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    Research Grants Awarded

    Development of Small Molecule Activator of Death Receptor for Breast Cancer Therapy

    Study Section:
    Tumor Cell Biology III

    Scientific Abstract:
    Background: The overall goal of this proposal is to develop novel drugs for breast cancer therapy. The activation of death receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) by TRAIL or agonistic antibody induces apoptosis in cancer cells, while sparing the normal cells. The activation of death receptors by small molecules will have better clinical application than TRAIL or its agonistic antibodies, because of higher penetrance and longer stability. We will investigate small molecule mediated activation of death receptor pathway in breast cancer cells using cell culture and animal models. Until today, there are no small molecules that will bind to TRAIL-R1/DR4 and/or TRAIL-R2/DR5 and activate death receptor pathway of apoptosis. We have recently screened chemical database of small molecules (about 3 million compounds) and found some lead compounds that bind to death receptors and induce caspase-8-dependent apoptosis. We have named a potent small molecule activator of death receptor as "death receptor activator 11" (DRA11). Thus, the development of DRA11 as a clinical therapeutic agent is a very innovative and novel idea for breast cancer therapy. Objectives / Hypothesis: The objective of the proposal is to investigate the molecular mechanisms by which DRA11 induces apoptosis in breast cancer cells, and to assess its preclinical application for breast cancer therapy. Our hypothesis is that DRA11 binds to death receptors TRAIL-R1/DR4 and/or TRAIL-R2/DR5 and induces apoptosis through the formation of active death inducing signaling complex (DISC) in breast cancer cells. Specific Aims: The specific aims of the project are: (1) To examine the molecular mechanisms of DRA11 in breast cancer cells; and (2) To examine the effects of DRA11 on tumor growth in an orthotopic model of human breast cancer in nude mice. Study Design: The molecular mechanisms of DRA11 will be examined using cells culture and an orthotopic model of human breast cancer in nude mice. Cell viability and apoptosis in human normal mammary epithelial and cancer cells treated with DRA11 will be measured by XTT and annexin-V-FITC assay. Expression of Bcl-2 family members, activation of caspases, and cleavage of PARP will be measured by Western blottings. The efficacy of DRA11 on tumor growth and mice survival will be examined in an orthotopic model of human breast cancer. The molecular changes during tumor development in vivo (from aim 2) will be correlated with the in vitro data of aim 1. The uptake and distribution of DRA11 will also be examined in vivo. Potential Outcomes and Benefits of the Research: We will examine the molecular mechanisms of DRA11 and examine its preclinical potential for the treatment of human breast cancer. Since the activation of death receptors triggers apoptosis mainly in cancer cells (regardless of ER and HER2/neu status), the development of DRA11 as an anticancer agent will revolutionize the field of breast cancer. DRA11 can be us

    Lay Abstract:
    Breast cancer is the second leading cause of cancer related deaths in women in United States, after lung cancer. The recurrence of breast cancer is largely due to progression of initially estrogen-dependent breast cancer cells to tumor cells that do not depend on estrogen any further for their proliferation. The reason for this loss of estrogen dependency is not known. Another major problem that we face in cancer therapy is the toxicity of drugs to normal organs. Thus, novel therapies directed against biological targets are needed to improve clinical outcome in cancer. Therefore, the developments of new agents that kill both estrogen-sensitive and -insensitive cancer cells, but have no toxic effects on normal cells, are required for effective breast cancer therapy. One such approach is the activation of death receptor pathway. The development of small molecules that bind to death receptors and activate specifically death receptor pathway of apoptosis will be very innovative and novel idea for the treatment of human breast cancer. Until today, there are no small molecule-based drugs that will bind to death receptors TRAIL-R1/DR4 and/or TRAIL-R2/DR5 and induce apoptosis in cancer cells, while sparing normal cells. Our preliminary data have shown that a death receptor agonist (a small molecule termed as ?DRA11?) induces caspase-8-dependent apoptosis in breast cancer cells, but has no effect on human normal mammary epithelial cells. The activation of death receptor by small molecules will have enormous clinical application due to their higher penetrance and longer stability. Our approach is very novel and innovative, which make cells more sensitive to treatment based on understanding the specific abnormalities occurring in the cancer cells and is potentially applicable to clinical use. The objective of the proposal is to investigate the molecular mechanisms by which DRA11 induces apoptosis in breast cancer cells, and to assess its preclinical application for breast cancer therapy. Our hypothesis is that DRA11 binds to death receptors TRAIL-R1/DR4 and/or TRAIL-R2/DR5 and induces apoptosis through formation of active death inducing signaling complex (DISC) in breast cancer cells. The specific aims of the project are: (1) To examine the molecular mechanisms of DRA11 in breast cancer cells; and (2) To examine the effects of DRA11 on tumor growth in an orthotopic model of human breast cancer in nude mice. At the end of the funding period, we hope to identify and develop new drugs that are more effective and non-toxic for the treatment of human breast cancer. Furthermore, DRA11 will kill breast cancer cells irrespective of their oncogene (e.g. estrogen receptor and Her2/neu) expression status. The information derived from these studies will provide a foundation for new therapeutic strategies for the treatment of breast cancer.