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    NB2 a Novel Antitumor Agent for Breast Cancer: Implication of Proteomics in Target Identification

    Scientific Abstract:
    SCIENTIFIC ABSTRACT NB2 a novel antitumor agent for breast cancer: Implication of proteomics in target identification Background. Breast cancer is one of the leading causes of death in women. Chemotherapy regimens including anthracyclines and taxanes combined with hormonal therapy are currently the treatment of choice for advanced breast cancer, although neither optimal sequence regimen nor optimal time administration have been determined. Moreover, despite the high-rate of response most of the patient relapse in a short period of time. Using computer-aided drug design we discovered a novel anticancer compound NB2 that exhibits remarkable activity in a battery of breast cancer cell lines. We have previously shown that NB2 exhibits in vivo efficacy against prostate cancer xenografts in nude mice with no apparent toxicity. We have recently demonstrated that NB2 was more potent in breast cancer cells (MCF7, MDA-MB-435 and MDA-MB-468) than in prostate cancer cells (PC3). Our preliminary results suggest that NB2 arrests breast cancer cells in G0/G1-phase of the cell cycle, induces apoptosis and alters the expression of several proteins. Objectives. Our immediate goal is to determine the cellular target(s) and mechanism of action(s) of NB2 using proteomic approaches. Proteomic technologies are beginning to be utilized to study the natural history and treatment of breast cancer. Two-dimensional gel electrophoresis (2DE) is still the foundation of most proteomic approaches. 2DE provides a global view of many proteins in a single experiment and when combined with fluorescent probes and sensitive imaging techniques it can quantitatively detect differentially expressed proteins in cells upon exposure to drugs. We also propose to evaluate the in vivo antitumor efficacy and toxicity of NB2 in mice xenograft models of breast cancer. Drug metabolism and pharmacokinetics aspects of NB2 will be also determined. Our long-term objective is to develop novel therapeutics for breast cancer and to carry out phase I clinical trial with NB2 or improved analogues. Specific aims. 1) To identify drug target(s) of a new investigational anticancer compound NB2 using proteomics; 2) to determine the mechanism of cytotoxicity of NB2 in breast cancer cells in vitro and in mouse models, and 3) to determine the in vivo efficacy of NB2 as a single agent and in combination with taxanes. Study design. We will determine the in vitro cytotoxicity of NB2 in a panel of human breast cancer cell lines. We will identify all proteins that are consistently altered in response to different concentration of NB2 by 2DE. Mass spectrometry will be used to analyze differentially expressed proteins. The in vivo efficacy of NB2 as well as its toxicity administered as a single agent and in combination with taxanes will be analyzed in nude mice xenograft models of human breast cancer MDA-MB-435 cells. Blood and tissue samples will be collected for our studies of drug-metabolism and pharmacokinetics of NB2. Potential outcomes and benefits of the research. Understanding the mechanism of action of NB2 is of paramount importance in selecting a drug with different mechanism for combination chemotherapy. The knowledge of its efficacy in vivo as well as the metabolism and pharmacokinetics of this compound will provide information to design future human clinical trials. We will also demonstrate that proteomic technologies can be effectively used to identify drug targets, eventually replacing the older laborious methods of target identification. If successfully carried out this study will catapult our efforts in developing NB2 as a novel small-molecule drug for phase I clinical trials.

    Lay Abstract:
    LAY ABSTRACT NB2 a novel antitumor agent for breast cancer: Implication of proteomics in target identification Breast cancer is the most commonly diagnosed invasive malignancy and one of the leading causes of death in Western women. In an effort to design compounds with new mechanisms of action, we have recently identified a novel small molecule drug, NB2 that shows remarkable potency against a panel of human tumor cell types including breast, prostate and ovarian cancer. We have previously confirmed the efficacy of NB2 in mouse xenograft models of human prostate cancer. However, we have recently observed that NB2 is 16 to 90-fold more potent in estrogen-dependent and -independent breast cancer cell lines as compared to prostate cancer cells. The immediate goal of the present study is to identify the cellular target(s) and the mechanism of action of NB2. Classical approaches in target identification require performing laborious cellular assays. In the present study, we propose to use proteomics technologies (the study of all cellular proteins in a given genome) to identify the target(s) of NB2. Proteomics has been used to discover new markers for diagnosis and to understand the molecular basis leading to the initiation and progression of breast tumors. We also propose to evaluate the efficacy and toxicity of NB2 administered as a single agent and in combination with taxanes against breast cancer models in mice. Our long-term objective is to conduct human clinical trials with NB2. The expected outcome of the present study is to demonstrate that NB2 is a highly potent new investigational compound effective for breast cancer. We will demonstrate the ability of proteomic approaches to identify the molecular drug target and the mechanisms involved in the antitumor activity of novel anticancer compounds such as NB2. Preclinical evaluation of pharmacokinetic aspects and the metabolism of NB2 will provide the basis for a rationale design of future clinical trials in humans with this compound. If successfully carried out, this preclinical study will expedite our efforts in developing NB2 as a potential drug for breast cancer patients.