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Apr 1, 2009 (Vol. 29, No. 7)

MDx Will Drive Personalized Medicine

Prediction Expected to Hold Only if the Novel Suite of Technologies Can Save Healthcare $$$

  • In Silico Approach

    Megan Laurance, Ph.D., senior scientist at Ingenuity Systems, described the company’s computational workflow for linking overexpression of miRNAs to cancer pathways to identify candidate pools of cancer-related genes. By layering and integrating molecular profiles, this in silico approach searches for profiles that are coregulated to affect cell function and disease phenotype.

    A study of gene profiles in ovarian cancer to search for inter-related pathways found an association between differential miRNA expression in neoplastic versus non-neoplastic samples and deregulation of the DNA damage repair response and of pro-angiogenesis genes.

    Yuriy Gusev, Ph.D., assistant professor at the University of Oklahoma, described computational methods his group is developing to identify genes that are collectively targeted by aberrantly expressed miRNAs in human cancer. In colon cancer, for example, Dr. Gusev presented a molecular signature of 20 overexpressed miRNAs.

    Computational analyses point to miRNA targets that establish tissue-specific biomarkers of cancer and identify cancer-specific pathways enriched for these miRNA targets.

  • Building on Biomarkers

    PDZ domains are highly conserved protein globules that serve a structural function in cells, linking signaling cascades, for example. The human genome codes for about 300 PDZ proteins, each 80–90 amino acids long. Arbor Vita is developing PDZ-based diagnostics and therapeutics, applying its PDZ discovery platform to three target areas: neuroischemia, oncology (cervical cancer), and infectious disease (seasonal influenza).

    The technology uses modeling to develop a library of PDZ interactions. In cervical cancer, for example, the cancer-causing human papilloma virus (HPV) targets a PDZ inside cervical cells, triggering cancerous changes. Notably, only high-risk HPV (the form most likely to cause cancer) specifically interacts with a PDZ.

    Whereas a test to detect HPV can only tell you if a virus is present, Arbor Vita has developed a test that detects the PDZ ligand sequence that is present only in high-risk HPV-E6. “E6 oncoprotein activity depends on PDZ binding,” explained Linda McAllister, M.D., Ph.D., executive vp of diagnostics and CMO at Arbor Vita.

    A positive test indicates increased cancer risk and can guide treatment decisions. The test “detects oncogenic activity of the virus” to help “triage women to surgical intervention,” said Dr. McAllister. The company plans to initiate a clinical trial in the third quarter of this year.

    A single molecule counting approach to early disease detection developed by Singulex, was the focus of a talk by John Todd, Ph.D., vp of R&D. This technology is based on the Erenna™ paramagnetic microparticle (MP)-based sandwich immunoassay, targets low abundance proteins in the bloodstream and can detect protein biomarkers at pg/mL concentrations.

    The company is evaluating the utility of cardiac troponin-I as a biomarker for acute myocardial infarction, and of plasma cytokines in inflammation. An Erenna assay against VEGF (a biomarker for angiogenesis) in the plasma of healthy women compared to women with breast cancer showed statistically significant differences in VEGF concentrations with <1 pg/mL sensitivity using 10 µL of plasma. Dr. Todd described the company’s programs to develop immunoassays capable of detecting small changes from a healthy baseline in plasma protein biomarkers for early detection of breast cancer and recurrent prostate cancer.

    High Throughput Genomics (HTG) presented its qNPA™ technology based on a nuclease protection assay for predictive multiplexed gene expression diagnostics. The qNPA platform offers several advantages, according to Bruce Seligmann, Ph.D., SCO and vp R&D at HTG: whole assay CV’s <10%; detection of <1.2-fold changes; single copy gene sensitivity at 1,000 cells; multiplexed mRNA and miRNA measures; and suitability for use with fresh tissue samples, archived FFPE tissue, or fixed and sorted cells.

    Researchers from the University of Illinois at Urbana-Champaign have developed a colorimetric “dipstick” test for molecular diagnosis of a range of targets based on functional DNA nanotechnology. Yi Lu, Ph.D., professor of chemistry, described the detection of metabolites—such as metal ions and organic molecules—as “a new approach for diagnostics.”

    Dr. Lu’s group chose to utilize functional DNA because it is biocompatible and cost effective, stable under harsh conditions, generally nonimmunogenic, can be denatured and renatured repeatedly, and can be readily modified to generate a signal. Additionally, DNA can recognize a variety of molecular targets, both large and small.

    Dr. Lu presented a general method to convert DNAzymes into fluorescent sensors using catalytic molecular beacons and described the design of a simple colorimetric biosensor that functions like pH paper. The method incorporates both positive selection for target detection and negative selection to reduce unwanted activity.

    The ability to detect cancerous lesions at an earlier and smaller stage will drive changes in clinical care. James Mulshine, M.D., professor and director, Rush Translational Sciences Consortium at Rush University Medical Center in Chicago, discussed the impact of high resolution computed tomography (CT) on lung cancer management.

    “CT resolution has been doubling every two years for more than a decade,” said Dr. Mulshine, and “image-processing capabilities are rapidly evolving.” Higher resolution CT imaging is allowing clinicians to measure tumor volume with greater accuracy and to monitor changes in tumor volume over time and in response to drug treatment.

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