offered by Leiden University, Leiden University Medical Center, Erasmus University Rotterdam, Erasmus Medical Center and Delft University of Technology.
The aim is to provide opportunities for international, intersectoral and interdisciplinary research training, as well as transnational and cross-sectoral mobility, by offering open recruitment and attractive working conditions. Three calls with fixed deadlines will be opened, accommodating first 20, then 40 and finally 30 fellows. Applicants can propose a project of their own choice, including a research proposal, career development plan, motivation letter, CV and support statement of his/her proposed supervisor in one of the universities or university medical centers of the program.
A selection of LUMC research groups that are interested to host a LEading Fellows postdoc are presented below. In addition, this website provides information for applicants about LUMC training and courses, strategic research collaborations and the 7 medical research profiles of LUMC. For more details about the LEaDing Fellows Postdocs Programme (including the call), please visit the LEaDing Fellows website.
Contact
LEaDing Fellows local contact point at LUMC: Pieter de Koning (Directorate of Research)
A selection of LUMC research groups that are interested to host a LEaDing Fellows postdoc:
- Uncovering dynamic small ubiquitin-like modifier signalling networks
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Functional activity of proteins is tightly controlled via reversible post-translational modifications including phosphorylation, acetylation and ubiquitylation. These modifications enable the orchestration of cellular responses to a wide variety of stimuli.
Small Ubiquitin-like Modifiers (SUMOs) are post-translational modifiers, which are essential for eukaryotic viability. We are interested in system-wide understanding of dynamic SUMO signal transduction. Our ERC-sponsored project is revealing at least 1,600 SUMO target proteins and over 4,300 exact SUMO acceptor sites. We demonstrate that SUMOylation plays a role in all nuclear processes, including transcription, chromatin remodelling, pre-mRNA splicing, DNA repair and ribosome assembly. Currently, we are uncovering system-wide dynamic SUMO signalling networks.
Our studies are detecting exciting novel SUMO target proteins relevant for genome stability and for cell cycle progression, which we are functionally characterizing by generating SUMOylation impaired mutants. We compare these mutants to wild-type proteins to study the functional relevance of SUMOylation, employing biochemistry, cell biology, genetics and mass spectrometry. Local embedding includes the research groups of Sjaak Neefjes, Huib Ovaa, Peter ten Dijke and Haico van Attikum, providing a highly stimulating and cooperative research environment.
Principle Investigator: Alfred Vertegaal (Dept. of Molecular Cell Biology)
Website - Immunogenetics and cellular immunology of bacterial infectious diseases
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Our scientific mission is to dissect immunological and host-genetic mechanisms of protective and pathologic immunity to mycobacterial infections and related infectious diseases, in order to design more effective intervention strategies (vaccines, treatments, diagnostics). We have established a research programme in the field of human immunology, cell biology and immunogenetics of mycobacterial infectious diseases. Amongst some of our scientific contributions are the discovery of the first specific antigens for mycobacterium reactive T-cells in humans; the identification of the first Thelper-1 cells in humans; the discovery of a new human immunodeficiency due to genetic mutations in the receptor for interleukin-12; the cloning of the first monoclonal T-regulatory cells in humans; involved in many human genetic studies that identified, with excellent collaborators, multiple new genetic variants impacting on risk of tuberculosis and leprosy; (together with prof. JJ Neefjes) the identification of a new human PKB/Akt1 controlled signaling pathway, that is manipulated by Salmonella and Mtb to inhibit phagosomal-lysosomal fusion. One current focus is on the role of T cell subsets (T-helper, T-regulatory), macrophage subsets, intracellular signaling networks, cellular function and systems biology. A related, translation-oriented focus is on Mtb antigen discovery, vaccine design and biomarker discovery. We also have executed several clinical phase I/IIa first in human trials with new TB vaccines, together with prof. Jaap van Dissel, including their immune monitoring. We participate and play prominent roles in many high profile international research consortia, which include partners from EU, US and developing countries in Asia, Africa and South America. Funding mostly comes from EC, BMGF, NL Leprosy Relief Foundation and other bodies.
Principle Investigator: Tom Ottenhoff (Dept. of Infection Diseases)
Website - Population epigenomics and integrative genomics of ageing and cardiovascular disease
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We are exploiting natural variation in the population to ask fundamental questions about genome biology and unravel disease mechanisms with a particular focus on ageing and cardiovascular disease. To this end, we analyse large-scale multiple omics data from population studies complemented with targeted in vitro experiments for further mechanistic insight. My group provides a stimulating environment to do science that is creative and of high-quality, and will offer you a great stepping stone for your further career. Please, contact me at bas.heijmans@lumc.nl if you wish to know more.
