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Oct 1, 2010 (Vol. 30, No. 17)

Profiling Looms Large in Cancer Research

Academics Spearhead Efforts to Enhance Discovery and Validation of Biomarkers

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    Genetic mutation-related glycoprotein changes are analyzed by high-throughput mass spectrometry-based proteomics. Potential biomarker candidates are then validated by targeted proteomics and tested for either diagnostic or therapeutic applications. [ETH Zurich—Institute of Molecular Systems Biology]

    Protein profiling, the quantitative assessment of protein-expression levels, has been at the vanguard of a brave new drug pipeline for the last four or five years. However, while the technologies that make protein profiling possible continue to evolve, they have not yet fulfilled their potential.

    “There are a lot of questions that researchers are trying to answer, but so far, at the early detection level, there hasn’t been much success,” noted Paul Tempst, Ph.D., a researcher at Memorial Sloan-Kettering Cancer Center who spoke at Select Bioscience’s “Cancer Proteomics” conference held recently in Berlin.

    “Proteomics hasn’t taken a biomarker to a clinical trial, yet. But we have promising candidates. NCI set up a system to evaluate technologies that make up a classic discovery/verification pipeline, but we now need to apply this pipeline to sample sets.”

    Ralph Schiess, Ph.D., researcher at the ETH—Institute of Molecular Systems Biology, agreed. “The identification of biomarkers for diagnosis, prognosis, and treatment selection—or really the lack thereof, at present—has been a barrier to the realization of personalized medicine in the cancer field.” 

    Dr. Tempst’s approach to protein profiling is unique to his lab, he said, in that instead of only looking for concentrations of protein they are actually measuring differences in enzymatic activity. “By correlating the proteolytic patterns with disease groups and controls, we have shown that exopeptidase activities contribute to the generation of, not only cancer-specific but also cancer type–specific, serum peptides. So there is a direct link between peptide marker profiles of disease and differential protease activity.” Because of this, Dr. Tempst explained that “the patterns we describe may have value as surrogate markers for detection and classification of cancer.”

    Dr. Tempst and his colleagues are focused on the relationship between exopeptidase activities and metastatic disease. “We monitored controlled, de novo peptide breakdown in large numbers of biological samples using mass spec, with relative quantitation of the metabolites, using magnetic, reverse-phase beads for analyte capture and a MALDI-TOF MS read-out,” Dr. Tempst noted.

    In a preliminary prostate cancer study, his group found a significant difference in activity levels of a single aminopeptidase in serum from patients with metastatic prostate cancer as compared to primary tumor-bearing individuals and normal healthy controls. However, there were no differences in amounts of the target protein, and this potential biomarker would have been missed if quantitative levels of protein had been the only criterion of selection.

    Many studies evaluating correlations between enzyme activity and cancerous states were executed in the 1950s and 1960s, according to Dr. Tempst. Acidic phosphatase activity was used as a blood-based marker for prostate cancer long before the PSA test was put into general use in the 1980s.

    “These older observations on enzymes, including aminopeptidases, by a number of different groups caught our attention. This convinced us that we were headed in the right direction,” he added.

    Dr. Tempst and his team are currently developing robust biomarker assays. “Our studies on patient samples and mouse models of cancer led to identification of single enzymes (as opposed to complex panels) that can now be individually monitored.”

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