Project Partners
Michael Boutros (Project Coordinator)
University of Heidelberg, Germany and German Cancer Research Center, Germany
Michael and his team at the Department for Cell and Molecular Biology within the University of Heidelberg work on signalling networks using model systems and human cells. While textbooks represent signalling networks as based on a linear relationship between a ligand and its receptor, the reality is much more complex. “A lot of these pathways interact with each other,” reveals Michael. “They don't only talk to their neighbours. They talk to the neighbours of their neighbours.” His research team uses special techniques to silence components of signalling networks so they can unpick their roles.
“We do large-scale screens using RNA interference (RNAi) to silence every gene in the genome. Then we measure the responses of genes to perturbations in the network.” RNAi silencing reveals what happens when certain components are absent. Such analyses allow scientists to establish hierarchical relationships between network components. But they also facilitate the identification of potential drug targets. “Mutations in the components of signalling pathways in humans are often the cause of cancer,” reveals Michael.
“We know there are many feedback regulatory mechanisms controlling how these pathways work.” Such networks need to be balanced otherwise unhealthy situations arise. “So we think it's really important to understand how cells naturally check and balance themselves,” adds Michael. “Our methodology involves taking many different snapshots of cells at different times. Such high-throughput screening allows us to identify critical intervention points and then gives us an opportunity to understand how pathways operate.”
In addition to the ERASysBio+ funded ApoNET project – which combines the research efforts of Michael's team with the work of tumour immunologist, Henning Walczak (Imperial College London, UK), and bioinformatician, Rainer Spang, (University of Regensburg, Germany) – Michael also co-ordinates the EU framework-7 funded CancerPathways integrated project.
Henning Walczak
At the Tumour Immunology Unit within the Faculty of Medicine, Henning's team is “trying to identify new ways of treating cancer and inflammatory diseases like rheumatoid arthritis and psoriasis, where the immune system doesn't work properly anymore.” In fact, he has already started a biotechnology company – Apogenix – together with a colleague, Peter Krammer. Apogenix developed a biotherapeutic drug called CD95-Fc or APG101, which is currently in phase II clinical trials. “If it successfully passes the next clinical trials, APG101 will be one of the first apoptosis drugs available to patients,” reveals Henning.
“Immune cells are stimulated by the TNF and TNF-receptor superfamily of proteins,” says Henning, “and cancer cells can be specifically killed by certain members of these families. ApoNET is focusing on TNF and TRAIL. “We believe that highly active but non-immunogenic forms of TRAIL could be used to treat cancer,” says Henning, “although this challenges past efforts of the big pharma companies.” They have not yet exploited this avenue. “So far they’ve looked at less active forms of TRAIL and other TRAIL receptor agonists that didn't really work in the clinic which, quite frankly, I don’t find very surprising,” adds Henning.
Within ApoNET Henning and his team are specifically looking at the effects of TRAIL on primary hepatocytes (liver cells). “We're exploring ways of stabilising TRAIL. Proteins in the TNF superfamily can be stabilised with a particular sequence to make them more effective. We noticed that forms of TRAIL that were highly effective at inducing cell death in cancer cells, did not exert any toxicity on normal cells, even when combined with a number of other cancer therapeutics. So this opened a therapeutic window, which we're currently exploring with apoNET.”
The EU framework-7 funded ApoNET project combines Henning's research efforts with those of Michael Boutros (University of Heidelberg and German Cancer Research Center, Germany) and bioinformatician, Rainer Spang, (University of Regensburg, Germany).
Rainer Spang
University of Regensburg, Germany
Rainer leads the Computational Diagnostics Group at the Institute for Functional Genomics. His team has two main research interests: diagnostic modelling and reconstructing cell signalling pathways. “We look at the diagnostic problems of disease, like the expression profiles of certain tumours,” explains Rainer. “We get a high-dimensional readout, so we're looking at the tumour in terms of approximately 20,000 numbers.” This corresponds to the number of genes in the human genome; the profiles highlight which genes are switched on in the cancer cell.
“We deal with such large outputs that we need computational approaches to look at them. So we use machine-learning. You give the computer examples – readouts of tumours that responded to certain drugs and tumours that didn't – to try to make the machine learn by example. So in future we could detect what is wrong with a patient based on their cell readout. We did this for the diagnosis of lymphomas (comparing Burkitt's with Diffuse Large B Cell Lymphoma). Their expression profiles clearly show that they're two different diseases, although previously it was difficult to tell them apart by looking at the tumour shape.”
“For ApoNET, we're taking the same sort of snapshots,” explains Rainer, “but comparing expression profiles between normal and cancer cells that have been perturbed. We knock down a gene and then get a readout of the downstream effects.” The team uses these data to help the computer learn about signalling networks. Project partners can then identify nodes in signalling networks implicated in liver cancer, which could lead to new drug targets.
The EU framework-7 funded apoNET project combines Rainer's research with the work of teams led by Michael Boutros (University of Heidelberg and German Cancer Research Center, Germany) and tumour immunologist, Henning Walczak, (Imperial College London, UK).