Potential projects include (but are not limited to!):- Dissecting the dysregulated genome as a driver of the ageing process
- Epigenetic priming of immune cells in atherosclerosis
- Epigenetic programming of foetal growth restricted identical twins
- Method development for the analysis and interpretation of population epigenomics data
Relevant recent publications (for full list see here): Van Iterson et al. Genome Biol 2017; Bonder et al. Nat Genet 2017; Slieker et al. Genome Biol 2016; Dekkers et al. Genome Biol 2016; Tobi et al. Nat Commun 2014; Mill et al. Nat Rev Genet 2013.
Principle Investigator: Bas Heijmans (Dept. of Molecular Epidemiology)
Website - Stem cells and gene therapy
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Our research is centered around the differentiation of blood-forming stem cells (hematopoietic stem cells, HSCs) to the major disease fighting white blood cells, the T-lymphocytes, both under normal and pathological conditions. This work is focused on three research lines:
- HSC biology, with focus on regulation of stemness, self-renewal and differentiation by the Wnt and Notch pathways. We study this in human, mouse and zebrafish models, with a translational application in HSC expansion via gene modified stromal cells.
- Development of T lymphocytes in the thymus and regulation of peripheral T cell function with emphasis on the role of Wnt signaling herein. The role of Wnt signaling in malignant T cell development (T-cell acute lymphoblastic leukemia, T-ALL) is studied as well.
- Development of gene therapy for various types of human Severe Combined Immunodeficiency (SCID) and other diseases that can be cured by HSC transplantation (thalassemia, lysosomal storage diseases). In SCID the normal differentiation process from HSC to T cell is disrupted due to genetic mutations in key molecules required for this process. We develop lentiviral, CRISPR/CAS and IPSC (induced pluripotent stem cell) approaches to cure SCID.
Principle Investigator: Frank Staal (Dept. of Immunohematology and Blood Transfusion)
Website - Signal transduction and chemical biology; identifying new targets and developing new therapeutics
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When communication between cells goes wrong this may lead to diseases. In our group we focus on how signaling by TGF-β family members is misregulated in cancer and other diseases. Gain and loss of function genetic screens have identified numerous leads for functional follow up analysis. In addition, we want to translate our mechanistic findings into innovative therapeutic application. Chemical biological approaches are employed in which synthetic molecules are analyzed for their capacity to specifically (in)activate signaling processes. Next to 3-dimensional cell culture systems that resemble in vivo structures, we use zebra fish and mouse models. We also have access to clinical samples to validate our preclinical discoveries. Specific projects in which LEaDing Fellows may participate:
- Targeting the TGF-β-induced oncogenic responses to inhibit cancer progression in patients
- Restoring deficient BMP receptor signalling in pulmonary arterial hypertension
- Restoring joint integrity in osteoarthritis by targeting age-related perturbations in TGF-β signalling.
Principle Investigator: Peter ten Dijke (Dept. of Molecular Cell Biology)
Website - Genome editing of human somatic cells
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Genome editing based on programmable nucleases is a fast-evolving field. Its goal is that of “rewriting”, in an efficient and targeted manner, the genetic information of living cells, including that of human cells. There are, however, several crucial aspects that require further research and refinement. These aspects include devising improved methods for delivering the large and complex genome editing tools into target cells and increasing the specificity and fidelity of genome editing procedures.
Our team’s main research interest is that of investigating new genome-editing strategies based on the delivery of programmable nucleases and exogenous DNA substrates into target cells with the purpose of improving the precision of gene editing after the activation of specific cellular DNA repair pathways. In particular, our team focuses on exploring delivery systems based on adenoviral vectors and lentiviral vectors as scaffolds on which to build various genome editing tools and donor DNA configurations to achieve targeted and high-fidelity gene correction in human cells. The genome editing strategies under investigation aim at repairing defective dystrophin-encoding alleles underlying Duchenne muscular dystrophy (DMD), a lethal X-linked muscle-wasting disorder. The insights gained from these research activities might be applicable to other gene-editing goals.
