Combination Of Bazedoxifene Research Articles

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer.

The interleukin 6 (IL-6)/glycoprotein 130 (GP130)/signal transducer and activator of transcription 3 (STAT3) signalling pathway, with GP130 as an intermediate membrane receptor, is involved in the survival, metastasis, and resistance of ovarian cancer. Bazedoxifene, an FDA-approved drug, is an inhibitor of GP130 and a selective estrogen modulator (SERM). We studied the mechanism of the combination therapy of bazedoxifene and paclitaxel in inhibiting the IL-6-mediated GP130/STAT3 signaling pathway in ovarian cancer. Surface plasmon resonance (SPR) was used to assess the binding of bazedoxifene to GP130. Migration, invasion, and apoptosis of ovarian cancer cells were assessed using bazedoxifene and paclitaxel. In addition, we determined the effects of bazedoxifene and paclitaxel alone or in combination on the GP130/STAT3 pathway and epithelial-mesenchymal transition (EMT). The results revealed that the combination of bazedoxifene and paclitaxel suppressed cell viability, migration, and invasion in the ovarian cancer cells. In addition, the combination treatment increased apoptosis. Furthermore, bazedoxifene combined with paclitaxel inhibited the growth of ovarian cancer cells in a xenograft tumour model. This combination reduced STAT3 phosphorylation and suppressed gene expression and EMT. In conclusion, inhibition of GP130/STAT3 signalling and EMT via a combination of bazedoxifene and paclitaxel could be used as a therapeutic strategy by which to overcome ovarian cancer.

Bazedoxifene increases the proliferation of human arterial endothelial cells but does not affect the expression of cyclins A, B, and D1 and of p27Kip1

Objective Endothelial dysfunction and denudation are considered a first step in atherosclerosis. Endothelial proliferation is key for cellular repair. The effect of bazedoxifene on the vascular endothelium has not been explored. We investigated the effect of bazedoxifene on endothelial cell proliferation. Methods Primary cultures from human umbilical artery endothelial cells were used in dose-response experiments (0.1, 1.0, and 10.0 EC50 dose) with bazedoxifene, estradiol, raloxifene and a combination of bazedoxifene and estradiol. Proliferation was assessed with the XTT colorimetric cell-proliferation assay. The possible participation of cyclins A, B, D1 and p27Kip1 was analyzed by the measurement of their expression at both the protein and the gene levels. Results A significant increase of similar size for cell proliferation was obtained with bazedoxifene, estradiol and raloxifene, but no significant change was observed for the association of bazedoxifene and estradiol. The impact was detected at the first 0.1 EC50 dose and was not dose-dependent. Estradiol achieved a significant increase in the protein expression of cyclin A and p27Kip1, but no change was detected for the other compounds at either the gene or protein level. Conclusion Bazedoxifene demonstrated a proliferative effect of similar size to estradiol in cultured human umbilical artery endothelial cells. The molecular mechanisms need further investigation.

Abstract 1099: Combination of bazedoxifene and lapatinib profoundly inhibits estrogen receptor positive (ER+) and Negative (ER-) mammary tumorigenesis

