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    Overcoming Apoptosis-Resistance by Bcl-2/Bcl-xL-Bispecific Small Molecule Inhibitors as a Novel and Molecular Targeted Therapy for Breast Cancer

    Scientific Abstract:
    Overcoming Apoptosis-Resistance by Bcl-2/Bcl-xL-Bispecific Small Molecule Inhibitors as a Novel and Molecular Targeted Therapy for Breast Cancer Background: Failure to respond to therapy represents an unmet medical need in the clinical treatment of breast cancer. Overexpression of anti-apoptotic protein Bcl-2 and Bcl-xL is implicated in breast cancer development, tumor progression and resistance to chemo/radiation therapy. Bcl-2/xL bispecific antisense studies have demonstrated the proof-of-principle that inhibition of Bcl-2 and Bcl-xL sensitizes breast cancer cells to chemotherapy, represents a novel and promising strategy for overcoming the resistance to apoptosis induced by current cancer therapy. Through structure-based 3D-database searching and computer-aided design, a number of novel and potent, small molecule inhibitors specific to both Bcl-2 and Bcl-xL have been discovered. Among them, TW-37 and analogs show the most potent binding to both Bcl-2 and Bcl-xL with a binding affinity similar to that of Bak BH3 peptide. Using NMR method, we conclusively confirmed that TW-37 binds to the same set of residues in the BH3 binding site of Bcl-2 as does the Bid BH3 peptide. TW-37 potently inhibits tumor cell growth and induces apoptosis in breast cancer cells with a high level of Bcl-2/xL protein, but has minimal effect on normal cells with low Bcl-2/xL. Preliminary in vivo study shows that TW-37 has a fairly potent in vivo anti-tumor activity, comparable to docetaxel in a nude mouse xenograft tumor model, and has no toxicity to animals at the dose-schedule used. Our preliminary data also indicate that combination of Bcl-2/xL inhibitors with chemotherapeutic agents in vitro improved anti-tumor activity of chemotherapy to breast cancer cells. A key question to be addressed: does the Bcl-2/xl inhibitor induce apoptosis of breast cancer cells indeed through inhibition of Bcl-2/xL function? Understanding the mechanism of action of the novel bispecific Bcl-2/xL inhibitor will provide substantial impetus in expediting its advancement towards molecular targeted therapy for breast cancer with Bcl-2/xL overexpression. Objective/Hypothesis: In this proposal, we will test two inter-related basic hypotheses: (1) A potent small molecule bispecific inhibitor of both Bcl-2 and Bcl-xL will induce apoptosis in human breast cancer cells that express high level of Bcl-2 and/or Bcl-xL; (2) Inhibition of the anti-apoptotic activity of Bcl-2/xL in turn will overcome resistance and restore sensitivity of breast cancer cells overexpressing Bcl-2/xL to chemotherapeutic agents and radiation. Our long-term goal is to develop the most potent small molecule bispecific inhibitor as a potential novel therapy targeting Bcl-2/Bcl-xL for the treatment of breast cancer. Specific Aims: Aim 1: To investigate in vitro and in vivo anti-tumor activity and the mechanism of action of TW-37 and its analogs using human breast cancer cell lines and xenograft models. Aim 2: To investigate the potential synergistic effects of TW-37 in combination with chemotherapeutic agents and radiation. Study Design: Our first major goal is to investigate the in vitro and in vivo anti-tumor activity of TW-37 and its active analogs using breast cancer cell lines and xenograft models. We will characterize the biochemical and biological activities of TW-37 and its analogs, and investigate the underlying molecular mechanism in induction of apoptosis. We will identify the optimal dose and schedule of TW-37 for the treatment of breast cancer xenograft models. Our second goal is to investigate the potential synergistic effects of TW-37 in combination with chemotherapeutic agents and radiation. The success of this aim will provide the proof-of- principle in vivo that a potent and bispecific small molecule inhibitor of Bcl-2/xL might be able to overcome the resistance and restore the sensitivity of breast cancer to chemo/radiotherapy. Potential Outcomes and Benefits of the Research: Combining the small molecule based Bcl-2/xL molecular therapy with conventional chemotherapy would improve the efficacy and overcome the drug resistance to current breast cancer therapy, especially those recurred, advanced or metastatic tumors, in which Bcl-2 and/or Bcl-xL protein is overexpressed and for which conventional therapy alone has failed. Successfully carried out, our studies will pave the way for future clinical studies of Bcl-2/xL inhibitor, alone or in combination with chemotherapeutic drugs or radiation, as an entirely new class of anticancer therapy, with the ultimate goal of personalized therapy for human breast cancer.

