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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Initially patented in 1996 by Ely Lilly, arzoxifene (LY-353381) is a SERM with a potent estrogen antagonist activity in mammary and uterine tissue while providing an estrogen agonist effect to maintain bone density and lower serum cholesterol. There was initial interest in development of arzoxifene as an anticancer agent because it was found to be highly effective and more potent than raloxifene for the prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea. Furthermore, unlike tamoxifen, it was found to be devoid of uterotrophic effects, suggesting that it should be unlikely to increase the risk of developing endometrial carcinoma during chronic administration. In a Phase 3 clinical study in postmenopausal women, arzoxifene was shown to increase bone, spine, and hip mineral density and to have no effect on the uterus and endometrium. However, in 2009 Lilly announced the preliminary results from a five-year clinical study which showed that while arzoxifene had met its primary endpoints of reduction in vertebral fractures and breast cancer in postmenopausal women, it had failed to meet secondary endpoints of reduction in nonvertebral fractures and cardiovascular events and improvements in cognitive function. Based on these results, development of the drug was halted. Interestingly, in 2015 a meta-analysis found that arzoxifene significantly reduced the relative risk (RR) of breast cancer (0.415) to a greater extent than raloxifene (0.572) or tamoxifen (0.708).
Hormonal regulation of the endometrium and the effects of hormonal therapies
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Gulcin Sahin Ersoy, Monica Modi, Myles Alderman, Hugh S. Taylor
Numerous SERMs have been developed to provide tissue-specific estrogen agonist–antagonist effects. Novel SERMs in various stages of clinical development are lasofoxifene, ospemifene, and arzoxifene. Lasofoxifene has been shown to reduce fracture risks and decrease the incidence of breast cancer, but has been associated with endometrial thickening and endometrial polyps (138). Lasofoxifene and ospemifene have beneficial effects on vaginal epithelium (138). Trials using idosifene and levormeloxifene were stropped early because of adverse uterine effects (138).
Progestin or anti-estrogen treatment for endometrial cancer: choosing the best option for selected patients
Published in Gynecological Endocrinology, 2021
Marta Caretto, Tommaso Simoncini
Hormonal therapy in endometrial cancer (EC) is an alternative treatment for women with metastatic or recurrent disease without curative options [1] and a strong desire to preserve their fertility. Historically, the most widely applied and still the first line hormonal treatment has been progestin therapy. Currently, there could be an alternative to progestins for EC: the anti-estrogen treatment. This treatment involves the use of several drugs: selective estrogen receptor modulators (SERM), down-regulators (SERD) and aromatase inhibitors. Tamoxifen has both stimulatory and blocking effects on estrogen receptors (ER) in the endometrium, while other SERMs (raloxifene and arzoxifene) only block ER. Fulvestrant is the main SERD and it has antagonistic effects through down regulation of the ER. Aromatase inhibitors (anastrozole, letrozole, and exemestane) reduce the tumor exposure to estrogens produced by aromatase in fat tissue, especially in postmenopausal women [2].
Management of postmenopausal vulvovaginal atrophy: recommendations of the International Society for the Study of Vulvovaginal Disease
Published in Gynecological Endocrinology, 2021
Faustino R. Pérez-López, Nancy Phillips, Pedro Vieira-Baptista, Bina Cohen-Sacher, Susana C. A. V. Fialho, Colleen K. Stockdale
Selective estrogen receptor modulators (SERMs) have different clinical effects on VVA. Tamoxifen and arzoxifene do not improve vaginal symptoms. Bazedoxifene associated with oral conjugated equine estrogens improves VVA. However, most of the effect may be related to the equine estrogens. The only SERM shown to improve the VMI, pH and VVA related dyspareunia is ospemifene [51]. It seems to be more effective than lubricants in the management of dyspareunia and moderate to severe VVA in postmenopausal women [52]. A meta-analysis of RCTs reporting objective outcomes and the perception of symptoms after 12 and 52 weeks of treatment with 60 mg/day of ospemifene showed a significant reduction of vaginal pH and dyspareunia and a significant improvement of vaginal maturation [53]. Hot flushes and urinary tract infections are the most commonly reported side effects at 12 weeks [54], but were not significant at 52 weeks. Ospemifene treatment was associated with significantly greater endometrial thickness at 12 and 52 weeks. Due to the short duration of the treatment, endometrial and breast cancer incidence, and metabolic changes could not be evaluated [55].
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
A further filing from Arvinas also exemplified ER-degrading PROTACs that recruited VHL and cereblon with a wide variety of linkers [45]. However, rather than employing a modified lasofoxifene moiety to bind ER, this filing exemplified the use of a modified arzoxifene scaffold in PROTAC design. Selected compounds demonstrated high target engagement as well as potent and efficient ER degradation in MCF-7 cells with both VHL (e.g. compounds 21–22, Table 2) and cereblon (e.g. compound 23, Table 2) E3 ligase recruiters. A Western blot degradation dose-response study of compound 21 was also reported in T47D cells. Interestingly, this compound and compound 22 bear significant structural similarity to compound 18 [44], differing only in the ER-binding moiety.