Abstract Bazedoxifene (Baz), a 3rd Gen SERM, is approved for prevention and treatment of osteoporosis as Duavee in the US. Baz downregulates ERα and inhibits growth of ER+ breast cancer (BC) cells, without stimulating the uterine endometrium. It also inhibits hormone-independent BC cell growth, presumably by inhibiting IL-6/GP130 interaction and downmodulating pSTAT3-cyclin D1 pathway, resulting in induction of apoptosis and reduction of tumor growth. Lapatinib (Lap), an FDA approved, small molecule dual inhibitor of both the EGFR/HER1 and HER2, is commonly used to treat patients with HER2-positive (HER2+) BC. We evaluated the efficacy of these two FDA-approved drugs, Baz and Lap, at lower doses, alone and in combination, for the prevention of BC in rodent models. Lap was given either daily or Ix/week by oral gavage while Baz was added directly to the diet. For ER+ mammary cancers, female Sprague-Dawley rats were given methylnitrosourea (MNU) at 50 days of age. The agents were started one week prior to MNU treatment in the following 6 groups: 1) Baz (5.0 mg/kg diet, 7x/week); 2) Lap (350 mg/kg BW, Ix/week); 3) Lap (50 mg/kg BW, 7x/week); 4) Baz + Lap as in Groups 1 and 2; 5) Baz + Lap as in Groups 1 and 3; and 6) none. At the end of the study (20 weeks after MNU), mammary cancer multiplicities in Groups 1 to 6 were: 0.75, 0.6, 0.2, 0.15, 0.1, and 4.25, respectively, demonstrating a profound (82-98%) inhibition of ER+ mammary cancers (p<0.0001). When the agents were started prior to dimethybenzanthracene (DMBA, 1.0 mg/gavage, Ix/week for 4 weeks) in MMTV/Neu mice (7 weeks age), cancer multiplicities at the end of the study (18 weeks after the initial DMBA treatment) were as follows: 1) Baz (5.0 mg/kg diet), 1.0; 2) Lap (625 mg/kg BW,1x/week), 2.1; 3) Lap (125 mg/kg BW, 5x/week), 2.65; 4) Baz + Lap as in Groups 1 and 2; 0.4; 5) Baz + Lap as in Groups 1 and 3, 0.2; and 6) none, 5.2, demonstrating similarly profound chemoprevention efficacy by the combination regimens with multiplicities reduced by 93-96% (p<0.01). Of note, giving lap Ix/week either alone or in combination with Baz resulted in significant decreases in cancer incidence, multiplicities and weights in both models. In a 2-week biomarker study, female MMTV/Neu mice treated with the combinations had significantly decreased proliferation rate (Ki67) in mammary epithelial cells by 74% (p<0.05). These findings indicate that the combination of low-dose daily Baz and weekly Lap is highly effective in preventing ER+ and ER- mammary cancers, and that treatment with the EGFR/HER2 inhibitor Lap once a week is similarly efficacious to daily treatment with divided doses in its cancer inhibitory activity without overt toxicity. Citation Format: Altaf Mohammed, Shizuko Sei, Robert Shoemakers, Clinton J. Grubbs. Combination of bazedoxifene and lapatinib profoundly inhibits estrogen receptor positive (ER+) and Negative (ER-) mammary tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1099.

Bazedoxifene enhances paclitaxel efficacy to suppress glioblastoma via altering Hippo/YAP pathway.

Glioblastoma multiform (GBM) is an aggressive type of brain tumor originated from astrocytes. Owing to the limited therapeutic options, intensive efforts are still being made to find novel treatments for GBM. In this study, we first identified that bazedoxifene bore the ability to reduce cell survival and cell invasion of glioblastoma cells. Furthermore, our results also revealed that bazedoxifene combining with paclitaxel had better efficacy to suppress glioblastoma progression by promoting apoptosis and reducing EMT. Combination of bazedoxifene and paclitaxel also accelerated YAP phosphorylation and inactivation. Importantly, preclinical animal model also verified our in vitro findings. Together, our data not only define the underlying mechanism responsible for action of bazedoxifene on glioblastoma cells but also build strong rational to develop bazedoxifene for the treatment of GBM patients.

