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Diagenode to Commercialize Clinical Breast Cancer Test Based on New Epigenetic Signature

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NEW YORK (GenomeWeb) –  Diagenode is working with a team of Belgian researchers to commercialize a DNA methylation–based immune response signature that developers claim can improve patient diagnosis in breast cancer.

The Liège, Belgium-based company recently received €3.6 million ($4.2 million) from BioWin, a health cluster for Belgium's Walloon Region, to develop the signature, called MeTIL, into a clinical test for breast cancer within the next three years.

Scientists at the Université libre de Bruxelles Cancer Research Center (U-CRC) originally developed the signature using microarrays. While the team has used bisulfate pyrosequencing to validate the 5-marker signature in various cohorts, they believe that by partnering with Diagenode, they can make it available in a more clinically viable real-time PCR format.

"We need to transfer the technology from pyrosequencing to a TaqMan-type platform, that's our number one goal," said François Fuks, a researcher at U-CRC who along with co-investigator Christos Sotiriou led the development of the MeTIL signature.

"With Diagenode, the idea is to have a technology constant," said Fuks. "We want to go from pyrosequencing to a more routine technology that clinicians use in day-to-day work."

According to Renaud Schoemans, project manager at Diagenode, the new project reflects the firm's ambition to combine its expertise in infectious disease molecular diagnostics and epigenetic research.

Diagenode, which also maintains a US subsidiary in Denville, New Jersey, develops, manufactures, and commercializes CE-IVD-marked and US Food and Drug Administration-cleared kits for infectious disease testing on a variety of multiplex RT-PCR platforms, with panels on the market for respiratory and sexually transmitted infections, as well as other pathogens and viruses.

The firm has also developed a menu of offerings focused on DNA methylation research, though, including its Bioruptor sonication products and its recently released automated epigenetics systems, such as its SX-8G and Compact IP-Star automation platforms.

The project with U-CRC is, therefore, a core element of Diagenode's plans to move into the business of DNA methylation diagnostics.

"It's a very practical way of doing things," said Schoemans. "We have people knowledgeable about developing kits on the clinical side and the regulatory side, especially in infectious disease. On the other side we have people knowledgeable about DNA methylation," he said. 

"The ingredients were just there," he added. "We didn't have to build a whole new expertise, just to connect two things that were already available."

According to Schoemans, the project with U-CRC commenced earlier this year and reflects the move of Diagenode's market ambitions to its first DNA methylation-based test onto the European clinical market by the end of the decade. He noted that IDDI, a Belgian contract research organization, is involved in the effort, as well as the University of Liege.

In terms of realizing those objectives, Fuks is an auspicious partner for Diagenode. As director of U-CRC's Laboratory of Cancer Epigenetics, he liaised with Illumina during the development of the San Diego vendor's HumanMethylation450K BeadChip, which his lab has used to profile methylation changes in breast cancer patients. Fuks said he has also worked with Diagenode to develop its menu of epigenetic research products.

According to Fuks, the development of the new signature goes back several years, much of which was spent perfecting the technology and analysis methods. His lab at U-CRC also received $2.2 million from the Walloon Region in 2014 to examine the role DNA methylation changes play in breast cancer.

Fuks and colleagues described the development and validation of the MeTIL signature in a paper published last month in the Journal of Clinical Investigation. They used Illumina arrays to evaluate the methylation of tumor-infiltrating lymphocytes (TILs) in breast cancer samples, honing in on particular markers that could be associated with a better clinical outcome.

While the presence of TILs in tumor samples is typically assessed by histopathological measurements or gene expression markers, the authors maintained that the conventional approach has "limited accuracy and reproducibility."

Fuks also noted that Illumina methylation arrays, such as the legacy 450K, or the newer Illumina MethylationEPIC BeadChip, which contains 850,000 markers, remain the favored technology for genome-wide analysis.

"It may be surprising that we still use microarrays in the era of next-generation sequencing, but as a matter of fact, for DNA methylation profiling, the most widely used technology so far is still DNA methylation microarrays," Fuks said.

And despite the vast amount of data generated using the arrays, Fuks and his team settled on a relatively small panel of five markers as its final signature. "The combination of these five gave us as good data as a longer list," he said. "That's why we went with these."

In the paper, the team maintained that the scores from the 5-marker, "methylation of TIL" (MeTIL) signature could be correlated with endpoints "reflecting overall or disease-free survival and a pathologic complete response" to preoperative anthracycline therapy in three breast cancer cohorts from the Jules Bordet Institute in Brussels.

Specifically, they reported that their markers predicted survival and response to chemotherapy in among different breast cancer subtypes better than histopathological assessment of TILs or gene expression–based immune markers did.

"By comparing the pathologies of the different subtypes with our MeTIL scores, we were able to quantify the number of TILs in a more accurate manner," said Fuks. "That's how we wound up with these assertions."

The team also looked at the signature in other cancer types from The Cancer Genome Atlas, where the MeTIL signature also improved the prediction of survival in other malignancies, including melanoma and lung cancer. Fuks said the results have encouraged his team to study the application of its signature in those indications.

"Clearly, we would like to go into other cancers, into melanoma, or lung," said Fuks. "We may want to go into other kinds of [cancer] treatments," he said, "but the current focus is on breast cancer."

According to Fuks, a test to predict the benefit from anthracycline chemotherapy in breast cancer is needed in Belgium, where roughly 10,000 women are diagnosed with the disease each year. It remains the leading cause of cancer death among women, only some of whom benefit from chemotherapy.

By partnering with Diagenode, the hope is that European oncologists will be able to use the MeTil signature to select the best treatment for their patients with breast cancer.

Schoemans noted, though, that the current project is funded to produce a breast cancer assay for the European market. Upon its completion, the company would like to make the kit available in the US, where it has launched a number of FDA-cleared kits.

He also said that the avenue for selling the test is "still a bit open," and that the company is interested in working with a partner that could assist in marketing the product.

"This market is very different from infectious disease, and very different from the epigenetic research market," he said. "It will require investments."

He also said that the company has not selected a definite platform for the test. Instead, the initial kit would be manufactured so that it could be used "in any hospital or clinic on two or three of the most widely used platforms," he said.

The MeTIL signature is not the only project underway as Diagenode seeks to build its new methylation testing business. The company also recently received finding to develop an epigenetics-based thyroid cancer diagnostic.

Diagenode and partners at the Austrian Institute of Technology and Platomics, an Austrian R&D company, received €1.5 million in EU funding last year to carry out the project over the next three years. 

Similar to its work with U-CRC, as part of the consortium, Diagenode will seek to develop a set of DNA methylation markers into a kit that will be tested in a proof-of-principle study. Diagenode and its partners will also develop an end product, with the design, manuals, software, and quality assurance necessary for CE-IVD marking.

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