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Study: 454 Sequencer Can Find Rare EGFR Mutations in Tumor; Dx Suited for Cancer Atlas?


For the first time, 454 Life Sciences has performed a proof-of-concept study showing that its next-generation sequencing platform could guide pharmacogenomic treatments in cancer. The company believes that the platform would be well suited to the NIH Cancer Genome Atlas pilot project, which kicked off in late 2005.

"We believe and hope so," Michael Egholm, 454's vice president of molecular biology told Pharmacogenomics Reporter this week. "We believe this paper demonstrates the kind of depth of analysis that you need to do when you analyze cancer samples — we think that this paper has very high relevance for that," he said.

"Fundamentally, we believe that sequencing is way, way underused, and if you could make it fast and inexpensive enough, the utility for sequencing would greatly increase," Egholm said.

Researchers at 454, the Dana Farber Cancer Center, and the Broad Institute report this week in Nature Medicine that they have been able to detect mutated epidermal growth factor receptor genes in samples of non-small cell lung cancer samples from 22 patients, including fresh tumors, formalin-fixed tumors, and pleural effusion tumors (a lung tumor that presents as a liquid accumulation in the lung sac).

In one pleural effusion sample, "it's 5 percent tumor cells, but only two-thirds of them have the resistance mutation in there," said Egholm. "In another example, we show a tumor mutation at about 0.3 percent — out of a very complex sample, most of it being normal DNA."

The heterogeneous mixture of normal body cells and various cancer cells is a major stumbling block to mutational analysis in tumors. A reliable and discriminating assay that can find a few mutated, specific genes may prove to be useful for identifying patients whose tumors are likely to respond to certain drugs, such as Genentech's and OSI Pharmaceuticals' Tarceva and AstraZeneca's Iressa. Both of these EGFR inhibitors have been shown to be more active against tumors harboring cells with certain mutations.

According to 454, its pyrosequencing method has a number of advantages over Sanger sequencing for molecular diagnostic purposes, including the ability to sequence entire exons in a single read, as well as high throughput, low cost, and high sensitivity. Sequencing allows investigators to find unanticipated mutations, said Egholm. The 454 system has a cost advantage over traditional sequencing by performing highly parallel tests, he added.

A single run on costs about $6,000, split between as many as 96 tests, Egholm said.

The company believes sequencing will work well in pharmacogenomics in such indications as "identifying the early stages of drug resistance and facilitating a change in treatment that is tailored to a patient's" genetics, Egholm said in a statement.

Anna Barker, NCI deputy director for Advanced Technologies and Strategic Partnerships, told Pharmacogenomics Reporter in December that the difficulty of obtaining homogeneous samples useful for sequencing and genomic analysis will be a primary criterion for the selection of the pilot's model tumor types. "We're trying to sift through all the tumors in storage in the country that are somewhat homogeneous — hematologic tumors probably being the major focus, but some other solid tumors," she said.

"If you expect that we may [make] additional findings that relate to something like EGFR, and the way in which that has given us insights into why certain cancers respond to Iressa and Tarceva, I think that's very likely to be the outcome — at least we hope so," Francis Collins, Director of the National Human Genome Research Institute said in a December interview.

In a previous interview with Pharmacogenomics Reporter, Barker said the pilot would also consider novel sequencing technologies. The NCI could not be contacted before deadline for further comment.

The NIH said last week that it has dedicated $6 million in funding for the 2007 fiscal year to support technology development for the Cancer Genome Atlas project.

In a notice titled, "Selection of Funding Opportunities for the Technology Component of the Cancer Genome Atlas Project," NCI said that the goal of the initiative is to "inspire and promote the development of highly innovative tools and new ways to interrogate genomic alterations in cancer." Technologies that the NIH is looking for may include those that interrogate "changes in DNA segment copy numbers, translocations, loss of heterozygosity, epigenomic modifications, and aberrant gene expression profiles."

That $6 million is comprised of three funding opportunities for 2007 of $3 million, $2 million, and $1 million.

The Atlas pilot project began in late 2005 and will go on for three years. It is funded mostly by $100 million contributed by the NCI and the US National Human Genome Research Institute, with each providing half of the total. The pilot will investigate between two and five tumor types and serve as a testbed for technologies needed for a larger Cancer Atlas project.

The US National Cancer Institute in March said it would provide $35 million over three years to support as many as four Cancer Genome Characterization Centers.

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