Abstract PD1-05: Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer

Abstract Background: Despite the efficacy of endocrine treatments (ETs), most patients with ER+ metastatic breast cancer (MBC) will ultimately develop resistance to these treatments. In most cases of endocrine resistance, ER continues to be expressed. About 30% of patients with ER+ MBC acquire an activating ER mutation that confers resistance to aromatase inhibitors. Thus, ER remains an important driver in a substantial number of patients with MBC despite resistance to currently available ETs. Bazedoxifene is a third generation selective ER modulator (SERM) with selective ER degradation (SERD) activity. The structural characteristics of bazedoxifene differ from those of tamoxifen and raloxifene. Pre-clinical studies showed that bazedoxifene has increased ER antagonistic activity compared to tamoxifen and fulvestrant and has synergistic activity in combination with the CDK4/6 inhibitor, palbociclib. We evaluated the safety and efficacy of bazedoxifene in combination with palbociclib in ER+ MBC. Methods: This was a phase Ib/II study of patients with ER+/HER2- MBC who had progressed on at least one line of ET for metastatic disease or within 12 months of adjuvant ET. Treatment included daily continuous bazedoxifene 40mg and palbociclib 125 mg for 21 days out of a 28-day cycle. Primary endpoint was clinical benefit rate (CBR; CR + PR + SD ≥ 24 weeks). Secondary end points included objective response, progression free survival (PFS) and safety. The study used a Simon optimal two-stage design and included a safety run-in phase with the first six patients. The sample size was chosen to have 90% power and a one-sided Type I error of ≤10% to reject the null (CBR of < 20%). A biopsy from a metastatic site was obtained from 21 patients and serial plasma samples were collected from all patients for correlative studies. Results: From July, 2015 to July, 2017 36 patients enrolled in the study (34 females, 2 males). More than 80% of the patients received at least 1 prior line of endocrine treatment for metastatic disease. 45% of the patients received ≥ 2 lines of endocrine treatment and 52% received 1-2 lines of chemotherapy prior to the study. More than 80% of the patients had visceral disease. The combination of bazedoxifene and palbociclib was well tolerated. The most commonly observed adverse events (any grade) were fatigue and neutropenia. Grade 4 adverse events were uncommon (2 patients). The CBR was 36% (95% CI 23-49%). The objective response rate was 8% (95% CI 2-22%). Median PFS was 3.6 months (95% CI 2-8.5 months). There were 5 patients with a durable clinical benefit of ≥12 months. Correlative analysis of the pre-treatment tissue samples and serial plasma samples are ongoing. Conclusions: The combination of bazedoxifene and palbociclib was well tolerated and demonstrated significant clinical activity in heavily pre-treated patients with ER+ MBC. Further studies investigating bazedoxifene in ER+ breast cancer are warranted. Citation Format: Jeselsohn R, Guo H, Rees R, Barry WT, Barlett CH, Tung NM, Krop IE, Brown M, Winer EP. Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-05.

Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol

A new strategy for menopausal hormone therapy replaces medroxyprogesterone with the selective estrogen receptor modulator bazedoxifene. While the agonist or antagonist activity of bazedoxifene has been examined in other tissues, the current study explored the impact of bazedoxifene on resistance artery reactivity. We hypothesized that bazedoxifene may induce greater vasoprotective effects than estradiol due to enhanced activation of the G-protein-coupled estrogen receptor. We measured the vasodilation of mesenteric resistance arteries from adult male and female wild-type and G-protein-coupled estrogen receptor knockout mice (n = 58) in response to increasing concentrations of bazedoxifene, medroxyprogesterone, and estradiol, and also the impact of these compounds on the responses to phenylephrine and sodium nitroprusside. Bazedoxifene-induced vasorelaxation was greater than estradiol and blunted phenylephrine-induced contraction-an effect not observed with estradiol. Neither estradiol nor bazedoxifene altered relaxation to sodium nitroprusside. The combination of bazedoxifene + estradiol promoted greater vasodilation than medroxyprogesterone + estradiol, and opposed phenylephrine-induced contraction, whereas medroxyprogesterone + estradiol failed to attenuate this response. Both bazedoxifene + estradiol and medroxyprogesterone + estradiol enhanced sodium nitroprusside-induced relaxation in females. Vascular responses were similar in both sexes in wild-type and G-protein-coupled estrogen receptor knockout mice. Bazedoxifene and bazedoxifene + estradiol relaxed mesenteric arteries and opposed vasoconstriction to a greater degree than estradiol or medroxyprogesterone + estradiol. These effects were independent of sex and G-protein-coupled estrogen receptor expression. We conclude that bazedoxifene may provide vascular benefits over estrogen alone or estrogen plus progestogen combinations in postmenopausal women.

