The role of fulvestrant in endometrial cancer

Bogliolo, Stefano; Cassani, Chiara; Dominoni, Mattia; Orlandini, Anna; Ferrero, Simone; Iacobone, Anna Daniela; Viazzo, Franco; Venturini, Pier Luigi; Spinillo, Arsenio; Gardella, Barbara

doi:10.1080/17425255.2016.1244264

Cited by 12 publications

(8 citation statements)

References 52 publications

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“…In subsequent studies, the SERM Ospemifene has been shown as an effective in treatment of vaginal symptoms in postmenopausal women (Archer et al 2019) and only acts as an agonist in endometrium in high doses. The SERD fulvestrant/faslodex (Table 2) has been investigated as a treatment for endometrial cancer in phase I/II trials, although well-tolerated, it has low oral bioavailability and further trials are needed (Bogliolo et al 2017). Another recent study suggested dual targeting of ERα with tamoxifen and ERRα with XCT790 may be beneficial for EC treatment, but this requires further validation (Mao et al 2019).…”

Section: Targeting Oestrogen Receptors In Endometrial Disordersmentioning

confidence: 99%

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

Gibson

Simitsidellis

Collins

et al. 2020

Journal of Endocrinology

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The endometrium is a complex multicellular tissue that is exquisitely sensitive to the actions of sex steroids synthesised in the ovary (endocrine system). Recent studies have highlighted a previously under-appreciated role for local (intracrine) metabolism in fine-tuning tissue function in both health and disease. In this review we have focused on the impact of oestrogens and androgens on endometrial function summarising data from studies on normal endometrial physiology and disorders including infertility, endometriosis and cancer. We consider the evidence that expression of enzymes including aromatase, sulphatase and AKR1C3 by endometrial cells plays an important role in tissue function, and malfunction, and discus results from studies using drugs targeting intracrine pathways to treat endometrial disorders. We summarise studies exploring the spatial and temporal expression of oestrogen receptors (ERalpha, ERbeta and GPER) and their role in mediating the impact of endogenous and synthetic ligands on cross-talk between vascular, immune, epithelial and stromal cells. There is a single androgen receptor and androgens play a key role in stromal-epithelial cross talk, scar-free healing of endometrium during menstruation and regulation of cell proliferation. The development of new receptor-selective drugs (SERMs, SARMs, SARDs) has reinvigorated interest in targeting receptor subtypes in treatment of disorders including endometriosis and endometrial cancer and some show promise as novel therapies. In summary, understanding the mechanisms regulated by sex steroids provides the platform for improved personalised treatment of endometrial disorders as well as novel insights into the impact of steroids on processes such as tissue repair and regeneration.

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Section: Targeting Oestrogen Receptors In Endometrial Disordersmentioning

confidence: 99%

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

Gibson

Simitsidellis

Collins

et al. 2020

Journal of Endocrinology

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“…Only recently has concern arisen that tamoxifen might also increase the risk of ovarian cancer, as it promotes lesions in the fallopian tubes and ovaries (Chene et al, 2014). Novel SERMs have been developed to combat estrogen-dependent cancers, including toremifene and raloxifene, together with the selective ER down-regulators, such as selective receptor downregulator fulvestrant (for reviews, see Bogliolo et al, 2017; Traboulsi et al, 2017). Further clinical studies on patients with endometrial and ovarian cancer are currently awaited.…”

Section: Pharmacological Interventions That Target Intracrine Actionsmentioning

confidence: 99%

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

2017

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Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.Keywords: sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase, transporters, OATP, ABC-transporter HORMONE-DEPENDENT CANCERSSteroid hormones have important roles in human physiology, and the disruption of androgen, estrogen, and progesterone actions are implicated in the development of hormone-dependent cancers and benign hormone-dependent diseases. Hormone-dependent cancers include prostate, breast, endometrial, and ovarian cancers, which comprise more than 20% of all cancers in humans, and more than 35% of cancers in women (Ferlay et al., 2013). Indeed, in women, breast cancer is the most frequent cancer in the developed world. In 2012, 1,671,149 new cases of breast cancer were estimated worldwide, with 521,907 associated deaths. In the developed world, endometrial cancer is the most common among gynecological cancers. Worldwide, there were 319,605 new cases and 76,160 deaths from endometrial cancer in 2012 alone (Ferlay et al., 2013). The most deadly of the hormone-dependent cancers is ovarian cancer. Worldwide, there were 238,719 new cases and 151,905 deaths from ovarian cancer in 2012 (Ferlay et al., 2013).

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“…Currently the only FDA approved SERD is fulvestrant, originally indicated for breast cancer progressing after tamoxifen or aromatase inhibitor (AI) treatment, but recently approved for first line endocrine therapy [ 1 – 4 ]. While fulvestrant has proven clinically effective with manageable adverse side effects, the drug is well known for its poor bioavailability [ 5 ]. It can only be administered as a monthly intramuscular injection and is believed to have limited drug exposure and ER turn-over in patients [ 6 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

ZB716, a steroidal selective estrogen receptor degrader (SERD), is orally efficacious in blocking tumor growth in mouse xenograft models

et al. 2018

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Advances in oral SERDs development so far have been confined to nonsteroidal molecules such as those containing a cinnamic acid moiety, which are in earlystage clinical evaluation. ZB716 was previously reported as an orally bioavailable SERD structurally analogous to fulvestrant. In this study, we examined the binding details of ZB716 to the estrogen receptor alpha (ERα) by computer modeling to reveal its interactions with the ligand binding domain as a steroidal molecule. We also found that ZB716 modulates ERα-coregulator interactions in nearly identical manner to fulvestrant. The ability of ZB716 to inhibit cell growth and downregulate ER expression in endocrine resistant, ERα mutant breast cancer cells was demonstrated. Moreover, in both the MCF-7 xenograft and a patient derived xenograft model, orally administered ZB716 showed superior efficacy in blocking tumor growth when compared to fulvestrant. Importantly, such enhanced efficacy of ZB716 was shown to be attributable to its markedly higher bioavailability, as evidenced in the final plasma and tumor tissue concentrations of ZB716 in mice where drug concentrations were found significantly higher than in the fulvestrant treatment group.

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The role of fulvestrant in endometrial cancer

Cited by 12 publications

References 52 publications

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

ZB716, a steroidal selective estrogen receptor degrader (SERD), is orally efficacious in blocking tumor growth in mouse xenograft models

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