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Bazedoxifene Exhibits Antiestrogenic Activity in Animal Models of Tamoxifen-Resistant Breast Cancer: Implications for Treatment of Advanced Disease

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Bazedoxifene Exhibits Antiestrogenic Activity in Animal Models of Tamoxifen-Resistant Breast Cancer: Implications for Treatment of Advanced Disease Published OnlineFirst March 27, 2013; DOI: 10.1158/1078-0432.CCR-12-3771 Clinical Cancer Cancer Therapy: Preclinical Research Bazedoxifene Exhibits Antiestrogenic Activity in Animal Models of Tamoxifen-Resistant Breast Cancer: Implications for Treatment of Advanced Disease Suzanne E. Wardell, Erik R. Nelson, Christina A. Chao, and Donald P. McDonnell Abstract Purpose: There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-a) antagonists, or that downregulate the expression of ER-a, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-a pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. Experimental Design: A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-a conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. Results: The high-affinity SERM bazedoxifene was shown to function as a pure ER-a antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-a that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Conclusion: Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer. Clin Cancer Res; 19(9); 1–12. Ó2013 AACR. Introduction tamoxifen subsequently respond to aromatase inhibitors The primary goal of endocrine therapies in breast cancer (1–3). This finding highlights the continued dependence a is to block the transcriptional activity of estrogen receptor on ER- signaling within tumors in advanced disease, (ESR1, ER-a) by either (i) inhibiting CYP19A1 (aromatase), raising the possibility that even in tumors that are resistant a the enzyme responsible for the conversion of androgens to to tamoxifen and aromatase inhibitors, the ER- signaling estrogens, or (ii) directly interfering with the transcriptional axis may remain a viable target. activity of the receptor. When used as primary interventions The primary mechanisms underlying resistance to tamox- both approaches are similarly efficacious and improve ifen and aromatase inhibitors are somewhat different. outcome to the same degree. Notable, however, is the However, it now seems that a common feature in either observation that a significant number of patients that case involves the reprograming of ER signaling pathways exhibit de novo or acquired resistance to the antiestrogen within tumor cells, allowing them to continue to capitalize on progrowth and survival pathways downstream of ER-a. The currently available aromatase inhibitors effectively reduce the production of both peripherally and intratumo- Authors' Affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina rally generated estrogens, and resistance to these agents is not associated with an inability to effectively suppress Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). estrogen production (4, 5). Rather, there is accumulating evidence that exposure of ER-a–positive breast cancer cells Corresponding Author: Donald P. McDonnell, Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, NC 27710. to aromatase inhibitors renders them hypersensitive to Phone: 919-684-6035; Fax: 919-681-7139; E-mail: either residual amounts of steroidal estrogens, dietary/envi- [email protected] ronmental compounds with estrogenic activity, or to doi: 10.1158/1078-0432.CCR-12-3771 endogenously produced molecules that exhibit estrogenic Ó2013 American Association for Cancer Research. activity but which do not require aromatization (6–8). With www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst March 27, 2013; DOI: 10.1158/1078-0432.CCR-12-3771 Wardell et al. determined that tamoxifen does not freeze ER-a in an Translational Relevance apo-state but rather it induces a conformational change Breast cancer remains the most commonly diagnosed that enables the presentation of unique protein–protein cancer among women and the leading cause of cancer interaction surfaces on the receptor that dictate its tran- mortality in women worldwide. Although targeted ther- scriptional coregulator-binding preferences (15). Thus, the apies such as tamoxifen and aromatase inhibitors are agonist activity of tamoxifen depends on the relative expres- effective in treating estrogen receptor (ER)–positive sion and/or the activity of functionally distinct coregulators tumors, de novo and acquired resistance remain an in target tissues (16, 17). Although the specific coregulators impediment to durable clinical responses. However, that enable the agonist activity of tamoxifen remain elusive, ER-a remains a therapeutic target in breast cancers that there are considerable additional data to support this are resistant to both first- and second-line endocrine hypothesis. Most notably, by screening for compounds that interventions. Evaluation of the molecular pharmacol- induced a conformational change in ER-a that did not ogy of clinically relevant ER modulators revealed that the present the protein–protein interaction surfaces required third-generation selective estrogen receptor modulator for tamoxifen action, we identified DPC974/GW5638 (SERM) bazedoxifene had a unique mechanism of (18, 19). This compound was shown to be an effective action and inhibited the growth of both tamoxifen- inhibitor of ER action in xenograft models of both tamox- sensitive and -resistant ER-a–positive breast cancer ifen-sensitive and -resistant breast cancers and yielded xenografts. These findings provide strong support for positive results in a heavily treated population of patients the clinical evaluation of bazedoxifene in patients with with breast cancer with endocrine treatment–resistant dis- breast cancer who relapse while undergoing treatment ease (20). Similarly, it has been shown that fulvestrant (ICI with tamoxifen and/or an aromatase inhibitor. 182,780; ICI) also induces a unique conformational change in ER-a, likewise functions as an antagonist in tamoxifen- resistant xenograft models and shows efficacy in patients with advanced disease (15, 21, 22). Together these data respect to the latter, we and others have shown that the suggest that by manipulating ER-a structure and influencing oxysterol 27-hydroxycholesterol, a primary metabolite of coregulator engagement it is possible to develop com- cholesterol, exhibits robust estrogenic activity and is pro- pounds with useful activities in breast cancer. duced at levels that are likely to promote substantial tumor Clearly, there is a very strong rationale to support the growth (ref. 9; unpublished data). Thus, it is anticipated that targeting of ER-a in the setting of tamoxifen- and aroma- high-affinity ER-a antagonists, or compounds that ablate tase-resistant disease. Considering the current state of the ER-a expression, would have clinical activity in aromatase- art in this field, it is likely that drugs with usage in these resistant disease. disease states can be identified by screening for agents that The mechanisms underlying resistance to tamoxifen are (i) bind ER-a with an affinity high enough to outcompete complex. When originally developed, tamoxifen was clas- both endogenous and exogenous estrogens, (ii) exhibit sified as an "antiestrogen," a compound that competitively minimal agonist activity on those genes on which tamox- inhibited the binding of estrogens to ER-a, thus freezing it ifen agonist activity is manifest in resistant breast cancer in an apo-conformation. However, this simple model failed cells, and (iii) induce a structural change in ER-a that to explain how tamoxifen could manifest agonist activity in disables the protein–protein interaction surfaces required bone and in the endometrium and did not explain the for tamoxifen agonist activity. With these criteria in mind, withdrawal responses noted in some patients with breast we conducted a comparative functional analysis of clin- cancer who progressed while on tamoxifen (10–13). It is ically relevant ER ligands, a study that revealed that now known that tamoxifen is not an antiestrogen per se, bazedoxifene, a recently developed high-affinity orally but rather a selective estrogen receptor modulator (SERM), a active SERM, inhibits ER-a action in both tamoxifen- compound whose relative agonist/antagonist activity can sensitive and -resistant xenograft models. This drug was differ between cells. Thus, although it is capable of func- recently approved for use in
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