Overview of PROTACs targeting the estrogen receptor: Achievements for biological and drug discovery

2021 ◽  
Vol 28 ◽  
Author(s):  
Hui Qin ◽  
Yiwen Zhang ◽  
Yutao Lou ◽  
Zongfu Pan ◽  
Feifeng Song ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Hormone Receptors ◽  
Locally Advanced ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Steroid Hormone Receptors ◽  
Endocrine Diseases ◽  
Estrogen Receptor Modulators ◽  
Er Positive ◽  
Er Targeting

: Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, entered clinical trials in 2019 to treat patients suffering from locally advanced or metastatic ER-positive/HER2-negative breast cancer and has since been approved by the US FDA. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.

scholarly journals Evaluation of the 12-Gene Molecular Score and the 21-Gene Recurrence Score as Predictors of Response to Neo-adjuvant Chemotherapy in Estrogen Receptor-Positive, HER2-Negative Breast Cancer

2020 ◽  
Vol 27 (3) ◽  
pp. 765-771 ◽  
Author(s):  
Hatem Soliman ◽  
Susanne Wagner ◽  
Darl D. Flake ◽  
Mark Robson ◽  
Lee Schwartzberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Adjuvant Chemotherapy ◽  
Locally Advanced ◽  
Recurrence Score ◽  
Long Term Outcome ◽  
Predictors Of Response ◽  
Er Positive ◽  
Neo Adjuvant Chemotherapy ◽  
Molecular Score

Abstract Background Neo-adjuvant chemotherapy (NaCT) facilitates complete surgical resection in locally advanced breast cancer. Due to its association with improved outcome, complete pathologic response (pCR) to neo-adjuvant treatment has been accepted as a surrogate for long-term outcome in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, or luminal B breast cancer patients. In contrast, NaCT is effective in only ~ 7–10% of estrogen receptor (ER)-positive, HER2-negative disease. Response biomarkers would enable such patients to be selected for NaCT. Methods Two commercially available breast cancer prognostic signatures [12-gene molecular score (MS) and the 21-gene Recurrence Score (RS)] were compared in their ability to predict pCR to NaCT in ER-positive, HER2-negative breast cancer in six public RNA expression microarray data sets. Scores were approximated according to published algorithms and analyzed by logistic regression. Results Expression data were available for 764 ER-positive, HER2-negative breast cancer samples, including 59 patients with pCR. The two scores were well correlated. Either score was a significant predictor of pCR (12-gene MS p = 9.4 × 10−5; 21-gene RS p = 0.0041). However, in a model containing both scores, the 12-gene MS remained significant (p = 0.0079), while the 21-gene RS did not (p = 0.79). Conclusions In this microarray study, two commercial breast cancer prognostic scores were significant predictors of response to NaCT. In direct comparison, the 12-gene MS outperformed the 21-gene RS as a predictive marker for NaCT. Considering pCR as surrogate for improved survival, these results support the ability of both scores to predict chemotherapy sensitivity.

Prediction of response to neoadjuvant chemotherapy in breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20005-20005
Author(s):  
J. Hannemann ◽  
H. Halfwerk ◽  
A. Velds ◽  
C. Loo ◽  
E. Rutgers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Neoadjuvant Chemotherapy ◽  
Hormone Receptors ◽  
Locally Advanced Breast Cancer ◽  
Expression Patterns ◽  
Locally Advanced ◽  
Cdna Array ◽  
Steroid Hormone Receptors ◽  
Response To Neoadjuvant Chemotherapy

