Predect

When it comes to developing new cancer treatments, most drugs fail before they ever reach patients. This is partly because the models which scientists use to predict the success of future drugs in the laboratory have been too simple when compared to the real tumours. IMI's PREDECT project has developed new laboratory models that more accurately mimic the three-dimensional complexity of tumours, and their behaviour within the microenvironment of the patient’s body. ###These models could help researchers discover more effective treatments in the future, thereby boosting survival rates. In an interview the IMI Programme Office, project coordinator John Hickman of Servier, and academic coordinator Emmy Verschuren of the Institute for Molecular Medicine Finland at the University of Helsinki, explain the project’s most significant breakthroughs, and how these achievements will help in the future search for new drugs. ‘We have published a series of papers, which are open access, about how to create and work with these types of more complex cancer models,’ said Hickman. ‘That data is now available for everyone – it’s kind of a recipe book.’ Read the full interview

Laboratory tests are not sufficiently predictive of cancer drugs’ activity in humans. The rate of failure to take drugs from laboratory to registration for clinical use has been estimated to be as high as 90 %. In clinical trials, patients are thus exposed to drugs that don’t work and the cost to industry is enormous and unsustainable.### Real human cancers are complex: genetic changes within tumours over time cause cells in one cancer to differ from each other. To this complexity is added the cancer’s interaction with normal cells. IMI’s PREDECT project tackled the problem of complexity by creating laboratory models of the disease that better represent the complex characteristics of different cancers. More appropriate laboratory models for preclinical studies should increase the ability to predict drug efficacy. This will expand the number of treatments available for different types of cancer, potentially providing patients with a higher chance of survival.

‘We chose to focus on complex and sometimes difficult models of cancer,’ explains project coordinator John Hickman of the Servier research institute in France. ‘As an academic-industrial consortium we believed that although our models may not be rapid, nevertheless they better represent the complexity of cancer. These models provide a high content of information more relevant to human cancer. With the high rate of failure of current high-throughput and rapid models to predict clinical activity, we considered something had to change in the way industry looks for drugs.’

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During the earlier stages of cancer drug development, researchers study cancer cells in the laboratory, for example in petri dishes. These two-dimensional models of cancer are relatively cheap and easy to use, so they are still widely used in research, yet they do not accurately replicate real tumours in the body.### This hinders the ability of researchers to study cancer in detail and develop new treatments. IMI’s PREDECT project has developed and analysed a number of more complex, three-dimensional models of prostate, breast and lung cancer that may more accurately mimic the behaviour of tumours in the body. According to Boehringer Ingelheim’s Ralph Graeser, there is no single perfect model that fits all purposes. To help scientists pick the right model for the right situation, the project team has written a paper in the journal Scientific Reports. The article sets out the strengths and weaknesses of the different models and provides detailed protocols for their use as well as advice on when and how to use them. ‘Although people have called for an end to use of 2D cultures, these models are still predominantly used, even though they poorly represent human tumours,’ explained Dr Graeser. ‘The robust protocols for the set-up and analysis of 3D cultures, as well as the cross-comparison of the platforms presented in this paper, should help scientists both in academia and industry to better incorporate these complex models in the drug discovery pipeline.’

Scientists from IMI’s PREDECT project have developed the first animal model of a common form of breast cancer that faithfully replicates the human disease, opening up new avenues for studying breast cancer and developing and evaluating treatments. The findings are published in the prestigious journal Cancer Cell.### Some three quarters of breast cancer cases feature tumours that have a receptor for the hormone oestrogen. Efforts to study these ER+ cancers have been hampered by the fact that animals (like mice) used to study the disease do not accurately replicate how the disease behaves in human patients. Now, PREDECT researchers have created a mouse model that mimics human ER+ cancer better than any other existing model. ‘With this breakthrough, breast cancer disease, progression and metastasis now become amenable to study,’ said George Sflomos of EPFL, the first author of the paper. ‘We can now study crucial factors, such as the action of hormones and molecular responses to therapies, for the first time in a relevant context. But more importantly, this model opens up new opportunities not only for the development but also for the evaluation of breast cancer therapies.’ Meanwhile an accompanying editorial states: ‘This finding is a potential-game changer for breast cancer research, and we predict that it will likely translate into new therapeutic strategies for ER+ breast cancer in the near future’.

IMI’s PREDECT project is making progress on its goal of improving lab-based cancer models to make them better, more reliable tools for use in medical research and drug development. Studying cancer in the laboratory is challenging; tumour samples in petri dishes simply do not behave in the same way as tumours in the body.### PREDECT is working to improve these over-simplistic models by designing complex three-dimensional models that also include cells from the body’s connective tissues which interact with the tumour. Analyses of the models reveal that these models’ behaviour is much closer to that of cancer in the body. Scientists in the project are now using these models in their research. Another group of researchers in the project is looking at improving ways of studying slices of tumours in the laboratory. Tumour slices provide a lot of information on the architecture and make-up of complex tumours. However, the act of creating a slice and keeping it alive can affect the cells’ behaviour. Scientists from PREDECT have found ways to get round some of these issues to create samples that give more reliable results. The models are all the result of collaboration between scientists from small companies, universities, and large pharmaceutical companies. Details of the models are published in open access papers. The new models offer a number of advantages. Most notably, their complexity means scientists will be able to study tumours in the lab in unprecedented detail, and this will reduce their reliance on animal models. ‘There is a growing wave of concern that an over-dependence on reductionist models is one factor contributing to limited success in drug discovery in all therapeutic areas,’ commented project coordinator John Hickman of Servier. ‘To go to more complex systems that model pathology usually means using more animals. This is also expensive. We are attempting some compromise solutions: complex in vitro models.’

• Details of the papers can be found on the PREDECT website