Principle Investigator: Manuel Gonçalves (Dept. of Molecular Cell Biology)
Website - Chemical biology of Ub and Ubl conjugation and deconjugation
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Research in the Ovaa lab aims at the development of tools to investigate biochemical processes in relation to disease with a focus on cancer and infection. The group plays a leading role in the development and application of novel techniques to profile cellular enzymatic activities associated primarily with ubiquitin and ubiquitin-like conjugation and deconjugation machineries. We combine biochemistry and cell biology with chemical synthesis in an interdisciplinary environment. Using the novel reagents, probes and small molecules that we develop we investigate ubiquitin and Ubl conjugation and deconjugation and their roles in cancer and infection.
The lab is located in the newly established department of Chemical Immunology at Leiden University Medical Center (LUMC) and is fully equipped for biochemistry and cell biology but also chemical synthesis. The lab houses multiple LC-MS(MS) machines, (MS-guided) purifiers, NMR, several scanners and also operates its own ultra-high troughput acoustic dispensing-based small molecule screening station able to test 100,000 drug like molecules a day easily. The LUMC is further equipped with state-of-the-art core facilities for mass spectrometry, flow cytometry and both light and electron microscopy and post translational modifications are a strong point of focus at the LUMC. An international team of young and motivated scientists works together in the Ovaa lab and the department of Chemical Immunology.
Principle Investigator: Huib Ovaa (Dept. of Chemical Immunology)
Website - Non-invasive biochemistry of brown adipose tissue
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The departments of Radiology and Medicine, div. Endocrinology, have an ongoing collaboration to develop novel technological platforms to measure biochemical properties of brown adipose tissue (BAT). The developed techniques will be used in the rapidly expanding number of clinical intervention studies intended to activate BAT to combat cardiometabolic diseases. BAT has recently been discovered as a major player in energy metabolism in humans, and its activation is widely believed to be of great potential in the treatment of cardiometabolic diseases. Current imaging techniques (such as PET and CT scans) used to evaluate BAT activity expose humans to ionizing radiation and rely on the use of injectable contrast agents. This makes longitudinal research studies impractical and clinical work on children, important for studies on early development of diabetes, impossible. This major problem has halted therapeutic advances in the field and generated a universal demand for the development of alternative approaches. Therefore, our research focusses on using magnetic resonance imaging and spectroscopy to assess activation of BAT in humans. The chemistry of human BAT is very unique, and we are working hard to develop methodology to assess this real-time in vivo using these techniques.
Principle Investigator: Hermien Kan (Dept. of Radiology)
Website - Nano-delivery systems and molecular imaging of pain
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The PainLess research group combines expertise of the Translational Nanobiomaterials and Imaging group, the Nerve Center and the Department of Anaesthesiology of the LUMC. In this context we have a 2-year PostDoc project available for an outstanding young scientist who has an interest in exploring novel biomarkers related to chronic pain for the development of nanoparticle-based molecular imaging tools for diagnostics and treatment.
Chronic pain is a severely debilitating disease, which affects millions of people around the globe. Current treatment is frequently insufficient or bears serious general side effects due to systemic application. It is currently not possible to visualize pain in the nervous system with the consequence that local targeted treatment of the source of chronic pain is difficult. We aim to visualize cells or molecules which are directly or indirectly associated with the generation of chronic pain to facilitate local treatment. To this end, we will explore novel biomarkers, upregulated in the dorsal root ganglion of mice (in a chronic pain model), identified by transcriptome analysis.
Having identified novel biomarkers, we will develop nanocarrier systems based on polymer vesicles, harbouring agents that can be visualized with Magnetic Resonance Imaging (MRI). The nanoparticles are made of polylactic-co-glycolic acid (PLGA), and are coated with polyethylene glycol (PEG) for optimal biocompatibility. The surface of the nanoparticles will be conjugated with antibodies against novel biomarker identified by transcriptome analysis.
In this project, we will incorporate innovations from nanotechnology, molecular biology, molecular imaging and nerve surgery. We envision that these nanocarriers will mark the advent of a new era of pain visualization and treatment.