Abstract 864: Repurposing FDA-approved drug bazedoxifene as a novel inhibitor of IL-6 signaling for triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a major cause of death among breast cancer patients and is the only subtype of breast cancer that is still lacking effective therapeutic options. IL-6 is one of the principal oncogenic mediators in breast cancer and systemic IL-6 levels correlates with poor prognosis, advanced disease, and metastases. Importantly, growth of TNBC cells are replied on autocrine cytokines including IL-6 and TNBC cells secret the highest levels of IL-6 comparing to other subtypes of breast cancer. Therefore, IL-6 signaling represents a novel approach with a potential to improve the therapeutic efficacy. To date, however, no small molecules that target IL-6 signaling are available for clinical cancer therapy. IL-6 binds to IL-6 Rα, then recruits Glycoprotein 130 (GP130) to form hexamer consisting two IL-6/IL-6 Rα/GP130 heterotrimers to trigger a signaling cascade downstream including JAK/STAT3, PI3-K/AKT/mTOR, and MEK/ERK. Therefore, it is possible to target IL-6 signaling by blocking IL-6 binds to GP130 or IL-6 Rα and thus inhibiting its signaling cascade downstream. We have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repurposing to target GP130 and have identified a FDA-approved drug Bazedoxifene (for the prevention of the osteoporosis in postmenopausal women) with a novel function to inhibit IL-6 and GP130 proteinprotein interactions and thus blocking IL-6 signaling cascade downstream. In this study, we examined the therapeutic efficacy of Bazedoxifene in combination with paclitaxel on human TNBC cells and TNBC tumor model, aiming to provide experimental results of Bazedoxifene and paclitaxel combination for TNBC therapy. Our data showed Bazedoxifene inhibited increased STAT3 phosphorylation induced by IL-6. Bazedoxifene also inhibited phosphorylation of STAT3, AKT, and ERK in TNBC cells that produced IL-6. In addition, combination of Bazedoxifene with paclitaxel exhibited more significant inhibition on cell viability and colony formation and induction of apoptosis than single agent alone in TNBC cells in vitro. Moreover, Bazedoxifene inhibits cell migration and combination of Bazedoxifene with paclitaxel more significantly inhibit cell migration than single agent alone. We also showed bazedoxifene could inhibit increased proliferation of TNBC cells induced by IL-6. The combination of Bazedoxifene with paclitaxel also showed significantly inhibition of tumor growth of TNBC in vivo furtherly supported the therapeutic effects of Bazedoxifene. The results support the significant therapeutic efficacy of Bazedoxifene and paclitaxel combination for further TNBC therapy. Citation Format: Xiang Chen, Shengling Fu, Jilai Tian, Yang Cao, Chenglong Li, Jiayuh Lin. Repurposing FDA-approved drug bazedoxifene as a novel inhibitor of IL-6 signaling for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 864.

Abstract 3261: Pilot study of the combination of bazedoxifene and conjugated estrogen to modulate risk biomarkers in women with hot flashes at increased risk for breast cancer

