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European Consortium Kicks off Sequencing-Based Biomarker Discovery Project in Colon Cancer

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By Monica Heger

An international collaboration
of academic groups, pharmaceutical companies, and biotech firms will combine next-generation sequencing and predictive modeling in order to aid in biomarker discovery, and potentially drug development, for colon cancer patients.

Dubbed OncoTrack, the project is being funded for five years with around €27 million ($39 million) and will involve whole-genome sequencing of the primary tumors of 60 colon cancer patients and matched normal genomes. For 20 of those patients, researchers will sequence the tumor transcriptomes and methylomes, circulating tumor cells, metastatic tumors, and xenograft tumors.

Bayer Schering is the coordinator of OncoTrack, along with the Max Planck Institute for Molecular Genetics. Pfizer, Eli Lilly, Merck, Roche, AstraZeneca, and Janssen Pharmaceutica are contributing a total of €11 million to the project, with the remainder of the funding coming from the Innovative Medicines Initiative, a public-private partnership between the European Federation of Pharmaceutical Industries and Associations and the European Union that is supported through the European Union's "Seventh Framework" program.

Academic partners in OncoTrack include Uppsala Universitet, University College London, Université Paris-Sud, Charité Universitätsmedizin Berlin, the Medizinische Universität Graz, and the Technische Universität Dresden. Additional industry partners include the International Prevention Research Institute, Experimental Pharmacology and Oncology, and Alacris Theranostics. A research project management firm called GABO:mi will coordinate the initiative.

While the short-term goal of OncoTrack is to identify biomarkers, "eventually, we want to be able to predict which patients will respond to which drugs," said Hans Lehrach, director of the Max Planck Institute for Molecular Genetics, who is leading the project.

Sequencing for the project will be conducted primarily at the Max Planck Institute, but also at Alacris Theranostics, an MPI spinout that counts Qiagen among its investors. Collaborators at University College London may also contribute methylome sequencing.

Lehrach said that MPI will likely use Illumina's HiSeq 2000, Roche's 454 GS FLX, and Life Technologies' SOLiD 5500 for the sequencing, but had not yet decided to what extent or for what application each machine would be utilized.

"We expect to be using all three of them, but that could change," Lehrach said. "There is lots of movement in this area, so it might make more sense to focus on one [platform] in particular."

Patient sequencing — including whole-genome, transcriptome, and methylome sequencing — will be used to identify potential biomarkers. Then xenograft sequencing will be used to develop predictive models of cancer to test the biomarkers.

Currently, the team is still in the process of enrolling patients, and sequencing of the samples will be done on an ongoing basis, with all sequencing expected to be completed by the end of the fourth year.

David Henderson, principal scientist in translational sciences at Bayer HealthCare Pharmaceuticals and coordinator of the OncoTrack consortium, told Clinical Sequencing News that pharmaceutical companies are facing a challenge because there are very few good biomarkers for colon cancer.

"A very large part of pharmaceutical development today is driven by biomarkers … so we can provide 'stratified' medicine … where you can select patients out who are not likely to benefit [from a therapy] and enrich for those patients who are likely to benefit," he said.

He added that because the initiative is focused on early-stage research, well before companies would begin to develop specific drug compounds, it falls into the "pre-competitive area," making it more attractive to industry.

While the pharmaceutical companies themselves are not doing the any of the sequencing, Henderson said that they are providing bioinformatic support for sequence analysis and interpretation.

What sets this project apart from other cancer sequencing projects, including the International Cancer Genome Consortium, is its focus on biomarker discovery, said Lehrach, and the fact that the team is attempting to develop predictive models.

"We're using the information to model tumors in order to optimize therapy and apply that to the patient," Lehrach said. "We want to get a much richer dataset, which will allow us to relate how all those different components of the disease relate to each other."

There is also a difference in scale. The ICGC is sequencing 500 tumors, while OncoTrack is sequencing 60, including very in-depth analysis of 20 of those tumors.

In another departure from the ICGC, results from the OncoTrack project will be available to patients if they request them.

In Germany, patients who participate in genetic studies can request access to the results of those studies. Results are then returned through the patient's physician, and the patient is provided with genetic counseling.

"It's a very complex process," Henderson said. "It's not the case that we would simply give the patient their sequence data on a DVD and send them home with it. … It has to be ensured that sequence information is only released to the patient under the care of a doctor that in the best case may also provide a scientific explanation for its medical utility."

For instance, whole-genome sequencing of a tumor and matched normal will reveal thousands of single-base changes, most of which cannot be interpreted for their medical significance. However, there are certain genes that, when mutated, are known to be oncogenic or to confer drug resistance, Henderson said. Information around those genes, which are interpretable and medically actionable, would be returned if a patient requested.

Lehrach is also involved in another cancer sequencing project known as Treat1000, which aims to use sequencing and predictive models to guide treatment of cancer patients (IS 3/3/2009).

While the two projects are similar and will include some overlap, the focus of OncoTrack is on biomarker discovery solely for colon cancer patients, whereas Treat1000 includes different cancer types and is not focused on biomarker discovery.

Lehrach said Treat1000 is ongoing, although he declined to provide further details.


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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