Principle Investigators: M.J.A. Malessy, M.D. (Dept. of Neurochirurgy), Ph.D., Dr. Luis J. Cruz (Dept. of Radiology), Albert Dahan, M.D., Ph.D. (Dept. of Anesthesiology)
Website - Induced pluripotent stem cell-based mapping of collaborating autism spectrum disorder (ASD) pathways
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Autism spectrum disorder (ASD) is the name of a group of developmental disorders with a wide range of symptoms, and levels of skill and disability. The combined forms of ASD affect 1 out of 68 children worldwide. However, most of the pathways leading to ASD have not been identified. We have set up a induced pluripotent stem cell (iPSC)-based genetic approach using the unique genomic background of ASD patients to uncover collaborating genes and pathways that lead to ASD. The phenotype of ASD-specific iPSC-derived neural cells is first determined through fluorescence imaging, Ca-imaging, and electrophysiological analyses (multi electrode arrays (MEAs) and patch-clamping), and in a later stage rescued by CRISPR-Cas9 mediated interventions. For further information please contact Dr. Harald Mikkers (h.mikkers@lumc.nl).
Principle Investigator: Harald Mikkers (Dept. of Molecular Cell Biology)
Website - Tumor-stroma interactions in gastrointestinal cancers
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Our current projects focus on how members of Transforming Growth Factor-β and Bone Morphogenetic Protein family influence interactions between epithelial tumour cells, cancer-associated fibroblasts (CAFs) and infiltrating immune cells in all stages of colorectal- oesophageal- and pancreatic cancer. We perform in vitro and in vivo studies to explore underlying mechanisms and clinical applications of these findings in close collaboration with clinicians and pharmaceutical companies. We make use of advanced in vitro and in vivo mouse orthotopic models for colorectal- pancreatic- and liver cancer. Our research has a strong translational character emphasized by collaborations with the LUMC medical research profile area Cancer Pathogenesis and Therapy. More information about members of the project team and current publications can be found on our website. For more information please email L.J.A.C.Hawinkels@LUMC.nl.
Principle Investigator: Luuk Hawinkels (Dept. of Gastroenterology and Hepatology)
website - Clinical metabolomics and lipidomics
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Metabolomics and lipidomics are of fundamental importance to personalized medicine and therapy. In the metabolomics group at the Center for Proteomics and Metabolomics novel approaches employing chromatographic techniques, mass spectrometry and nuclear magnetic resonance spectroscopy are developed and applied in a variety of research fields. Our research efforts together with our partners from several (clinical) groups include, the development of novel lipid analysis approaches (lipid mediators, lipidomics, short chain fatty acid analysis and others), the analysis of metabolic changes during cancer/immune interaction, lipidomic analysis of inflammatory diseases such as for example COPD or arthritis, biomarker discovery studies for brown fat activation and atherosclerosis as well as immune cell metabolism (macrophages, dendritic cells, the influence of neuronal guidance proteins) and epidemiological studies. Besides these topics a recent line of research has emerged around the function of the enzyme 24-dehydrocholesterol reductase for which we have developed selective chemical probes and are aiming at their application in different disease models, while using OMICS approaches to longitudinally monitor metabolic changes.
In our group focus is put on the development and use of analytical chemistry approaches in the context of translational research in a great variety of cutting edge disease related projects.
Principal Investigator: Martin Giera (Center for Proteomics and Metabolomics)
Website - Fundamental aspects of Clostridium difficile biology
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Clostridium difficile is a Gram positive, spore forming, anaerobic enteropathogen. It is the main cause of health-care associated diarrhoea and is increasingly found in the community in patients that have not had health care exposure. Strains circulating among animals and humans overlap, suggesting transmission to (and possibly from) human hosts. The LUMC’s Department of Medical Microbiology hosts the Dutch National Donor Feces Bank as well as the C. difficile Reference Laboratory, providing a unique environment for research.
We study C. difficile at the genetic, biochemical, cell biological level and biophysical level focussing on topics such as DNA replication, stress response, antimicrobial resistance and protease structure and function. Where possible, our findings are related to (pre)clinical research on antimicrobial drugs, and molecular epidemiology. Our infrastructure includes equipment for anaerobic culture of (genetically modified) C. difficile, protein purification and analysis of macromolecular interactions.
Local embedding includes long standing collaborations with the Center for Proteomics and Metabolomics for advanced proteomics analyses (dr. P. Hensbergen) and the Leiden Genome Technology Center and LUMC’s Sequence Analysis Support Core for next generation sequencing analyses.
