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Research Consortium, Testing Service Hope to Turn Cancer Genome Analyses into Rx Selections

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A public-private research consortium that includes Harvard Medical School and the Max Planck Institute for Molecular Genetics in Berlin plans to sequence the genomes and transcriptomes of 1,000 cancer patients, and to make treatment recommendations based on the results.

The alliance, called Treat1000, currently also includes the Charité University Hospital cancer center in Berlin and the startup companies Alacris Pharmaceutials and CollabRx. Last week, the two companies launched a commercial personalized-oncology service called CollabRx One that provides cancer patients molecular tumor analysis and treatment recommendations.

Both the research project and the service are designed to offer patients detailed information about their tumors at a timescale that can help their physicians tailor their treatment. However, some experts doubt that many patients will benefit from the results at this point.

"Given the information that one can already retrieve from the genome in terms of mutations, and the knowledge that we have in terms of how the key oncogenic pathways respond to these mutations, we should be able to predict which drugs would be efficacious, and which drugs would not be efficacious," said Shahid Imran, co-founder and head of operations at Alacris Pharmaceuticals.

The company, a Max Planck spinout, was founded last fall by researchers from the MPI of Molecular Genetics, Harvard Medical School, and former executives of German drug developer GPC Biotech.

Treat1000

Treat1000, scheduled to be completed within about three years, is currently at an early stage and has not yet secured sufficient funding for the entire study.

In late January, the organizers — including George Church from Harvard Medical, Bernhard Herrmann and Hans Lehrach from the MPI for Molecular Genetics, and representatives from CollaboRx and Alacris — met in Boston to discuss how to get the project off the ground.

Also present at the meeting were representatives from vendors of second-generation sequencing and related technology, including Life Technologies' Applied Biosystems unit, Illumina, Roche's 454 Life Sciences, Helicos BioSciences, Roche Nimblegen, and RainDance Technologies. None of these currently has an official relationship with the project, according to Imran.

Several of the vendors told In Sequence they were interested in the project in general, while one, Roche, said it has committed to participate in Treat1000. Roche said it will sponsor the use of its NimbleGen Sequence Capture 2.1M Human Exome arrays in conjunction with its 454 sequencing technology during the pilot phase of the project, according to a company spokesperson.

"Large-scale sequencing efforts of this kind will be pivotal as we head down the path towards personalized healthcare," the spokesperson told In Sequence in a statement via e-mail.

By comparison, an ABI spokesperson said the company participated in the meeting but said that its involvement is still pending since negotiations have not yet been finalized.

Meantime, Helicos President Steve Lombardi said that his company believes its technology is well suited to the genomic analysis of cancer, in particular of formalin-fixed paraffin-embedded samples. "We continue to talk to [Treat1000 organizers] about how we can enable things," he said.

And Steve Becker, vice president of commercial operations of RainDance, said he "see[s] this as a really good example of a private-public partnership that is working well together to try to accelerate healthcare research." He said the company will likely play a role in Treat1000, but "we will just need to sort that out over the coming months."

Illumina did not respond to a request about the company's interest or participation in the project.

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This year, Treat1000 aims to analyze between 10 and 30 patient samples. Alacris Pharmaceuticals' Imran said he and his colleagues at MPI expect to receive within the next few weeks from the Charité their first two patient samples for sequencing. This part of the project will focus on melanoma and colon cancer.

In addition, Imran said that CollabRx plans to contribute samples to the study from patients who have enrolled in its commercial analysis service. These samples could be of any cancer type, he added.

The first few samples will be sequenced at the Max Planck Institute and at Harvard Medical, according to Imran, who is the former senior director of discovery informatics at GPC Biotech. The plan is to generate 30-fold coverage of the exome for both tumor and normal control tissue from the same patient, he said, as well as "light coverage" of the entire genome.

From fresh tumor samples, the researchers also plan to separate out stem cells from the bulk of the tumor and sequence the exome of these cells separately. In addition, they plan to use reverse-phase protein arrays to characterize the tumor's proteome.

The data will be analyzed using "novel modeling technology" developed at the Max Planck Institute that "allows us to model much larger pathways" than traditional methods, according to Imran.

This resulting information might help oncologists decide which drug, or combination of drugs, patients are likely to respond to, or what side effects they might experience, according to Lehrach, a researcher at the MPI for Molecular Genetics and co-founder of Alacris.

But how the information will be used by clinicians will also depend on non-scientific factors. "The regulatory mechanisms are not really in place to use this information to its full benefit," said Lehrach. "I think it will take some examples that are striking enough that maybe something changes on that side."

Treat1000 does not intend to compete with other large-scale cancer genome studies, such as the International Cancer Genome Consortium, in which the MPI of Molecular Genetics also plans to participate.

One key difference between the two projects is that Treat1000 aims to apply insights from the study directly back to the patients enrolled. "What we are trying to do is to go straight from the sequencing to the application in the clinic, and I think the technology is ready to do that," Lehrach said.

And according to Imran, Treat1000 will generate not only information about a patient's tumor but also "clinical information about the treatment options that were suggested, and, whenever treatment options were followed, how the patient did."

Funding for analyzing the first few samples comes from MPI researchers' grants. But the project organizers are in the process of setting up two foundations — one each in Germany and in the US — and plan to knock on the doors of government agencies and corporate partners in the near future.