20005 Background: Neoadjuvant chemotherapy is increasingly employed in operable breast cancer. Our initial studies on a cDNA array platform failed to identify gene expression patterns predicting response to neoadjuvant chemotherapy in breast cancer patients (J Clin Oncol 23:3331, 2005). Now we included more patients and used oligo microarrays. Methods: Patients with operable or locally advanced breast cancer were included in a randomized phase II study or received neoadjuvant chemotherapy off protocol. All except 7 patients began chemotherapy with 3 courses of dose-dense adriamycin and cyclophosphamide (ddAC) and response was evaluated by MRI. Patients with a response and a HER2-positive tumor were then randomized between either 3 additional courses of ddAC or six weekly courses of carboplatin, paclitaxel and trastuzumab (CPT). Patients without response were switched to CPT. Patients with HER2-negative tumors were randomized between 3 courses of either ddAC or capecitabine and docetaxel (CD). After evaluation, patients without response were switched to the alternative treatment arm. From all patients 14G core needle biopsies were taken before treatment and total RNA was isolated. Amplified mRNA was labeled and hybridized to 35k human oligo microarrays from our microarray facility. Results: So far, 77 patients have been included into the study. From 48 of these, good quality RNA from tissue with >50% tumor cells was isolated. 43 patients had received ddAC as initial chemotherapy; 32 of these had not been switched to another regimen. In a training set containing 11 pathological complete remissions (pCR) and 9 non-responders (NR) we could separate these groups by using 20 genes in a supervised classification and a 9-step cross validation. These results could be validated in an independent set of 11 samples (6 pCR, 5 NR). From 10 out of 11 samples, response status could be predicted correctly, independent from the treatment regimen. Although ER-positive tumors have a lower pCR rate than ER-negative ones, the steroid hormone receptors were not present in the classifier. Conclusions: We conclude that it should be possible to identify a reliable gene expression profile associated with response to adriamycin based neoadjuvant chemotherapy in breast cancer. No significant financial relationships to disclose.

Meeting Highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer

2003 ◽  
Vol 21 (17) ◽  
pp. 3357-3365 ◽  
Author(s):  
Aron Goldhirsch ◽  
William C. Wood ◽  
Richard D. Gelber ◽  
Alan S. Coates ◽  
Beat Thürlimann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Ductal Carcinoma ◽  
Steroid Hormone ◽  
Endocrine Resistance ◽  
Steroid Hormone Receptors ◽  
Average Risk ◽  
Primary Therapy ◽  
High Quality ◽  
The Impact

This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor–absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer—both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers.

scholarly journals The Significance Of Hormone Receptors In Male Breast Cancer

2020 ◽  
Author(s):  
Yevhen Hotko
Keyword(s):  
Breast Cancer ◽  
Survival Rate ◽  
Hormone Therapy ◽  
Hormone Receptors ◽  
Malignant Tumors ◽  
Locally Advanced ◽  
Male Breast ◽  
Steroid Hormone Receptors ◽  
Malignant Neoplasms ◽  
Breast Cancer Patients

Abstract Background Male mammary glands are usually considered a rudimentary organ. However, they may be exposed to similar pathological influences as female breasts. These pathological influences may cause the development of malignant breast tumors. Breast cancer in males is a rare disease, nevertheless, it is a serious problem. According to numerous national cancer registries from around the world, this disease takes 1% on average in the structure of morbidity of malignant neoplasms of this organ in both sexes. Methods In our study (168 patients) estrogen receptors were positive in the tumors of 75% of patients. The positive rate of progesterone receptors was observed in 44% of patients. The detection rate of steroid hormone receptors in malignant tumors of the male breast ranges from 65 to 100%, depending on the criteria for identifying their positivity level. The hormone therapy in the early and late stages of cancer include antiestrogens, steroid and non-steroid aromatase inhibitors, both as monotherapy and in combination with LHRH-agonists, fulvestrant and other hormonal agents. Results There was no dependence found between the receptor status of the tumors and the age of patients with breast cancer. Breast cancer in men has a more aggressive course than the same disease in women. This means lower survival rate of male patients, greater number of locally advanced and metastatic cases, with delayed primary treatment, and resistance to treatment compared to female breast cancer patients. The incidence of receptor positive tumors in men does not increase with age, as observed in women with breast cancer. Despite numerous reports on the effectiveness of hormone therapy in men with breast cancer, many aspects of this type of therapy remain largely unexplained. Conclusions Hormone therapy appears the most effective in patients with the so-called feminization syndrome, which includes signs of hyperestrogenemia, as well as in patients with multiple unfavorable prognostic signs (stage III of cancer, low differentiation of tumor cells, status of regional lymph nodes N2-3, medium, severe and morbid obesity). Orchiectomy does not increase the survival rate, therefore, its application is impractical.

scholarly journals The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1028 ◽  
Author(s):  
David Rodriguez ◽  
Marc Ramkairsingh ◽  
Xiaozeng Lin ◽  
Anil Kapoor ◽  
Pierre Major ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Estrogen Receptor ◽  
Cancer Stem Cells ◽  
Hormone Therapy ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Therapy Resistance ◽  
Breast Cancer Stem Cells ◽  
Er Positive

Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.

