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Merck Proteomics Research Matches Drugs to Activated Pathways

By Allison Proffitt

August 5, 2010 | Yesterday, Merck scientists published new research showing that biomarkers for the PI3 signaling pathway can predict the sensitivity of cancer cells to AKT-inhibiting drugs. The research was published in the August 4 issue of Science Translational Medicine and included authors from Merck, the Fred Hutchinson Cancer Research Center in Seattle, Biogen Idec, and Daiichi Sankyo.

The research features phosphoproteomics, a technology that measures the addition of phosphate groups to serine or threonine residues on cellular proteins to identify drug-specific biomarkers for PI3-kinase pathway inhibitors. “There is published evidence of PI3K-signaling disregulation in many human cancers including ovarian, breast and lung cancer,” author Ron Hendrickson of Merck Sharp & Dohme told Bio-IT World over email.

Researchers looked at 375 phosphorylation sites in the PI3-kinase pathway, and used three pathway inhibitors to identify drug-regulated phosphorylation events. Each of the three test drugs modulated a specific array of phosphopeptides, with some overlap. The hope, Hendrickson said, is that “by measuring biomarkers in tumor tissue before treatment, clinicians can directly test whether the cancer-causing mechanisms that a drug specifically targets are active in the patient’s tumor.”

Merck researchers focused on three early pipeline drug candidates that inhibit AKT, an enzyme that spurs cell growth, said Hendrickson. “Merck may seek to explore the full impact that this technology could have on our oncology pipeline of kinase inhibitors as well as our broader pipeline but it is still early days.”

Most tumor characterization looks at genetic mutations causing cancer, but this approach provides only vague information about the molecular causes of tumor growth. Phosphoproteomics, however, reveals activated pathways in tumors, providing a more precise way to directly tell whether or not a certain drug will work for a patient.

“These results point to a way, after further development of more biomarkers, to routinely characterize the activated pathways in patients' cancers,” said Hendrickson. “A characterized tumor can then be treated with the appropriate pathway-specific drugs, optimizing the chances of eradicating the tumor.”

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    In regards to Merck’s proteomic research, both genomics and proteomics can identify potential new therapeutic targets, but these targets require the determination of cellular endpoints, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell.
    The cell-based profiling platform has the capacity to measure genetic and proteomic events as a functional, real-time adjunct to static genomic and proteomic platforms. By examining small clusters of cancer cells (microspheroids) in their native state, a snapshot can be presented of the response of tumor cells to chemotherapy, combinations and targeted therapies.
    The proteomic platform does not clarify how the response to EGFR inhibitors compares with that to chemotherapy, combinations, or other targeted therapies. There is a challenge to identify which patients the targeted treatment will be effective.
    The introduction of targeted drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of these drugs. However, given the technical and conceptual advantages of cell-based functional analysis, together with its performance and the modest efficacy of therapy prediction on analysis of genome and proteome expression, there is reason for a renewal in the interest of functional profiling assays for optimized use of medical treatment of malignant disease.

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