A portion of the research will be patient-funded. "If anybody is interested in having their tumor sequenced and is willing to cover the cost of the sequencing, we will sequence their tumor for them," Imran said, citing an initial cost of approximately €30,000 ($38,000).

The MPI of Molecular Genetics is currently equipped with five Illumina Genome Analyzers, four ABI SOLiD sequencers, two 454 GS FLX machines, and one Polonator, which it has not yet run in full production. The institute has also been looking into a Helicos sequencer but has not yet tested it. For Treat1000, the researchers plan to use a mix of its existing platforms initially, depending on available capacity and other factors, according to Lehrach.

In addition, within the next two to three months Alacris plans to set up its own sequencing facility in space leased by the Max Planck Institute in order to support Treat1000 and to house the commercial oncology service it plans to offer with partner CollabRx.

The company has not yet decided which sequencing platforms to bring in-house, but "it makes sense to mix technologies," according to Lehrach. He added that outsourcing sequencing services to third parties, such as Complete Genomics, could be "quite attractive" in the future, but said such services do not currently offer the kind of exome and transcriptome sequencing that Treat1000 wants to do.

Alacris is currently supported by an undisclosed amount of seed funding from its founders but hopes to raise additional capital from other sources, such as venture capital firms or pharmaceutical companies. It also banks on near-term income from patient funding for Treat1000.

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CollabRx One

Under their CollabRx One service launched last week, CollabRx and Alacris provide a fee-for-service that produces a comprehensive analysis of a cancer patient's tumor, including its genome sequence, according to a company statement.

Over the last year or so, CollabRx has been running a pilot version of the service "with a select group of physicians and patients," according to the statement. As part of that offering, it formulated treatment recommendations based on the integrated results from gene-expression, SNP, and copy number-variation analyses of a patient's tumor.

The company outsources these molecular-analysis services to CLIA-certified partner laboratories, including Expression Analysis and Genome Diagnostics.

Now, through the Alacris collaboration, "we can … deliver, in partnership with Alacris, the added benefit — if it in fact proves to be a benefit — of whole-genome sequencing," Marty Tenenbaum, chairman and chief scientist of CollabRx, told In Sequence.

The cost of the full service, which includes whole-genome sequencing, will vary on a case-by-case basis, but will typically run between $50,000 and $100,000, according to Raphael Lehrer, CollaboRx's head of personalized oncology services. He has said the company seeks to lower this price.

It takes the partners between one and two months to generate and analyze the gene-expression, SNP, and copy-number data, while the sequencing analysis takes between four and six months — which he said is fast enough to provide patients with at least some information that could help make treatment decisions.

The companies do not expect insurance to cover the service, but "we are very interested in finding partners to do a large-scale validation study to show that in fact you can do much better treatment of patients if you do the very deep genomic analysis that we are doing," said Tenenbaum, himself a melanoma survivor.

He said CollabRx One could add other analyses to its services menu over time. The goal is "to come up with the best integration of knowledge, with the best recommendations for the patients and their doctors."

According to Lehrer, the service has already yielded treatment-option insights, among them "significantly new findings [that] proposed a course of the therapy that was previously not considered by the oncologists, in far more cases than we had anticipated."

'Promising Too Much'

But some experts don't believe that many patients will immediately benefit from such a service, or from participating in Treat1000.

"I think it's very appealing as a research effort," said Marc Ladanyi, chief of the molecular diagnostics service at Memorial Sloan-Kettering Cancer Center. However, "it may be promising too much in terms of making patients expect that there would be some clear consequences for them, based on the information provided."

Ladanyi explained that major cancer centers already offer tests for specific genomic alterations that are relevant to certain cancer drugs.

"The alterations that have the biggest current impact are being studied in the major cancer centers already," he said. "The question is, 'How many patients are going to actually gain therapeutic benefit from information in addition to those already established markers?'"

Though a comprehensive analysis of a patient's tumor would certainly turn up additional mutations, "it's not clear … how these are going to be linked to therapies, because the overall menu of possible therapies is not as large as it would seem," he said.

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As an example of the limitations of genomic analyses today, Ladanyi pointed to a study of glioblastoma that was published last year by the Cancer Genome Atlas Research Network (see In Sequence 9/9/2008). In that study, researchers sequenced several hundred candidate cancer genes in 91 glioblastomas. According to Ladanyi, the study did not reveal much new treatment-relevant information that tests currently used for glioblastoma patients would not have shown.

"At this point, [the results] would have had very little impact on the treatment of those patients," he said. "That reflects the fact that we are still missing a lot of drugs that might specifically target some of these patterns of alterations."

Commenting on Treat1000, Ladanyi said: "I think the scenario in the more immediate future for this as a research project is to make some discoveries of significant alterations that, then, can be transferred into more routine testing."

According to CollaboRx's Tenenbaum, the project serves a dual purpose: generating research results and funneling them back to study participants. "You can really think about this as personalized research, but also aggregating the results to drive the field," he said.

"The name 'treat' was chosen because our goal is to learn to use that information in order to actively treat patients," he said. "It's really an attempt to try to accelerate the application of that knowledge, as well as just the compilation of it."

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