scholarly journals Roles for miRNAs in endocrine resistance in breast cancer

2015 ◽  
Vol 22 (5) ◽  
pp. R279-R300 ◽  
Author(s):  
Penn Muluhngwi ◽  
Carolyn M Klinge
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Aromatase Inhibitors ◽  
Estrogen Receptor Alpha ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Breast Cancer Patients ◽  
Initial Tumor ◽  
Bona Fide

Therapies targeting estrogen receptor alpha (ERα), including selective ER modulators such as tamoxifen, selective ER downregulators such as fulvestrant (ICI 182 780), and aromatase inhibitors such as letrozole, are successfully used in treating breast cancer patients whose initial tumor expresses ERα. Unfortunately, the effectiveness of endocrine therapies is limited by acquired resistance. The role of microRNAs (miRNAs) in the progression of endocrine-resistant breast cancer is of keen interest in developing biomarkers and therapies to counter metastatic disease. This review focuses on miRNAs implicated as disruptors of antiestrogen therapies, theirbona fidegene targets and associated pathways promoting endocrine resistance.

scholarly journals Minireview: G Protein-Coupled Estrogen Receptor-1, GPER-1: Its Mechanism of Action and Role in Female Reproductive Cancer, Renal and Vascular Physiology

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 2953-2962 ◽  
Author(s):  
Edward J. Filardo ◽  
Peter Thomas
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Mechanism Of Action ◽  
Knockout Mice ◽  
Mammalian Cells ◽  
Hormone Receptors ◽  
Bone Growth ◽  
Steroid Hormone Receptors ◽  
Vascular Physiology ◽  
G Protein Coupled

Using cDNA cloning strategies commonly employed for G protein-coupled receptors (GPCR), GPCR-30 (GPR30), was isolated from mammalian cells before knowledge of its cognate ligand. GPR30 is evolutionarily conserved throughout the vertebrates. A broad literature suggests that GPR30 is a Gs-coupled heptahelical transmembrane receptor that promotes specific binding of naturally occurring and man-made estrogens but not cortisol, progesterone, or testosterone. Its “pregenomic” signaling actions are manifested by plasma membrane-associated actions familiar to GPCR, namely, stimulation of adenylyl cyclase and Gβγ-subunit protein-dependent release of membrane-tethered heparan bound epidermal growth factor. These facts regarding its mechanism of action have led to the formal renaming of this receptor to its current functional designate, G protein-coupled estrogen receptor (ER) (GPER)-1. Further insight regarding its biochemical action and physiological functions in vertebrates is derived from receptor knockdown studies and the use of selective agonists/antagonists that discriminate GPER-1 from the nuclear steroid hormone receptors, ERα and ERβ. GPER-1-selective agents have linked GPER-1 to physiological and pathological events regulated by estrogen action, including, but not limited to, the central nervous, immune, renal, reproductive, and cardiovascular systems. Moreover, immunohistochemical studies have shown a positive association between GPER-1 expression and progression of female reproductive cancer, a relationship that is diametrically opposed from ER. Unlike ER knockout mice, GPER-1 knockout mice are fertile and show no overt reproductive anomalies. However, they do exhibit thymic atrophy, impaired glucose tolerance, and altered bone growth. Here, we discuss the role of GPER-1 in female reproductive cancers as well as renal and vascular physiology.

scholarly journals The immunomodulatory effects of endocrine therapy in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Huanhuan Huang ◽  
Jun Zhou ◽  
Hailong Chen ◽  
Jiaxin Li ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Checkpoint Inhibitors ◽  
Endocrine Resistance ◽  
Tumor Development ◽  
Immune Microenvironment ◽  
Antitumor Effects ◽  
Estrogen Receptor Modulators ◽  
Cancer Multiple

AbstractEndocrine therapies with SERMs (selective estrogen receptor modulators) or SERDs (selective estrogen receptor downregulators) are standard therapies for patients with estrogen receptor (ER)-positive breast cancer. Multiple small molecule inhibitors targeting the PI3K-AKT-mTOR pathway or CDK4/6 have been developed to be used in combination with anti-estrogen drugs to overcome endocrine resistance. In addition to their direct antitumor effects, accumulating evidence has revealed the tumor immune microenvironment (TIM)-modulating effects of these therapeutic strategies, which have not been properly acknowledged previously. The immune microenvironment of breast tumors plays a crucial role in tumor development, metastasis and treatment response to endocrine therapy and immunotherapy. Therefore, in our current work, we comprehensively review the immunomodulatory effect of endocrine therapy and discuss its potential applications in combination with immune checkpoint inhibitors in breast cancer treatment.

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