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    Research Grants Awarded

    A Novel Approach To Reduce The Side Effects And Resistance Associated With Aromatase Inhibitor Therapy

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    A novel approach to reduce the side effects and resistance associated with aromatase inhibitor therapy [Beckground and Innovation]. Based on results from several major Phase III clinical trials, three third-generation aromatase inhibitors (AIs), anastrozole (ANA), exemestane (EXE) and letrozole (LET), are now considered to be important drugs for the hormonal therapy of breast cancer in postmenopausal women. AIs were demonstrated to be superior to tamoxifen (TAM) with regard to disease progression, incidences of locoregional and distant relapses, and contralateral breast cancers. While these findings are exciting, two questions have been frequently raised by breast cancer patients. They are concerned about the side effects associated with the use of AIs, e.g., bone loss and fractures, joint pain/arthralgia, bone pain/muscle pain, disabling/debilitating/intolerable side effects and etc. In addition, the possibility of developing resistance to AI treatment is often asked. Studies from this and two other laboratories have found that the expression of aromatase in breast cancer tissue is driven by promoters different from those used in non-cancer tissue. Therefore, a selective suppression of aromatase expression/estrogen biosynthesis in breast cancer tissue through the down regulation of breast tumor-specific promoters would be a novel approach to reduce side effects associated with whole-body reduction of estrogen (by using AIs) and to delay the time to progression (resistance). Our recent research has found that LBH589, an HDAC inhibitor, is a potent inhibitor of aromatase expression (IC50 = 15 nM; LBH589 is 40 times more potent than SAHA in the suppression of aromatase expression). Exciting preliminary results also indicate that LBH589 selectively suppresses promoters I.3/II of the human aromatase gene, the promoters preferentially used in breast cancer tissue. Furthermore, using a cell culture model, we learned that to achieve the same degree of the inhibition of aromatase activity/estrogen biosynthesis, the needed concentrations of LET, in the presence of 25 nM LBH589, were one fifth those in the absence of LBH589. [Hypothesis and Objective]. Based on the preliminary results, we hypothesize that a combined use of an AI, such as LET, and LBH589 will be a novel therapy to treat hormone dependent breast cancer in postmenopausal women. Such treatment strategy will preferentially suppress estrogen formation in breast cancer tissue and will significantly reduce side effects and delay AI resistance because a lower level of letrozole will be used. While we are excited about these recent findings, essential preclinical data are necessary for the design of new clinical trials using LET + LBH589. [Specific Aims]. 1. Experiments will be performed to characterize the molecular mechanisms as to how LBH589 down regulates the activity of promoters I.3/II. Such information will be critical for a better design of clinical trials with LBH589. This compound has been found to induce the degradation of Hsp90 client proteins and is currently in Phase II/III clinical development in patients with CTCL. 2. Cell culture experiments will be performed to demonstrate the synergistic action of LBH589 + LET in suppressing the proliferation of hormone-responsive breast cancer cells. We also plan to determine whether a combined use of these two drugs delays the onset of hormone resistance. 3. Animal experiments will be carried out to confirm the in vivo effect of these drugs in the suppression of the growth of hormone-responsive tumors. [Study Design]. This laboratory has extensive experience in aromatase gene expression studies and has a good collection of research reagents for proposed studies under Aim 1. Furthermore, our preliminary results have indicated that LBH589 down regulates the activity of aromatase promoters I.3/II through an epigenetic fashion. Experiments will be performed to determine the molecular mechanisms involved. For Aim 2, we have developed a MCF7 (ER+ breast cancer cells)-H295R (whose expression of aromatase is driven by promoters I.3/II) co-culture method. The proliferation of these cells can be induced by testosterone, indicating an active conversion of androgen to estrogen that promotes cell proliferation. In addition, we have established a set of AI-resistant cell lines as acquired resistance models. Therefore, we have the research tools and expertise to accomplish the research goals under Aim 2. Finally, we are familiar with studies on tumor induction in nude mice. Such experience will assure our success of the proposed experiments under Aim 3. It is our belief that these studies will produce critical preclinical results for the development of novel AI treatment strategies with fewer side effects, a delay of the time to progression (resistance), and improve the effectiveness of AIs.

