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Jun 15, 2010 (Vol. 30, No. 12)

Characterizing Proteins to Bolster Pipelines

Basic Science and Chemistry Play Key Roles in Developing New Therapeutics

  • Characterizing MEKK3 Regulators

    The regulation of serine/threonine protein kinase pathways that function in stress-related signal transduction pathways is the research focus of Dr. Vaillancourt’s laboratory at the University of Arizona. “Many yeast proteins have mammalian homologs, and MEKK3 was identified in mammalian cells due to similarities with a well-characterized yeast protein. However, the function of MEKK3 is poorly understood in mammalian cells.”

    Dr. Vaillancourt noted that MEKK3 has never been purified. “It represents more of a genomics approach, where you have a piece of DNA you can isolate from looking at a sequence in the human genome. What does the protein encoded by this DNA do?  In a lot of ways, that’s how this project evolved.”

    For his lab, this work is connected to MAP kinase signaling. “All signaling of cells come through these pathways, but the puzzle is finding out what route is used by a hormone, toxicant, or any kind of stimulated growth factor. To get a better idea of how it functions, we took a biochemical approach. Proteins are generally regulated by phosphorylation. If you can figure out how they are phosphorylated, you can identify how they function.”

    Another phosphorylation he identified was by a different kinase, called PIM, which has been implicated in cancer and  as functioning in viral infections. “So this suggests that MEKK3 can also be implicated in pathways for cancer and in viral infections. This allows us to suggest that MEKK3 could be a target for therapies, and that blocking it can be used as a therapeutic. We have the tools to identify molecular targets, but not the chemicals to develop therapeutics, which is an issue.”

  • Novel Dx Define Metastic Process

    Breast cancer is among the leading causes of cancer-related deaths in women, and in the vast majority of cases, death occurs as a result of metastatic disease, noted Massimo Cristofanilli, M.D., professor and chairman, department of medical oncology at the Fox Chase Cancer Center.

    “What we discovered and published in the New England Journal of Medicine in 2004 was that the detection of circulating tumor cells (CTCs) was the single most powerful prognostic factor in metastatic disease. In practice, the number of CTCs  before treatment is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer.”

    Dr. Cristofanilli commented that, while the prognostic value of CTCs was confirmed in subsequent studies, the most recent molecular evaluation of biomarkers in CTCs suggests that cancer cells in the peripheral blood of metastatic patients express a different phenotype than those in the primary tumor. In fact, research now shows a discordance between CTCs and tumor cells with respect to expression of biomarkers assessed for treatment planning (e.g., ER and Her-2).

    “This result seems to confirm data from preclinical work indicating the existence of a population of cancer cells, known as cancer stem cells, that may have a more aggressive behavior and different phenotype,” said Dr. Cristofanilli. “Studies have shown that cancer stem cells can survive standard therapy. We believe that improved diagnostics can help us to better understand the dynamics of the disease and evaluate changes in protein expression that can make a difference in prognosis and treatment planning.”

    Dr. Cristofanilli presented on some of the novel technologies that are advancing the field. “The CTC chip developed by investigators from Massachusetts General Hospital is highly innovative in that it allows researchers to capture and collect cells for molecular analysis. This technology may represent a step forward in our effort to find better technologies capable of better isolation and molecular profiling of these cells.

    “Such an innovation can create a new paradigm for more personalized medicine. In fact, we believe that the data generated suggests that molecular characterization of CTCs can provide additional information for the development of personalized therapies in breast cancer. By allowing real-time evaluation of gene and protein expression, we will be able to select effective therapies.”

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