    Lay Abstract:
    Overcoming Apoptosis-Resistance by Bcl-2/Bcl-xL-Bispecific Small Molecule Inhibitors as a Novel and Molecular Targeted Therapy for Breast Cancer The recent remarkable success of Gleevec (STI-571) for the treatment of leukemia has provided a powerful example that a small molecule drug targeting a specific cancer-causing protein is not only highly effective or may even provide a “cure” but also has very mild side effects. The success of Gleevec marks the beginning of a new era for designing and developing anticancer drugs that specifically target cancer-causing proteins that are overexpressed in cancer cells but have very low levels in normal cells. As demonstrated by Gleevec, such new molecular target-based drugs are expected to be more effective and also have fewer side effects than conventional chemotherapy. Designing new therapies targeting cancer specific proteins is a new and extremely promising area of research in novel anticancer drug discovery. Failure to respond to therapy represents an unmet medical need in the clinical treatment of breast cancer. When breast tumors recur after initial treatment, they always become resistant to chemotherapy and/or radiotherapy. It is imperative to find new approaches to reverse the resistance of breast tumors to current breast cancer therapies. In the last several years, programmed cell death, or apoptosis, has been found to play an important role in cancer progression. Cancers are now believed to be the results of uncontrolled cell proliferation and lack of appropriate programmed cell death. Overexpression of anti-apoptotic proteins, Bcl-2, Bcl-xL or both, are observed in majority of human breast cancer, and are associated with advanced disease, poor prognosis and shortened survival. Bcl-2/Bcl-xL has been shown to confer resistance to chemotherapy or radiation therapy when overexpressed. Inhibition of the anti-apoptotic functions of Bcl-2/xL represents a novel and promising strategy to overcome the resistance and improve efficacy for the treatment of breast cancer, especially those advanced and invasive breast cancer. Through structure-based design, we have discovered a number of novel and potent small molecule inhibitors of Bcl-2 and Bcl-xL. Among them, TW-37 and its analogs are the most potent small molecule inhibitors of both Bcl-2 and Bcl-xL. TW-37 binds to a particular binding pocket in Bcl-2/xL and potently inhibits the anti-apoptotic activity of Bcl-2/xL. Our preliminary data indicate that TW-37 and analogs potently inhibit cell growth and induces apoptosis in breast cancer cells with high level of Bcl-2/xL, but has minimal effect on normal cells with low target proteins. Combination of the inhibitors with chemotherapy drugs used for breast cancer showed improved anti-tumor activity and enhanced apoptosis induction in breast cancer cells with high Bcl-2/xL. Our goal is to develop these potent Bcl-2/xL inhibitor as a novel molecular target-based therapy for the treatment of breast cancer with Bcl-2/xL overexpression. Toward this goal, we will employ various human breast cancer cell lines and tumor models with different levels of Bcl-2 and Bcl-xL proteins, to investigate the anti-tumor activity of Bcl-2/xL inhibitor and its synergy with conventional chemo/radiotherapy. If successfully carried out, our proposed studies will pave the way to develop Bcl-2/xL inhibitor as a novel Bcl-2/xL targeted molecular therapy, and will also lay the foundation for developing a novel drug combination regime of the Bcl-2/xL inhibitor and chemo/radiotherapy, for improved anti-tumor efficacy without increasing toxicity. The Bcl-2/xL-bispecific inhibitors are predicted to be effective to both ER+ and ER- patients with high levels of Bcl-2 and/or Bcl-xL. Combining the small molecule based Bcl-2/xL molecular targeted therapy with conventional cancer therapy would improve the efficacy and overcome resistance in breast cancer, especially those recurred, advanced or metastatic tumors, in which Bcl-2 and/or Bcl-xL protein is overexpressed and conventional therapy alone has failed. The success of the proposed project will establish the basis for future clinical study of this novel combination treatment modality, with the ultimate goal of personalized therapy for human breast cancer.