Principal investigator: Wiep Klaas Smits (Department of Medical Microbiology)
Website - The evolutionary adaptation of blood coagulation proteins
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Our research focuses on the identification of novel targets and engineering of improved therapeutic proteins for the treatment of blood coagulation disorders, such as the bleeding disorder hemophilia, or, conversely, thrombosis. Blood coagulation is a uniquely complex process that protects organisms from significant blood loss following vascular damage. Interestingly, this key regulatory system has been hijacked by a subset of snakes for their survival. Through molecular adaptations and functional innovations, specific blood coagulation proteins have been converted into potent biological weapons that support envenomation of prey. While we and others have previously described some of the unique biochemical characteristics that hallmark the ‘venomization’ of these proteins, little is known on if and how adaptive evolution may have affected the proteins essential to normal blood clot formation in snakes. Furthermore, information on whether the regulatory pathways that govern the coagulation system are similar between separately evolved snakes is lacking.
In this research line, we aim to identify whether substantial modifications have occurred in functional protein regions by generating a resource comprising DNA and protein sequences of snake coagulation proteins. This will involve the development, implementation, and execution of an innovative research program involving the generation, interpretation, and validation of genomic and protein snake sequences relevant to blood coagulation. The functional impact of sequence and/or structural motifs unique to the snake coagulation system will be characterized in detail using well-defined purified recombinant protein variants and biochemical approaches. We anticipate that the insights obtained in the evolutionary innovation of coagulation proteins and associated enzymatic pathways will provide a framework for the development of novel therapies to treat a deregulated hemostatic response.
Relevant key publications are Verhoef D. et al. Nature Communications 2017; Bos MHA. et al. Blood 2009. Local embedding includes collaborations with the Leiden Genome Technology Center and LUMC’s Sequence Analysis Support Core for next generation sequencing analyses, and we have long-standing international collaborations with specialists in snake (venom) evolution, structure-function studies on blood coagulation proteins, and other related expertise. For more information, please contact M.H.A.Bos@lumc.nl.
Principal Investigator: Mettine Bos (Dept. of Internal Medicine, Section of Thrombosis and Hemostasis)
Website - Structural biology of DNA replication
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The Lamers lab studies the molecular mechanisms of DNA replication. The replisome, a large multi-protein complex, performs the many activities required to simultaneously duplicate the two strand of the DNA duplex. At each cell duplication, millions of bases of DNA are copied with an astonishing high accuracy of one mistake in ~10 million base-pairs synthesized. An increase in the mutation frequency of DNA replication leads to cancer in humans and drug resistance in pathogenic bacteria such as Mycobacterium tuberculosis.
The aim of the lab is to unravel the molecular mechanism of the replisome as a whole, and decipher how mutations arise in the genome during DNA replication. To do so, we use structural (cryo-EM, protein crystallography), biochemical, and single molecule light microscopy methods. The knowledge obtained will be invaluable to combat cancer and to find new ways to prevent drug resistance in Mycobacterium tuberculosis.
We are looking for an enthusiastic postdoctoral scientist with experience in structural biology or single molecule light microscopy to join our group.
Principle Investigator: Meindert H. Lamers (Dept. of Chemical Immunology)
Website - Neuroimaging of migraine and cluster headache - unravelling disease mechanisms
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Our overall aim is to unravel the pathophysiology of two primary headache disorders: migraine and cluster headache. In the last 2 decades, we studied both disorders and their variants, and progressed from conventional MRI techniques to sophisticated multi-timepoint functional MRI studies in humans, always strongly correlating imaging findings with clinical observations.
Migraine is very prevalent. Mechanisms behind migraine headache and aura symptoms are relatively well understood, but it is still largely unknown how attacks are initiated. A disturbance of the cortical excitation-inhibition balance is suggested to underlie the initiation of attacks. Glutamate and GABA seem to play a dominant role in setting and disturbing this balance.
Cluster headache patients suffer from recurrent attacks of headache so excruciating it is referred to as ‘suicide headache’. An extraordinary feature is its episodic nature: attacks occur at predictable times of day, frequently during sleep, awakening the patient. The episodic nature and the link with sleep suggest a role for the hypothalamus, a brain structure which regulates essential bodily functions.
We are looking for one postdoctoral LEaDing Fellow for the following project:- Neuroimaging of Migraine and Cluster Headache – To gain further insights in the pathophysiology of these primary headache disorders, we plan to perform new neuro-imaging studies based upon clinical observations. State-of-the-art techniques are available both on 3.0T and (ultrahigh-field) 7.0T MRI systems, including structural imaging, diffusion tensor imaging (DTI), perfusion imaging (eg. using arterial spin labelling, ASL), MR spectroscopy (on 7.0T allowing proper measurement of glutamate/GABA), and both event-based and resting-state functional MR (fMRI). The latter techniques allow localization and identification of involved functional networks. We plan to implement simultaneous neurophysiological measurements of cortical function (intra-MRI-EEG), both in-between and during attacks, and during visual challenges. We are looking for a post-doc that is experienced in neuroimaging, preferably in (some of ) the techniques mentioned above.