Abstract Uptake of anti-hormonal agents for primary prevention of breast cancer is poor due to concern about side effects, especially induction of menopausal symptoms. A combination of 20 mg bazedoxifene plus 0.045 mg conjugated estrogen is FDA approved (as Duavee®) for treatment of hot flashes and prevention of osteoporosis in postmenopausal women with a uterus. We undertook a pilot study to assess the feasibility of using this formulation as a breast cancer prevention agent in women at increased risk for development of breast cancer. Feasibility was to be assessed by accrual, retention, and documentation of a lack of enhanced proliferation in benign breast tissue acquired by random periareolar fine needle aspiration (RPFNA). Eligibility criteria included risk >2X that of average risk woman for age group, postmenopausal having hot flashes or night sweats and not on systemic hormone replacement, and at least 500 cells on a baseline RPFNA. Women were ineligible if they had LCIS or DCIS, a BRCA1/2 germline mutation, had had a hysterectomy, or had >4% Ki-67 positive cells by immunocytochemistry. Fasting blood draw, digital mammography with Volpara software, and DXA scan for body composition was performed at baseline along with QOL questionnaires. Women then received Duavee® daily for 6 months, followed by repeat of baseline tests. We accrued the first 20 subjects in 14 months. Many of the women followed in our cohort and interested in the trial were not eligible due to prior hysterectomy, prior LCIS or a high penetrance gene mutation. Thus accrual was slower than anticipated. All women have reported improvement in hot flash frequency and intensity. None have discontinued prematurely or had a study related serious adverse event. Fourteen women have completed the 6-month intervention and are evaluable for modulation of biomarkers. There have been no protocol-defined increases in proliferation (to >2% Ki-67 for baseline Ki-67 <1% or doubling if baseline Ki-67 ≥1%), with 10 of 14 paired specimens exhibiting a decrease. Ten women had Volpara fibroglandular assessments pre- and post-study with a median relative decrease of 11% (8 decreased and 2 increased). For the first ten subjects where serum hormones and growth factors were assessed in paired assays, favorable modulation was observed for estradiol, testosterone, SHBG, bioavailable testosterone, IGF-1, and the molar ratio of IGF1:IGFBP3. A primary prevention trial in symptomatic women appears feasible given the favorable initial results. The current pilot will continue to accrue so as to inform the design of a randomized, placebo-controlled Phase II trial of Duavee® in women at risk for breast cancer. Financial support provided by grants from the Breast Cancer Research Foundation (BCRF-16-049, BCRF-17-049). Duavee® provided by Pfizer, Inc. which was not involved in design, conduct, or analysis of the study. Citation Format: Carol J. Fabian, Kandy R. Powers, Jennifer L. Nydegger, Amy L. Kreutzjans, Trina Metheny, Teresa A. Phillips, Lauren Nye, Carola M. Zalles, Bruce F. Kimler. Pilot study of the combination of bazedoxifene and conjugated estrogen to modulate risk biomarkers in women with hot flashes at increased risk for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3261.

Abstract 1148: Bazedoxifene as a novel GP130 inhibitor for the treatment of triple-negative breast cancer

Abstract Triple negative breast cancer (TNBC) is the only subtype of breast cancer still lacking effective therapeutic options. Thus, finding novel targets and therapies to treat TNBC is an urgent clinical issue. IL-6 is one of the principal oncogenic mediators in breast cancer and systemic IL-6 levels correlates with poor prognosis, advanced disease, and metastases. Importantly, growth of TNBC cells are replied on autocrine cytokines including IL-6. Therefore, IL-6 signaling represents a novel approach with a potential to improve the therapeutic efficacy. To date, however, no small molecules that target IL-6 signaling are available for clinical cancer therapy. IL-6 binds to IL-6 Rα, then recruits GP130 to form the IL-6/IL-6 Rα/GP130 heterotrimer and triggers a signaling cascade downstream including JAK/STAT3, PI3-K/AKT/mTOR, and MEK/ERK. Therefore, it is possible to target IL-6 signaling by blocking IL-6 binds to GP130 or IL-6 Rα and thus inhibiting its signaling cascade downstream.To effectively target IL-6 signaling, we have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repurposing to target GP130, since its structure is more druggable than IL-6 Rα. We have identified a FDA-approved drug Bazedoxifene (for the prevention of the postmenopausal osteoporosis in postmenopausal women) with a novel function to inhibit IL-6 and GP130 protein-protein interactions and thus blocking IL-6 signaling cascade downstream. In this study, we examined the therapeutic effect of Bazedoxifene on TNBC, aiming to verify Bazedoxifene as a Novel IL-6/GP130 Inhibitor for TNBC treatments.Our data of western blot showed Bazedoxifene inhibited increased STAT3 phosphorylation induced by IL-6. In addition, Bazedoxifene inhibited phosphorylation of AKT and ERK in TNBC cells that were also produced by IL-6. Furthermore, combination of Bazedoxifene with paclitaxel exhibited more significant inhibition than single agent alone on cell viability in TNBC cells either in 2D or 3D culture model in vitro. Results of colony formation showed that Bazedoxifene could significantly inhibit cell survive and proliferation at 20 μM, which were more effective than Evista and SC144. Moreover, Bazedoxifene could inhibit cell migration. We tested the increased proliferation of TNBC cells using BrdU with the added IL-6, which were then inhibited by Bazedoxifene, demonstrating the Bazedoxifene could achieve a competed inhibition of IL6. The result of significant inhibition of tumor growth in vivo furtherly verified the therapeutic effects of Bazedoxifene. All results showed the significant therapeutic effects of Bazedoxifene in TNBC cells by competed blocking IL6 signaling. Thus, Bazedoxifene holds a great potential for TNBC therapy. Note: This abstract was not presented at the meeting. Citation Format: Jilai Tian, Yang Cao, Xiang Chen, Hui Xiao, Chenglong Li, Jiayuh Lin. Bazedoxifene as a novel GP130 inhibitor for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1148. doi:10.1158/1538-7445.AM2017-1148

