Despite advances in cancer therapeutics, tumor heterogeneity remains a major challenge when developing techniques for personalized diagnosis and prediction of response to treatment. While cancer research is increasingly moving toward turning tumor-specific biomarkers into diagnostic tools, there is still a need for an improved systematic approach to biomarker discovery and quantification before cutting-edge, targeted therapies can be broadly implemented.
This challenge led to the establishment of OncoTrack — an international consortium of researchers managed by Bayer HealthCare Pharmaceuticals and the Max Planck Institute for Molecular Genetics in Berlin — and the development of a five-year project called Methods for Systematic Next-Generation Oncology Biomarker Development. OncoTrack is funded by the Innovative Medicines Initiative, a public-private partnership between the pharmaceutical industry and the European Union.
The goal of this collaboration is to generate high-quality genomic and epigenetic data from the tumors of 60 cancer patients as well as from those patients' normal genomes. OncoTrack investigators will also use next-generation sequencing to analyze the tumor methylomes, transcriptomes, metastatic tumors, and xenograft tumors of 20 of the 60 patients, all in order to support biomarker qualification.
The project aims to pull together leading researchers from academic institutes across Europe — including Uppsala Universitet in Sweden, Technische Universität in Germany, and the University College London — as well as pharmaceutical companies like AstraZeneca, Merck, Pfizer, and Roche Diagnostics. The project will be supported by both the pharmaceutical companies and the IMI, which will provide a combined total of €25.8 million for five years.
At the end of the five-year timeline, Max Planck's Bodo Lange says the research and pharmaceutical consortium members hope that the systems biology approach and predictive modeling will result in significant inroads in the biomarker discovery process, as well as provide new possibilities for virtual drug and patient trials.
"The OncoTrack project will revolutionize and make much more efficient the way new drugs, new targets for old drugs, and more efficient chemotherapeutic approaches are identified and brought into practical application," Lange says. "Hence the large body of work that has already been carried out over the last 10 years or so by establishing the framework for such a model — for example, the predictive modeling system established by the Max Planck Institute for Molecular Genetics now used and expanded upon by Alacris Theranostics — will find real applications in the clinic and in the pharmaceutical industry over the next few years."
Lange says that to take advantage of all the new genomics data for the purposes of developing next-generation cancer therapeutics, large-scale, multi-site collaborations that include pharma and academic research institutes are the way forward. "The development in this field is strongly technology-driven, and this requires, and will for the next foreseeable future demand, a relatively large input in the form of expensive equipment and very specialized expertise from both industry and academic partners," Lange says. "Once real translation of the technologies has been achieved, the developed technologies will need to be adapted and find their application also in the day-to-day work in the doctor's practice or clinic."
Managing the group
In order to maintain effective management and control over such a large collaboration, the project leaders decided to rely upon IMI executives and an outside management team, says David Henderson, a principal scientist at Bayer and an OncoTrack coordinator. "The challenges of managing this project are quite considerable. We are now in the fortunate position that IMI itself has a quite well-organized executive team in Brussels, which takes care of the interface between ourselves and the European Commission in terms of contract agreement grant payments," Henderson says. "Within our consortium, we have also included a professional project management company that takes care of the routine project management and administrative work that you need to keep a group like this going. … Having good lines of communication and an efficient project management system is very critical for the success of a group like this, and the financing delineates very clearly what the goals and milestones are, and this is integrated into the project management system so we can keep track of how things are running also on the time frame of the project."
In addition to the managerial aspects of the project, the exchange and flow of data to and from 18 different sites in a coordinated and efficient fashion is challenging. According to Lange, this is especially the case with a systems biology-driven project composed of partners from disparate backgrounds, including clinical, academic, and industry. "The consortium had to come up with an especially efficient system of project organization and data exchange, and this is very well managed by dedicated work packages that organize the logistics of sample and data exchange," Lange says. "Critical are common data standards using, for example a Data-Integration Platform for Systems Biology Collaboration, and the possibility to exchange data via a virtual data warehouse."
Lange adds that there are several technological challenges facing the consortium, including the production of detailed molecular analysis of circulating tumor cells and free-tumor DNA derived from serum.
Setting the best goal
While OncoTrack is currently focused on the identification of novel markers for colon cancer, the collaboration's organizers did not set out to study a particular type of cancer. Instead, they sought to attract the best proposals from the most cutting-edge labs. "The project was originally formulated without specifying what cancer we would work on, or what biomarker we would work on, and this was done deliberately because we wanted to make sure that we had academic groups that came to us with their expertise and not a group that said, 'Well, if that's what they want, then we can do it,'" Henderson says. "There are a fairly significant number of groups who applied to do this work, but the way that the EU works is that for each call, only one consortium is selected to work on the project and it's a really competitive grant situation and the applications are all reviewed by a board of experts."
OncoTrack's short-term goal is to refine xenograft tumor models and gain information about the predictive quality of those models for the characterization of patients, and a set of candidate biomarkers that can be used independently of genomic data in the clinical setting. In the long term, the team plans to take novel candidate biomarkers and analyze them in an independent group of tumor samples obtained from biobanks.
Ultimately, it's not just the possibility of finding novel biomarkers that has Henderson hopeful, but rather the prospect of showing what a systems biology approach can contribute to bedside care. "Obviously having a new set of biomarkers that we can apply in a clinical setting is going to be very valuable to us. And I think also the basic work of demonstrating that a systems biology approach is a useful way of going about utilizing genomic data as a starting point in a search for biomarkers is going to be a major contribution because this is something that people have not really tried before," Henderson says.
Participants: AstraZeneca, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Janssen Pharmaceutica, Merck, Pfizer, Roche Diagnostics, the Max Planck Institute for Molecular Genetics, Uppsala Universitet, University College London, Université Paris-Sud, Charité Universitätsmedizin Berlin, the Medizinische Universität Graz, the Technische Universität Dresden, International Prevention Research Institute, Experimental Pharmacology and Oncology, Alacris Theranostics, and GABO:mi
Funding: €25.8 million from various sources over a five-year period
Timeline: 2011 through 2016