Our research is embedded within the Leiden University Medical Center profile areas Biomedical Imaging and Translational Neuroscience, consisting of a multidisciplinary team from the departments of Radiology and Neurology, in close collaboration with Prof. Dr. Michel Ferrari and Dr. Gisela Terwindt. We are world leading in the field of migraine and cluster headache research with active (inter)national collaborations within academia, clinical centers and industry. Our clinic treats a unique, large cohort of migraine and cluster headache patients who are treated and followed in the headache center of the Leiden University Medical Center. This cohort is clinically well-described and willing to participate in research.
Principle Investigators: Dr. Mark Kruit (Dept. of Radiology) and Dr. Rolf Fronczek (Dept. of Neurology).
Website - Next-generation immunotherapies for colorectal cancer patients
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Cancer immunotherapy currently constitutes one of the most promising treatment options for cancer patients. We are working on the development of personalized neo-antigen-targeted immunotherapies, by applying next-generation sequencing technologies for the screening of cancer genomes in advanced colorectal cancer patients.
The lab is also focusing on the development of novel cell-based immunotherapies. Recent research, supported by a tremendous technological development, demonstrates that the diversity of immune cell entities might be greater than expected. In a publication in 2012 (de Miranda, Clin Cancer Res) we described an immune cell subset that was specifically encountered in colorectal cancers that had not metastasized. By applying state-of-the-art technologies like (imaging) mass cytometry and single-cell transcriptomics we are working towards the characterization of this immune cell population so that its anti-cancer potential can be assessed. The ultimate objective of this endeavour is to develop an innovative immune cell therapy for metastatic cancer patients.
Principal Investigator: Noel de Miranda (Dept. of Pathology)
Contact - Neuronal guidance cues for healthy blood vessels
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Our team’s main research interest is to elucidated new roles of neuronal guidance proteins in vascular and immune biology. Neuronal guidance proteins involve the 4 major families of netrins, slits, semaphorins, and ephrins and are originally known to guide the coordinated patterning of neuronal cells during embryonic development. Next to their developmental function, evidence is accumulating that neuronal guidance proteins are expressed by many cells and play a central role various in adult tissues. To that end, we have identified specific neuronal guidance proteins important for vascular health. Since neuronal guidance proteins can modulate various cellular functions important in inflammation and tissue repair, they are attractive putative targets for intervention. In order to make good use of these opportunities their mode of actions need to be unravelled in detail.
We are looking for one postdoctoral LEaDing Fellow with experience in molecular and cellular biological techniques and an interest in vascular research to join our international team of young motivated scientist. You will work in the stimulating environment of the Einthoven Laboratory for Vascular and Regenerative Medicine to do science that is creative and of high-quality, and providing opportunities for your further career. For more information please contact Janine van Gils (jm.vangils@lumc.nl).
Principle Investigator: Janine van Gils (Dept. of Internal Medicine)
Website - Molecular and cellular characterization of a new selective tumour cell inhibitor
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A fundamental aim of our department is the discovery of new treatments that eliminate tumours, are minimally toxic and are not susceptible to acquired resistance. Rather than targeting the upstream components of cell signalling 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 and potentially the blood vessels that fuel their growth. In collaboration with the European lead Factory (a consortium of leading academic institutions and pharmaceutical companies offering access to one of the largest libraries of lead-like small molecules in Europe), we have performed ultra-high throughput screens to find selective small molecules inhibitors of ETS transcription factors. This family of transcription factors sits downstream of RAF-RAS-MAP kinase pathways that are 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 and could drive tumour angiogenesis. From 450,000 molecules originally screened, we have refined a qualified hit list of novel compounds. To date, there are no reported examples of such a class of molecule. This is an excellent opportunity for a highly motivated post-doctoral fellow with experience in molecular and cell biology techniques to join a multi-disciplinary team working at the interface between science and medicine. The researcher will have access to established mouse models, 3D tissue-culture systems and global transcriptomics approaches enabling a thorough characterization of unique tumour cell inhibitors ultimately as a stepping stone to their phased introduction to the clinic. .
For more information please e-mail David Baker (d.baker@lumc.nl) or Luuk Hawinkels (L.J.A.C.Hawinkels@LUMC.nl).