A Selective Estrogen Receptor Modulator for the Treatment of Hot Flushes

Wallace, Owen B.; Lauwers, Kenneth S; Dodge, Jeffrey A.; May, Scott A.; Calvin, Joel R.; Hinklin, Ronald J.; Bryant, Henry U.; Shetler, Pamela; Adrian, Mary D.; Geiser, Andrew G.; Sato, Masahiko; Burris, Thomas P.

doi:10.1021/jm0509795

Cited by 40 publications

(19 citation statements)

References 20 publications

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“…The third-generation of SERMs include the compounds discovered after raloxifene that display further improvements in tissue specificity. An example is LSN2120310, (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, which is based on the raloxifene chemical scaffold; it displays agonist activity in the bone and antagonist activity in the breast and uterus, but unlike tamoxifen and raloxifene it may actually prevent hot flashes (Wallace et al, 2006). Going forward, 724 the next generation of SERMs will build upon our understanding of ligand-specific regulation of individual genes within a single tissue, not only displaying tissuespecific agonist or antagonist activity but also differential upregulation or downregulation of specific genes within a single cell type (Bramlett and Burris, 2003).…”

Section: Nuclear Receptors and Their Selective Modulatorsmentioning

confidence: 99%

Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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Section: Nuclear Receptors and Their Selective Modulatorsmentioning

confidence: 99%

Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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“…A common adverse event associated with SERMs to date seems to be an increased incidence of hot flushes and warrants further study to determine a solution. There are several novel agents being evaluated to address hot flashes [207][208][209][210]. Bazedoxifene has been shown to maintain or increase BMD, reduce bone turnover, and decrease the risk of new vertebral fracture in postmenopausal women without evidence of endometrial or breast stimulation in large, prospective phase III studies [196][197][198].…”

Section: Discussionmentioning

confidence: 99%

“…We will now 133 briefly consider the evolving subcellular mechanism of estrogen action in its target Early studies with clomiphene used a mixture of geometric isomers [53,57,207 58]. The cis and trans isomers were separated [67] and each has been reported to Structure-Activity Relationships in the Rat 7 208 possess different biologic activities [68][69][70]; however, some controversy 209 surrounded the designation of the isomers in relation to their observed biologic 210 properties. They were originally labeled as geometric isomers!…”

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confidence: 99%

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

Jordan¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEJune PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Georgetown University PERFORMING ORGANIZATION REPORT NUMBERWashington, DC 20057-0004 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe purpose of the CoE is to discover the molecular mechanisms and the modulation estrogen-induced apoptosis. The laboratory research project is focused on genomics and proteomics with a current focus on molecular interrogation to decipher mechanisms that may be applied to aid patient treatment. In parallel, but not supported by the CoE, is a pilot clinical study of estrogen-induced apoptosis in patients with metastatic breast cancer, that have had repeated cycles of successful antihormone therapy, but have subsequently failed and relapsed. A new low dose protocol is being completed. The molecular pharmacology laboratory of the Principle Investigator (PI) is advancing in all areas originally designated in the grant, e.g. a description of the time dependent changes in estrogen-responsive growth and apoptosis in model cell lines, an evaluation and description of the early proteomic pathways associated with estrogen-induced apoptosis dependent on the estrogen receptor (ER) co-activator AIB1 (SRC-3), the critical importance of the shape of the ER complex, the mechanism of c-Src activity that mediates apoptosis and the genomic spectrum of our endocrine resistant cell lines to define cell sensitivity to estrogen-induced apoptosis. We have discovered and described all the stages of the development of estrogen induced apoptosis through the (mitochondrial) pathway that becomes reinforced by the extrinsic (death receptor) pathway. We have correlated rises in reactive oxygen species (ROS) with intrinsic apoptosis and through RNAseq analysis, identified AP-1 (cFos and cJun) as the critical mediators for estrogen-induced apoptosis. SUBJECT TERMS-Gene expression micr...

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“…The estrogenonly arm of this study indicated increased risks for coronary disease and thromboembolism (Anderson et al, 2004). The search for selective estrogen receptor modulators with favorable effects on menopausal symptoms and bone health, but without increasing breast cancer and cardiovascular risk, is an area of intense pharmaceutical activity (Riggs and Hartmann, 2003;Wallace et al, 2006). Nevertheless these adverse reports have led to unprecedented numbers of women abruptly stopping ERT medications containing synthetic sex steroids (Mclntosh and Blalock, 2005).…”

Section: Introductionmentioning

confidence: 92%