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    Research Grants Awarded

    Synthesis Of Signal Transduction Inhibitor-Steroidal Antiestrogen Hybrids Using "Click Chemistry" And Their Evaluation As Breast Cancer Therapeutic Agents

    Study Section:
    Treatment

    Scientific Abstract:
    Background. One characteristic of many advanced, recurrent breast cancers is an over-expression of growth factor receptors, such as HER2/neu that make the cells resistant to hormonal mechanisms. Studies suggest that combination therapy-antihormonal agents plus signal transduction (e.g., EGFR kinase) inhibitors- offers a means to restore sensitivity in these cells. Objective/Hypothesis . The objective is to develop a single molecular entity that can prevent the progression of breast cancer cells to an endocrine resistant state. We hypothesize that linking a steroidal antiestrogen through a biocompatible polyethylene glycol linker to a potent growth factor receptor kinase inhibitor, would provide such a compound. The antiestrogenic component would provide targeting to the breast cancer cells as well as directly blocking estrogenic responses while the EGFR kinase inhibitor would independently block the signal transduction mechanisms that, via crosstalk, lead to endocrine resistance. Specific Aims. Specific aim 1. To synthesize the initial series of kinase inhibitor-tether-steroidal antiestrogen ligands. Specific Aim 2. To screen the new compounds and the intermediates for estrogen receptor and growth factor related activity. Specific Aim 3. To evaluate the best compounds as inhibitors of breast cancer cell proliferation in four cell lines. Study Design: We will synthesize the individual subunits - the 11ß-substituted steroidal antiestrogen (A), the bifunctional polyethylene glycol tether with an azido group (B), and the EGFR kinase inhibitor with an ethynyl group (C) and assemble them using “click chemistry.” All compounds will be evaluated as inhibitors of estrogen binding (ERa-LBD), inhibitors of alkaline phosphatase induction in Ishikawa cells, and as inhibitors of receptor tyrosine kinase enzymes. The best compounds (nanomolar activity in binding or submicromolar activity in enzyme inhibition) will be tested as inhibitors of cell proliferation in four breast cancer cell lines. One or more compounds will be selected for advanced biological evaluation or serve as the basis for optimization of one or more units of the bivalent compounds. Potential Outcomes and Benefits of Research : The benefit of the successful development of such agents would be for the treatment of estrogen responsive breast cancer and prevention of the progression to endocrine resistant disease.

    Lay Abstract:
    Background . One characteristic of many advanced, recurrent breast cancers is an over-expression of growth factor receptors that make the cells resistant to hormonal control mechanisms. Studies suggest that combination therapy-antihormonal agents plus signal transduction inhibitors- offers an effective means to restore sensitivity in these cells. Objective/Hypothesis . Our objective is to develop a carefully designed single molecular entity that can reverse or prevent the progression of hormone responsive breast cancer cells to an endocrine resistant state. We hypothesize that linking a potent steroidal antiestrogen through a biocompatible linker to a potent growth factor receptor kinase inhibitor would provide such a compound. The antiestrogenic component would provide targeting to the breast cancer cells as well as directly blocking estrogenic responses while the EGFR kinase inhibitor would independently block the signal transduction mechanisms that lead, via crosstalk, to endocrine resistance. Specific Aims. Specific aim 1. To synthesize the initial series of kinase inhibitor-tether-steroidal antiestrogen hybrids. Specific Aim 2. To screen the new compounds and the intermediates for estrogen receptor and growth factor related activity. Specific Aim 3. To evaluate the best compounds as inhibitors of cell proliferation in four breast cancer cell lines. Study Design: We will synthesize the individual subunits independently- the 11ß-substituted steroidal antiestrogen (A), the bifunctional polyethylene glycol tether with an azido group (B), and the EGFR kinase inhibitor with an ethynyl group (C). These can be assembled to form the final compound using “click chemistry.” The final compounds, as well as the intermediates, will be evaluated as inhibitors of estrogen binding and as inhibitors of receptor tyrosine kinase enzymes. Those compounds that demonstrate the best responses (nanomolar affinity in binding or submicromolar activity in enzyme inhibition) will be tested as inhibitors of breast cancer cell proliferation in four breast cancer cell lines. The results will be evaluated to either select compounds for advanced biological (preclinical) evaluation or serve as the basis for optimization of one or more units of the bivalent compounds. Potential Outcomes and Benefits of Research : The benefit of such agents would be for the treatment of estrogen responsive breast cancer and prevention of the progression to endocrine resistant disease.