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    Research Grants Awarded

    Combination Therapy For Treatment Of Hormone-Resistant Breast Cancers

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Background, preliminary studies and rationale for the proposed study: Approximately two-thirds of all breast carcinomas are estrogen receptor positive (ER +) and are treated effectively with either Tamoxifen or Aromatase Inhibitors (AIs). In postmenopausal women with ER + tumors, recurrent disease is usually treated with either tamoxifen or aromatase inhibitors (AIs). Although these drugs may lead to an initial tumor regression, extended use eventually results in secondary resistance and relapse. The EGFR/HER2 family is often over-expressed in secondarily resistant breast tumors. Accordingly, current work focuses mainly on targeting the proliferative components of growth factor signaling pathways. The goal of blocking proliferation with anti-growth factor compounds is to inhibit growth of the resistant cells while maintaining regression of the tumor cells which are still responsive to tamoxifen or AIs. While rationally based, these therapies have not as yet proven highly successful. Preliminary studies indicate that long-term estrogen deprivation causes adaptive changes in breast cancer cells such that they are now sensitive to killing by the administration of physiological concentrations of estrogen. Profound deprivation of estradiol is analogous to AI therapy in post-menopausal women. I plan to capitalize on a ?window? of opportunity during which estradiol paradoxically kills only malignant ?adapted? cells. This window of time occurs during emerging hormonal resistance. However, my preliminary data shows that estrogen alone is not enough to kill all breast cancer cells. My in vitro data using two highly potent apoptotic modulators, FTS and TMS, along with estrogen short term, shows a synergistic killing of adapted cells. In addition, the use of FTS and TMS on non-adapted cells also results in strong apoptosis. This data serves as our rationale for proposing an innovative new strategy which will make use of synergistic modulators of apoptosis to enhance estradiol induced cell kill of adapted breast cancer cells as well as death of non-adapted breast cancer cells. Hypothesis: My hypothesis is that estrogen used in conjunction with FTS and TMS can be used as a potent anti-cancer therapy to ?purge? long term estrogen deprived breast cancer cells (adapted cells) and that FTS and TMS can be used to kill non-adapted breast cancer cells. The plan would be to test the biological concepts in vitro and then segue into in vivo mouse models. The Specific Aims and Study Design of this proposal are: 1)To precisely determine the molecular mechanisms whereby E2, FTS, and TMS alone or in combination cause cell death in breast cancer cells in vitro. 2)To use mouse xenograft models to investigate the molecular mechanisms whereby E2, FTS and TMS alone or in combination purge breast cancer cells in vivo. 3)To compare the magnitude of cell kill of adapted vs. non-adapted cells with the pro-apoptotic ?purge strategy? and to determine if this therapy: (1) completely eliminates tumors which have initially responded to AIs, but then become resistant to these agents due to estradiol deprivation (i.e. adapted cells) (2) eliminates non-adapted cells through the effects of TMS and FTS. Potential Outcomes and Benefits of the Research are: The proposed in vitro studies will enhance our understanding of the molecular mechanisms of how E2, FTS and TMS invoke apoptosis in adapted long term estrogen deprived breast cancer cells and how FTS and TMS promote apoptosis in non adapted breast cancer cells. The proposed in vivo studies will provide a foundation for future clinical trials in postmenopausal women with secondarily resistant hormone-dependent breast cancers.

    Lay Abstract:
    Background: Approximately two-thirds of all breast carcinomas are estrogen receptor positive (ER +). Recurrent disease is treated effectively with either Tamoxifen or Aromatase Inhibitors (AIs). However, their extended use leads to resistance and eventually death. Research has shown that hormone-dependent cancers become resistant to these treatments predominantly because growth factor pathways are upregulated. Past research emphasis was focused on blocking cancer cell proliferation by modulating the growth factor pathways. Although this work helped to extend the efficacy of tamoxifen or AIs, the cancer cells were still able to develop complete resistance to these agents by utilizing other compensatory growth pathways. The overall goal of this proposal is to come up with a superior treatment plan for women with secondarily resistant breast cancer. The overall aim of this proposal is to kill the resistant cancer cells through a non-toxic hormonally induced apoptosis. Preliminary studies indicate that long-term estrogen deprivation causes adaptive changes in breast cancer cells such that they are now sensitive to killing by the administration of physiological concentrations of estrogen. Profound deprivation of estradiol is analogous to AI therapy in post-menopausal women. I will capitalize on a ?window' of opportunity during which estradiol paradoxically kills only malignant ?adapted? cells. However, my preliminary data shows that estrogen alone is not enough to kill all breast cancer cells. This may be due to the fact that not all adapted cells are killed by estrogen or that there are non-adapted cells where estrogen would not result in cell kill. Therefore, I propose to use combination therapy with two non-toxic pro-apoptotic compounds, FTS and TMS, to synergistically enhance the estrogen kill and ?purge? any non-adapted tumor cells left hopefully leading to a cure. Hypothesis: My hypothesis is that estrogen used in conjunction with FTS and TMS can be administered as a potent anti-cancer therapy to ?purge? long term estrogen deprived breast cancer cells (adapted cells) and that FTS and TMS can be used to kill non-adapted breast cancer cells. The Specific Aims and Study Design of this proposal are: 1) Human breast cancer cells will be used to learn about the cell death pathways. We will also learn how well the individual agents and their combinations kill both adapted and non-adapted breast cancer cells. 2) To assess the level of tumor cell death human breast cancer cells will be injected into nude mice and tumors will form. The tumors will be treated with either control or with individual agents (estrogen,FTS, TMS) or their combinations and measure the level of tumor death. 3) To determine if this strategy will end in cure of the breast cancer we will use nude mice to compare the degree of human breast tumor cell kill of adapted cells vs. non-adapted cells with the pro-apoptotic ?purge strategy? and determine if this therapy: a.) completely eliminates tumors (cure) which have initially responded to AIs but have become resistant to AIs due to estradiol deprivation (i.e.-adapted cells) b.) eliminates non-adapted cells through the effects of TMS and FTS. Potential Outcomes and Benefits of the Research are: This new concept of using non-toxic synergistic modulators of cell death to enhance hormonally induced apoptosis addresses treating the whole tumor cell population. Because it treats the whole tumor population this strategy provides hopes for a cure. Even if a cure is not possible, this strategy will likely provide for a prolonged response to AIs. Because each of the individual agents used to promote cell death are non-toxic, if used in women in the future, few adverse side effects are anticipated. The information gained from these translational studies will provide a foundation for early clinical trials.