Abstract P3-05-09: Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance

Abstract INTRODUCTION Despite effective endocrine treatments, endocrine resistance remains a major clinical challenge. We and other groups have recently detected ligand-binding domain ESR1 mutations in metastatic estrogen receptor positive ( ER+) breast cancers. Our preclinical studies showed that these mutations confer constitutive activity and relative resistance to tamoxifen and fulvestrant. In this study we sought to investigate therapeutic strategies to overcome resistance rendered by the ESR1 mutations. Since our previous studies showed relative resistance to tamoxifen or fulvestrant, we hypothesized that bazedoxifene, a high affinity third generation SERM/SERD could overcome resistance driven by the ER mutant resistance. Additionally, we hypothesized that inhibiting cyclin D1, a key ER transcriptional target gene and cell cycle regulator, is a second potential therapeutic strategy to circumvent resistance rendered by mutant ER. Therefore in this study we tested the effects of bazedoxifene, palbciclib and their combination on cell proliferation in the presence and absence of the ESR1 mutations. METHODS For this study we established doxycycline inducible MCF7 cell lines expressing the ER-LBD mutations (Y537S, Y537N and D538G) and WT-ER as control. Cell proliferation response to bazedoxifene, tamoxifen, fulvestrant, palbociclib and the bazedoxifene-palbociclib combination was evaluated. RESULTS Cells harboring mutant ER were relatively resistant to tamoxifen and fulvestrant, as expected, and remained sensitive to single agent bazedoxifene and palbociclib. The combination of bazedoxifene and palbociclib was found to be superior to the single agents and exhibits synergistic activity. CONCLUSION The combination of bazedoxifene and palbociclib inhibits mutant ER cell growth and other cell models of endocrine resistance and is a potential therapeutic combination. Citation Format: Nguyen M, Buchwalter G, Luo F, Garraway L, Brown M, Jeselsohn R. Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-09.

Estrogen Replacement Therapy Regulation Of Energy Metabolism In Female Mouse Hypothalamus

Estrogens play an important role in the regulation of energy homeostasis in female mammals and a reduced ovarian function, due to natural aging or surgery, is associated with body weight increase and fat redistribution. This disruption of energy homeostasis may constitute a trigger for several pathologies known to be associated with climacterium; however, so far, limited attention has been devoted to the ability of estrogen replacement therapies (ERT) to reinstate the balanced energy metabolism characteristic of cycling female mammals. The purpose of the present study was to compare the efficacy of selected ERTs in reversing the ovariectomy-induced gain in body weight. To this aim female ERE-Luc mice were ovariectomized and, after 3 weeks, treated per os for 21 days with: conjugated estrogens, two selective estrogen receptor modulators (bazedoxifene and raloxifene), and the combination of bazedoxifene plus conjugated estrogens (tissue-selective estrogen complex, TSEC). The study shows that the therapy based on TSEC was the most efficacious in reducing the body weight accrued by ovariectomy (OVX). In addition, by means of in vivo imaging, the TSEC treatment was shown to increase estrogen receptor (ER) transcriptional activity selectively in the arcuate nucleus, which is a key area for the control of energy homeostasis. Finally, quantitative analysis of the mRNAs encoding orexigenic and anorexigenic peptides indicated that following ERT with TSEC there was a significant change in Agrp, NPY, and Kiss-1 mRNA accumulation in the whole hypothalamus. Considering that prior studies showed that ERT with TSEC was able to mimic the rhythm of ER oscillatory activity during the reproductive cycle and that such fluctuations were relevant for energy metabolism, the present observations further point to the ER tetradian oscillation as an important component of the ER signaling necessary for the full hormone action and therefore for an efficacious ERT.

