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Apr 1, 2010 (Vol. 30, No. 7)

Cancer Diagnostics Seek to Fulfill Promise

Improvements in Techniques and Approaches Energize a Once Stagnant Field

  • Nucleic Acid Biomarkers

    Charles R. Cantor, Ph.D., CSO at Sequenom, explained that oncogenes are the pathways and the targets for next-generation drug development. “The challenge is in somatic mutations,” he said. “They occur in tumor cells, and they do not occur in normal cells at all. Additionally, a tumor biopsy is small and only a small fraction is tumor, so these mutations present at low abundance. Many methods like conventional DNA sequencing cannot find low-abundance mutations and even nextgen is not cost effective to find low-abundance mutations.”

    Mass spectrometry, he explained, stands a better chance of picking up these changes because it is sensitive, quantitative, and can detect changes that occur fractionally. Procedures have been developed to enhance the collection of RNA and DNA fragments that enter the peripheral circulation as a result of apoptosis. These include optimized methods of recovering small fragments, amplifying them, and then detecting and quantifying sequence characteristics by nucleic acid mass spec.

    Dr. Cantor showcased a customizable commercial product that enables workers in a clinical setting to detect these changes on a larger scale. He noted that the product is used for research purposes by many labs and is sensitive down to about 5%. “We have work ongoing in house that will push sensitivity down to 1 percent or below,” he said. “We currently scan in a research setting 240 mutations in 19 genes and can suggest to a physician what kind of therapies work. It surprises us, but a number of clinicians already want to use it. By the end of the year you will see this in at least three institutions.”

  • 3-D Breast Carcinoma Model

    Ray Mattingly, Ph.D., associate professor of pharmacology at Wayne State University, has developed a tractable, in vitro model of ductal carcinoma in situ (DCIS) based on 3-D overlay culture in reconstituted basement membrane.

    “Tumors that are the hardest to treat are those that grow slowly but relentlessly,” he said. “Benign breast tumor—ductal carcinoma in situ—is the fourth most common diagnosed cancer in the U.S. It’s hard to study because these lesions are tiny. What we did was to grow a model in a gel, to study and genetically profile.”

    Dr. Mattingly’s group has applied and cross-validated whole-genome microarray and digital gene-expression (DGE) analyses to explore the networks and pathways that underlie DCIS. “Not too many people are working on a progression model,” he reported. “We started doing this whole-gene profiling, but we still weren’t getting a full picture.”

    DGE analysis revealed a broad range of products that are transcribed outside of standard (NCBI 36.3) genes models. With digital gene expression there’s no preconceived notion of what you are going to find, Dr. Mattingly said. “With DGE, the real work is to get someone who knows what they’re doing to analyze the data. Bioinformatics is an emerging skillset needed in this field, and we are getting an emerging picture of ductal carcinoma that will progress and those lesions that won’t do anything. We are hoping to make this a prognostic tool.”

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