The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index; none of the 29 sources its claims cite is checked for support yet.
Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer
Open accessAbstract
Drugs that inhibit estrogen receptor alpha (ERα) or that block the production of estrogens remain frontline interventions in the treatment and management of breast cancer at all stages. However, resistance to endocrine therapies, especially in the setting of advanced disease, remains an impediment to durable clinical responses. Although the mechanisms underlying resistance to existing agents are complex, preclinical studies suggest that selective estrogen receptor downregulators (SERDs), molecules which eliminate ERα expression, may have particular utility in the treatment of breast cancers that have progressed on tamoxifen and/or aromatase inhibitors. The discovery and development of orally bioavailable SERDs provide the opportunity to evaluate the utility of eliminating ERα expression in advanced metastatic breast cancers.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This perspective argues that orally bioavailable selective estrogen receptor downregulators (SERDs) represent a promising advance for ERα-positive breast cancer that has progressed on tamoxifen or aromatase inhibitors, because they eliminate ERα rather than merely antagonizing it. It frames GDC-0810 (ARN-810), described by Lai et al. in the same issue, as the most advanced next-generation oral SERD and outlines open questions about its clinical utility.
Key findings
- Resistance to tamoxifen is now attributed to changes in coregulator expression/activity that let tamoxifen act as an agonist, rather than to ERα loss, drug metabolism, or MDR1 efflux; ligand-independent ERα activation reduces SERM antagonist efficacy but leaves SERD sensitivity unaffected.
- Up to 20% of tumors in metastatic, endocrine-resistant breast cancer are reported to contain activating mutations in the receptor, and preclinical studies support SERDs as a viable approach for these tumors.
- GW5638 is a prodrug converted to the more potent metabolite GW7604; cross-species microsome profiling found only ~16% conversion in human liver microsomes, a liability mitigated in the GDC-0810 series by modifications that increased potency and removed the primary glucuronidation site.
- In the Paloma 3 trial, combining the cdk4/6 inhibitor palbociclib with fulvestrant produced an improvement in progression-free survival (10 months) versus fulvestrant plus placebo in women with ER-positive metastatic breast cancer.
Methods
- Design: a narrative perspective/commentary in the Journal of Medicinal Chemistry; no primary experimental data are reported.
- Data: synthesis of prior literature and clinical/preclinical reports, plus discussion of the companion paper by Lai et al. identifying GDC-0810.
- Main analysis: conceptual review of ER pharmacology (conformation-based compound profiling, coregulator biology), the history of fulvestrant and GW5638/GW7604, and the development path of oral SERDs.
Limitations
- Stated: data describing the activity of GDC-0810 on ERα under conditions where it is constitutively active are missing from Lai et al.; the extent to which elimination of the need for metabolic activation contributes to clinical activity remains to be determined; whether SERDs have any therapeutic advantage over high-affinity competitive ERα antagonists without SERD activity remains unresolved; results of clinical trials of pipendoxifene (ERA924) and acolbifene (EM652) were never published, so the criteria for their discontinuation are unclear.
- Evident from the text: as a commentary, it presents no new experimental data, and its claims about GDC-0810's clinical value rest on trials described as ongoing and eagerly awaited rather than completed.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Claims the paper makes
24 Not checked yet · 6 Own interpretation
None of the sources cited for this claim have been checked yet.
In the paper
“Evidence in support of this model came from structural studies that revealed that upon binding tamoxifen, ERα adopted a unique conformation that resulted in the presentation of protein-protein interaction surfaces required for its partial agonist activity.12, 13”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“it is now believed that resistance to tamoxifen results from changes in the expression (or activity) of coregulators that enable tamoxifen to manifest agonist activity11.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [11] Musgrove E. A., 2009, Nat. Rev. Cancer source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notwithstanding the recent clinical success of these newer targeted therapies, it is unlikely that they will have as significant an impact on the pharmacotherapy of estrogen receptor (ER) positive breast cancer as drugs that interfere with the estrogen signaling axis.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
- Rests on an assumption: ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
In the paper
“Thus, the same receptor-ligand complex can have completely different activities in different cells.8”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [8] McDonnell D. P., 2010, Curr. Opin. Pharmacol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“preclinical studies suggest that selective estrogen receptor downregulators (SERDs), molecules which eliminate ERα expression, may have particular utility in the treatment of breast cancers that have progressed on tamoxifen and/or aromatase inhibitors.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [7] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
In the paper
“The molecule selected for development, GDC-0810, has significantly improved exposure over benchmark compounds in animals, was equivalent to GW5638 in its ability to degrade ERα, and maintained the ability to inhibit the growth of tumors in a clinically relevant xenograft model of tamoxifen resistance.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [7] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Using cross-species microsome profiling, it was determined that the conversion of GW5638 to GW7604 was variable with only ~16% conversion observed in human liver microsomes.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [7] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, dual or multiple pathway inhibition may be required to realize the full potential of SERDs or SERMs.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition to GDC-0810, there are several new ER modulators at various stages of development and it is reasonable to expect, given the underlying science, that several of these will be effective enough to warrant their registration as monotherapies.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
In the paper
“The molecule selected for development, GDC-0810, has significantly improved exposure over benchmark compounds in animals, was equivalent to GW5638 in its ability to degrade ERα, and maintained the ability to inhibit the growth of tumors in a clinically relevant xenograft model of tamoxifen resistance.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [7] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 7
In the paper
“The orally bioavailable drug described by Lai et al in this issue, GDC-0810 (ARN-810), is the most advanced of the next generation SERDs and is currently being evaluated in clinical trials in breast cancer patients who have progressed on standard endocrine therapy.7”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [7] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
In the paper
“Unfortunately, fulvestrant has significant pharmaceutical liabilities (requiring intramuscular injection) which have negatively impacted its widespread use.6”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [6] Robertson J. F. R., 2007, Oncologist source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In conclusion, as evidenced by the studies presented in Lai et al, there has been considerable progress of late in developing orally bioavailable SERDs and it is likely that these will have a significant impact on the pharmacotherapy of breast cancer.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [7] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
None of the sources cited for this claim have been checked yet.