Hormone replacement therapy and the prevention of postmenopausal osteoporosis.

Fracture prevention is one of the public health priorities worldwide. Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis, the most common metabolic bone disease. Different effective treatments for osteoporosis are available. Hormone replacement therapy (HRT) at different doses rapidly normalizes turnover, preserves bone mineral density (BMD) at all skeletal sites, leading to a significant, reduction in vertebral and non-vertebral fractures. Tibolone, a selective tissue estrogenic activity regulator (STEAR), is effective in the treatment of vasomotor symptoms, vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT. Selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures. The combination of bazedoxifene and conjugated estrogens, defined as tissue selective estrogen complex (TSEC), is able to reduce climacteric symptoms, reduce bone turnover and preserve BMD. In conclusion, osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms. The use of a standard dose of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover, with compelling scientific evidence.

Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture

Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women’s Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.

Inhibitory Effects of a Bazedoxifene/Conjugated Equine Estrogen Combination on Human Breast Cancer Cells In Vitro

Breast cancer incidence is increased in women receiving menopausal hormone therapy with estrogen plus progestin but not with estrogen alone. The use of a tissue-selective estrogen complex (TSEC) has been proposed as a novel menopausal hormone therapy strategy to eliminate the requirement for a progestogen. Combination of bazedoxifene (BZA) with conjugated estrogens (CEs), the first TSEC, has shown beneficial effects. Whether it would exert antiestrogenic effects on breast cancer is not clear. To address this issue, we compared estradiol (E(2)) and CE alone on proliferation and apoptosis in MCF-7 breast cancer cells. CE stimulated growth of MCF-7 cells at a peak concentration 10-fold higher than required for E(2). Both CE and E(2) alone increased DNA synthesis and reduced apoptosis with activation of MAPK, Akt, and p70S6K and up-regulation of antiapoptotic factors survivin, Bcl-2, and X-linked inhibitor of apoptosis protein, These effects could be completely blocked by BZA. Gene expression studies demonstrated that CE and E(2) were equally potent on expression of cMyc, pS2, and WNT1 inducible signaling pathway protein 2, whereas the stimulatory effects of CE on progesterone receptor and amphiregulin expression were weaker than E(2). BZA effectively blocked each of these effects and showed no estrogen agonistic effects when used alone. Our results indicate that the stimulatory effects of E(2) or CE on breast cancer cells could be completely abrogated by BZA. These studies imply that the CE/BZA, TSEC, exerts antiestrogenic effects on breast cancer cells and might block the growth of occult breast neoplasms in postmenopausal women, resulting in an overall reduction in tumor incidence.

Tissue-Selective Estrogen Complex Bazedoxifene and Conjugated Estrogens for the Treatment of Menopausal Vasomotor Symptoms

Menopause occurs on average at age 51.4 years. Most, but not all, women who undergo menopause experience significant vasomotor symptoms (VMS). Although single agent estrogen therapy can relieve VMS, over time estrogen can stimulate the endometrial lining leading to an increased risk for endometrial hyperplasia and adenocarcinoma. Although a progestin has traditionally been given in combination with estrogen to 'protect' the endometrium, a new and innovative approach to this traditional combination hormone therapy is to substitute the progestin with an alternative agent. One such alternative agent is bazedoxifene, an estrogen agonist-antagonist. Based on data from randomized trials, when bazedoxifene is given in combination with oral conjugated estrogens to post-menopausal women, the risk of estrogen-associated endometrial stimulation is significantly reduced. The combination of bazedoxifene and conjugated estrogens has also been shown to relieve menopause-associated VMS and vaginal atrophy, and has been shown to be safe for short-term use. Long-term studies of this combination are needed to determine if the combination of conjugated estrogens/bazedoxifene can be used for >3 years without increasing the risk of breast cancer, stroke, cognitive deficit, pulmonary embolism or coronary heart disease. Short-term data regarding this combination has been submitted to the FDA and is currently under review for clinical use, with the relief of VMS as its primary indication. Data regarding the effects of combination conjugated estrogens/bazedoxifene therapy on bone are promising in terms of the prevention and treatment of post-menopausal osteoporosis.