A Good Drug Made Better: The Fulvestrant Dose-Response Story

Robertson, J. F. R.; Lindemann, Justin P.O.; Garnett, Sally; Anderson, Elizabeth J.; Nicholson, Robert Ian; Kuter, Irene; Gee, Julia Margaret Wendy

doi:10.1016/j.clbc.2014.06.005

Cited by 58 publications

(65 citation statements)

References 42 publications

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“…Thus, a strategy already underway is the improvement of pharmacokinetic properties to increase the internal exposure of tumors to highly potent antagonists. Some emerging orally active antiestrogens, such as AZD-9496, GDC-0810, as well as others, appear to provide just such encouraging behavior 34,63,87–95 although further studies are needed regarding side-effect profiles and prevention of disease recurrence.…”

Section: Discussionmentioning

confidence: 99%

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

et al. 2018

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Estrogen receptor alpha (ERα), a key driver of breast cancer, normally requires estrogen for activation. Mutations that constitutively activate ERα without the need for hormone are frequently found in endocrine therapy-resistant breast cancer metastases and are associated with poor patient outcomes. The location of these mutations in the ER ligand-binding domain and their impact on receptor conformation suggest that they subvert distinct mechanisms that normally maintain the low basal state of wild-type ERα in the absence of hormone. Such mutations provide opportunities to probe fundamental issues underlying ligand-mediated control of ERα activity. Instructive contrasts between these ER mutations and those that arise in androgen receptor (AR) during antiandrogen treatment of prostate cancer highlight differences in how activating functions in ER vs. AR control receptor activity, how hormonal pressures (deprivation vs. antagonism) drive the selection of phenotypically different mutants, and how altered protein conformations can reduce antagonist potency and altered ligand-receptor contacts can invert the response that a receptor has to an agonist vs. an antagonist. A deeper understanding of how ligand regulation of receptor conformation is linked to receptor function offers a conceptual framework for developing new antiestrogens that might be more effective in preventing and treating breast cancer.

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Section: Discussionmentioning

confidence: 99%

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

et al. 2018

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“…The poor pharmacokinetic properties of ICI 182,780 may limit its effectiveness in the clinic; indeed, increasing monthly intra-muscular injections of fulvestrant from 250 mg to 500 mg led to significant gains in overall survival in metastatic patients having recurred or progressed after prior endocrine therapy in the CONFIRM study and resulted in subsequent adoption of this regimen in the clinic (Di Leo et al . 2010, 2014, Robertson et al . 2014).…”

Section: Serms Vs Serds: Two Separate Classes Of Antiestrogens?mentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…Currently, fulvestrant (Faslodex, AstraZeneca) is the only approved SERD for the treatment of postmenopausal women with advanced ER þ breast cancer who have progressed on endocrine therapies (http://www.accessdata.fda.gov/drugsatfda_docs/ label/2011/021344s015lbl.pdf). In the metastatic setting, fulvestrant has been shown to be effective as a single agent and a recent study demonstrated that the increased dose of 500 mg fulvestrant is superior to the historical 250 mg dose in terms of overall survival (8,12,13). However, there is evidence to suggest that even at the 500 mg dose, suboptimal occupancy of the estrogen receptor can occur in some patients, which may correlate with an earlier progression of disease (14).…”

Section: Introductionmentioning

confidence: 99%

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Bihani

Patel

Arlt

et al. 2017

Clinical Cancer Research

122

105

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Purpose: Estrogen receptor-positive (ER þ ) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER þ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER þ breast cancer models, including several patientderived xenograft models.

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A Good Drug Made Better: The Fulvestrant Dose-Response Story

Cited by 58 publications

References 42 publications

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

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