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PamGene Fashions Kinase-Screening Arrays for Drug Discovery, Companion Diagnostics Use

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By Justin Petrone

Dutch array vendor PamGene is working closely with partners in the pharmaceutical industry and academia to optimize internally developed kinase-screening assays for use in drug discovery and as companion diagnostics, according to a company official.

Rob Ruijtenbeek, vice president of biological sciences at the firm, told BioArray News this week that PamGene has been publishing papers demonstrating the use of the firm's three-dimensional PamChip platform in profiling recombinant kinases, cell-line lysates, and kinase inhibitors in tumor tissues.

Last month, PamGene and collaborators from Utrecht University published a study that used the firm's technology to identify bisubstrate-based kinase inhibitors that could bind highly homologous isoforms of the drug target protein kinase C at several locations. Using PamGene's PamChip serine/threonine kinase, or STK, array, the researchers were able to identify inhibitors that could more selectively inhibit PKC isoforms, according to the paper, which appeared in ChemBioChem.

In July, PamGene's technology was described in a Molecular Cancer Therapeutics paper by scientists from J&J's pharmaceutical R&D division in Beerse, Belgium. In that paper, J&J used PamGene's tyrosine kinase-profiling peptide microarrays to model the response of patients to certain inhibitors. According to the paper, the authors were able to successfully use the array in a range of cell lines to stratify responders and non-responders to a multi-targeted kinase inhibitor.

"Many people are interested in studying kinases," Ruijtenbeek said of the recent publications. "Pharma is interested in developing kinase inhibitors, while for academics signal transduction research is still one of the hottest topics in molecular biology."

According to Ruijtenbeek, PamGene's ultimate goal is to "assist clinical investigators and pharma in improving running clinical trials by providing more molecular info about tumors and patients." The company envisions that its arrays could be used to stratify patients for clinical trials and increase overall drug efficacy.

While PamGene has been targeting the drug development market for several years, it was not always its main focus. Founded in 2000, the Hertogenbosch-based company originally used its flow-through 3D arrays for applications as diverse as gene expression, copy number-variation detection, and human leukocyte-antigen testing.

"When I joined PamGene, it was a genomics company," Ruijtenbeek said. "We started with DNA mutation detection and then we moved into gene expression," he said. "Now, PamGene is totally focused on using peptide arrays in functional proteomics," he added.

According to Ruijtenbeek, it was partially his background in peptide work that spurred PamGene's reorientation from competing against the likes of Affymetrix and Agilent Technologies in the gene expression-array market, to narrowing in on array-based kinase activity profiling, an area where there are but a handful of competitors, including Vancouver, Canada's Kinexus and Lelystad, the Netherlands-based PepScan,

"It was my personal interest to work in peptides," he said. The company inked a pact with Berlin-based Jerini JPT Technologies in 2004 to begin co-development of kinase-screening assays on the 3D PamChip platform, which provides kinetic information by enabling customers to look at multiple kinases in one sample over time in the platform. An early partner was J&J, which began using the firm's platform shortly after PamGene and Jerini began collaborating.

"It was commercially very fruitful," Ruijtenbeek said of the firm's focus on kinase screening. "Kinases are one of the main drug targets in the pharmaceutical industry." While PamGene has pharma and academic customers that use its assays, most of the work is geared towards drug development. A goal of PamGene's is to have its platform adopted for understanding patient populations in correlation with drug treatment.

"We are very interested in investigating to what extent this technology can be used with clinical samples towards predicting a patient's response to anti-kinase drugs," Ruijtenbeek said. "That will help pharma identify the right population for clinical trials," he said. "These anti-kinase drugs are often successful but only in a smaller subset of the population," he added.

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Assay Validation

Part of the motivation behind the ChemBioChem and Molecular Cancer Therapeutics papers is to show the pharma industry that PamGene's assays have been validated in preparation for these kinds of applications, Ruijtenbeek said.

"For the work with Utrecht University, the point was the validation of the STK assay. For J&J, it was the validation of the PTK," he said. "The next step, profiling in clinical samples, has now been validated, as well," he added, citing additional publications in Cancer Research, British Journal of Cancer, and Nature Medicine."

Rob Liskamp, co-author on the ChemBioChem paper and professor of medicinal chemistry at Utrecht University, told BioArray News this week that researchers previously were studying kinases one at a time. "In the old days, it was one compound, one substrate, and a limited number of data points,"

Liskamp said of the older methodology. "With arrays, it’s a multidimensional way of finding the compounds and determining which ones are important."
Liskamp's research is involved in finding new compounds that can modulate kinase activity, especially those important in diseases like cancer and Alzheimer's, he said. His group is particularly interested in studying PKC, which has several similar isoforms.

"There are very subtle differences between the different kinases and this setup is suitable for finding the difference between them," he said. "I think you need arrays where you have a whole collection of compounds that can be a little different but still can be phosphorylated by one kinase isoform and not by another," he said. "You can tune in and find the subtle differences."

Liskamp also cited the ability of obtaining kinetic information from the 3D chips as a factor for his adoption of the technology. "These arrays allow you to look in real time and you can see how fast a modification has taken place," he said. "You are not only looking at the end point. You are looking at how things change over time."

Liskamp added that, because of its ability to provide kinetic information, the PamGene platform could be useful for reevaluating the performance of drugs already in the market, in addition to those in development.

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