In the paper
“Significantly, these drugs inhibited 17β-estradiol-dependent growth of ERα-positive breast tumor xenografts and more importantly were shown to be extremely effective in tumor models of tamoxifen resistance.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [14] Connor C. E., 2001, Cancer Res.
- Not checked yetcites [15] Willson T. M., 1994, J. Med. Chem. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ligand-independent activation of ERα reduces the antagonist efficacy of SERMs while the sensitivity to SERDs is unaffected.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
In the paper
“This is of concern as the aromatase enzyme (cyp19) is expressed in brain and considering that the ERα-partial agonist 27-hydroxycholesterol is the most abundant oxysterol in brain.22”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
- Not checked yetcites [22] Simpson E. R., 2003, J. Steroid Biochem. Mol. Biol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been shown for instance that resistance to HER2/EGFR inhibitors and to PI3K inhibitors is associated with increased intratumoral expression of ERα and in relevant models it has been shown that such resistance can be reversed by the SERD fulvestrant.23-25”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Resistance to endocrine therapies, especially in advanced disease, remains an impediment to durable clinical responses.
“However, resistance to endocrine therapies, especially in the setting of advanced disease, remains an impediment to durable clinical responses.”
The paper relies on this without support.
ERα remains engaged in advanced disease, contributes to disease pathogenesis, and remains a viable therapeutic target.
“It is now well established that ERα remains engaged in advance disease, contributes to disease pathogenesis, and remains a viable therapeutic target.”
The paper relies on this without support.
The Paloma 3 clinical trial reported that combining palbociclib with fulvestrant improved progression-free survival (10 months) compared to fulvestrant plus placebo in women with ER-positive metastatic breast cancer.
“Indeed, the recent results of the Paloma 3 clinical trial were very encouraging as it was reported that regimens in which the cdk4/6 inhibitor (palbociclib) and fulvestrant were combined demonstrated an impressive improvement in progression free survival (10 months) when compared to fulvestrant plus placebo in women with ER positive metastatic breast cancer.”
The paper relies on this without support.
There is little data on the ability of existing ER modulators and aromatase inhibitors to cross the blood-brain barrier.
“There is little data on the ability of existing ER modulators and aromatase inhibitors to cross the blood brain barrier (BBB) and thus there is considerable interest in evaluating brain penetrant SERDs or SERMs in patients with BCBM.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The ER in breast cancer38,39 and the AR in prostate cancer33 are the leading examples of such targets.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [38]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
“additional compounds with structural similarity to GW5638 (e.g. AZD9496) are also currently making their way through clinical development.”
§ Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer > Abstract
“Given that GDC-0810 and AZD9694 are already in clinical trials”
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Metadata
- Authors
- McDonnell, D. P., Wardell, S. E., & Norris, J. D.
- Affiliations
- Duke University (US)
- Corresponding author
- McDonnell, Donald P.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-06-03
- Volume
- 58
- Issue
- 12
- Pages
- 4883-4887
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC4708081
- OpenAlex
- W2411335118
- Semantic Scholar
- 76771fb08cb3351347b0fb6ac913cde0e5a1f1c7
- Cited by
- 178
- References
- 28
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 14 · 2023: 20 · 2022: 20 · 2021: 13 · 2020: 26 · 2019: 20 · 2018: 20 · 2017: 17 · 2016: 10 · 2015: 3
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048807, DK048807, R37DK048807)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- selective estrogen receptor downregulators, estrogen receptor alpha, breast cancer, endocrine therapy, tamoxifen resistance, aromatase inhibitor resistance, oral bioavailability, metastatic breast cancer, advanced breast cancer
- MeSH terms
- Animals, Breast, Breast Neoplasms, Female, Humans, Tamoxifen, Antineoplastic Agents, Hormonal, Selective Estrogen Receptor Modulators, Aromatase Inhibitors, Estrogen Receptor alpha, Drug Discovery
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