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    Research Grants Awarded

    Evaluating The Role Of Mps1 Over-Expression In Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    SCIENTIFIC ABSTRACT This project will investigate novel molecular targets for taxanes, one of the most important and effective classes of drugs used to treat both early and advanced breast cancer. Although taxanes have been widely used for more than two decades, it is likely that the clinical use of these drugs is far from optimal. For example, not all breast cancer patients benefit from this drug, and ability to prospectively identify patients who will respond could prevent unnecessary toxicity in other patients. Furthermore, the dosing protocols used for taxanes are based on limited clinical ?trial and error? experience in patients, and not on a thorough understanding of the biology of these drugs. Our project proposes to take a fresh look at the mechanisms of taxanes, based on our recent findings that some breast cancer cell lines are far more sensitive to docetaxel (a taxane commonly used to treat breast cancer) than previously recognized, and that initiation of apoptosis in these cells is not cell-cycle dependant. These results suggest that the widely accepted mechanism for cell killing by taxanes (microtubule stabilization and mitotic block) cannot explain this sensitivity, and provide a rationale for us to seek other molecular targets of this drug. We propose to use a number of innovative technical approaches in this project to identify targets of deocetaxel and study the function of these targets. First, in specific aim #1, we will construct drug affinity columns and use extracts of sensitive and relatively insensitive cancer cells as a means to identify docetaxel-binding proteins. This work will use a novel multiplex mass spectrometry technical approach (pioneered by Dr. Pandey), which will quantitatively identify the proteins that are differentially expressed (or differentially bind docetaxel). Expression levels of proteins will be correlated with sensitivity of cell lines to prioritize candidate targets for further studies. For specific aim #2, we will use mass spectroscopy with ?spiking? to methodology for quantitatively measuring levels of candidate proteins in clinical samples of breast cancer that have been characterized for response to docetaxel-based therapy. Again, correlating levels of proteins in these samples with response will help us to prioritize candidate targets. Specific aim #3 will use RNAi technology to initiate studies that will test leading candidate protein targets for functional significance. Together, these studies offer the potential to fundamentally change our understanding of how taxanes work as anti-cancer drugs. This information could be rapidly translated to clinical applications, including development of markers for identifying patients that will respond to these drugs and refining treatment protocols.

    Lay Abstract:
    PUBLIC ABSTRACT This project will study docetaxel, one of the the most important and effective drugs used to treat both early and advanced breast cancer. Although docetaxel has been available for over a decade, it is likely that the clinical use of docetaxel is far from optimal. For example, not all breast cancer patients benefit from this drug, and ability to prospectively identify patients who will respond could prevent unnecessary toxicity in other patients. Furthermore, the dosing protocols used for docetaxel are based on limited clinical ?trial and error? experience in patients, and not on a thorough understanding of the biology of this drug. The widely accepted mechanism for docetaxel is binding to microtubules and ?freezing? cells when they try to divide. However, various pieces of evidence are not consistent with this mechanism, and our own preliminary data suggests that, particularly in breast cancer cells that are highly sensitive to the drug, some other mechanism is operating. Our project proposes to take a fresh look at the mechanisms of docetaxel, using a number of innovative technical approaches. First, in specific aim #1, we will construct a drug affinity column and use extracts of sensitive and relatively insensitive cancer cells as a means to identify docetaxel-binding proteins. This work will use a novel multiplex mass spectrometry technical approach (pioneered by Dr. Pandey), which will quantitatively identify the proteins that are differentially expressed (or differentially bind docetaxel). Expression levels of proteins will be correlated with sensitivity of cell lines to prioritize candidate targets for further studies. For specific aim #2, we will use mass spectroscopy with ?spiking? to methodology for quantitatively measuring levels of candidate proteins in clinical samples of breast cancer that have been characterized for response to docetaxel-based therapy. Again, correlating levels of proteins in these samples with response will help us to prioritize candidate targets. Specific aim #3 will use technologies (RNAi) that can decrease the specifically levels of our candidate target proteins in cancer cells and thus help us to understand the role of these proteins as targets for docetaxel. Together, these studies offer the potential to fundamentally change our understanding of how doctaxel works as an anti-cancer drug. This information could be rapidly translated to clinical applications, including development of markers for identifying patients that will respond to the drug and refining treatment protocols.