    Lay Abstract:
    A novel approach to reduce the side effects and resistance associated with aromatase inhibitor therapy [Beckground and Innovation]. Based on results from several major Phase III clinical trials, three third-generation aromatase inhibitors (AIs), anastrozole (ANA), exemestane (EXE) and letrozole (LET), are now considered to be important drugs for the hormonal therapy of breast cancer in postmenopausal women. AIs were demonstrated to be superior to tamoxifen (TAM) with regard to disease progression, incidences of locoregional and distant relapses, and contralateral breast cancers. While these findings are exciting, two questions have been frequently raised by breast cancer patients. They are concerned about the side effects associated with the use of AIs, e.g., bone loss/fractures, joint pain/arthralgia, bone pain/muscle pain, disabling/debilitating/intolerable side effects and etc. In addition, the possibility of developing resistance to AI treatment is often asked. Studies from this and two other laboratories have found that the expression of aromatase in breast cancer tissue is controlled by mechanisms different from those used in non-cancer tissue. Therefore, drugs to selectively suppress aromatase expression/estrogen biosynthesis in breast cancer tissue would be a novel approach to reduce side effects associated with whole-body reduction of estrogen (by using AIs) and to delay the time to progression (resistance). Our recent research has found that LBH589, a drug to suppress gene expression, is a potent inhibitor of aromatase expression. Exciting preliminary results also indicate that LBH589 selectively reduces the level of aromatase in breast cancer cells. Furthermore, using a cell culture model, we learned that to achieve the same degree of the inhibition of aromatase activity/estrogen biosynthesis, the needed concentrations of LET, in the presence of 25 nM LBH589, were significantly reduced. [Hypothesis and Objective]. Based on the preliminary results, we hypothesize that a combined use of an AI, such as LET, and LBH589 will be a novel therapy to treat hormone dependent breast cancer in postmenopausal women. Such treatment strategy will preferentially suppress estrogen formation in breast cancer tissue and will significantly reduce side effects and delay AI resistance because a lower level of letrozole will be used. While we are excited about these recent findings, essential preclinical data are necessary for the design of new clinical trials using LET + LBH589. [Specific Aims]. 1. Experiments will be performed to characterize the molecular mechanisms as to how LBH589 selectively reduces aromatase levels in breast tumors. Such information will be critical for a better design of clinical trials with LBH589. This compound has been found to induce the degradation of proteins driving cancer growth and is currently in Phase II/III clinical development in patients with CTCL. 2. Cell culture experiments will be performed to demonstrate the synergistic action of LBH589 + LET in suppressing the proliferation of hormone-responsive breast cancer cells. We also plan to determine whether a combined use of these two drugs delays the onset of hormone resistance. 3. Animal experiments will be carried out to confirm the in vivo effect of these drugs in the suppression of the growth of hormone-responsive tumors. [Study Design]. This laboratory has extensive experience in aromatase gene expression studies and has a good collection of research reagents for proposed studies under Aim 1. Furthermore, our preliminary results have indicated that LBH589 reduces the levels of aromatase in breast cancer through an epigenetic fashion. Experiments will be performed to determine the molecular mechanisms involved. For Aim 2, we have developed a novel cell culture model to study the effect of LBH589 on the proliferation of breast cancer cells. In addition, our laboratory has established a set of AI-resistant cell lines as acquired resistance models for testing the possibility to fight against AI resistance using LBH589. Therefore, we have the research tools and expertise to accomplish the research goals under Aim 2. Finally, we are familiar with studies on tumor induction in mice. Such experience will assure our success of the proposed experiments under Aim 3. It is our belief that these studies will produce critical preclinical results for the development of novel AI treatment strategies with fewer side effects, a delay of the time to progression (resistance), and improve the effectiveness of AIs.