The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein-coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-pharmtox-031122-121944

G Protein-Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications.

Update on prognostic and predictive biomarkers of breast cancer.

Simple Summary Acquiring of resistance is a common outcome after prolonged cancer treatment and consecutive treatments are, in general terms, limited. Here we published the results of REVERT clinical study that aimed to REVERT the resistance to hormonal treatment that often occurs in breast cancer patients positive for hormone receptors. According to previous published data, adding drug called eribulin to hormonal treatment may sensitized the tumor to the hormonal treatment due to switch of cancer cell phenotype. Even though this theory was not proved in this study, the outcomes of this study open a new door for further investigation since the results suggests that the patients treated with hormonal therapy and inhibitors of cyclins may have further clinical benefit, if eribulin is added to the therapy. Importantly, no additional unexpected side effects were reported with this drug combination. Abstract Background: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial. Methods: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/− AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design. Results: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8–55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7–71.0%). The difference between the study arms was not significant (p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR (p = 0.018) and progression-free survival (p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported. Conclusion: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo–endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.

/pdf/challenging-endocrine-sensitivity-of-hormone-receptor-k094cc8q.pdf

Challenging Endocrine Sensitivity of Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer with the Combination of Eribulin and Endocrine Therapy: The REVERT Study

Breast cancer (BC) is one of the most widely diagnosed cancers and a leading cause of cancer death among women worldwide. Globally, BC is the second most frequent cancer and first most frequent gynecological one, affecting women with a relatively low case-mortality rate. Surgery, radiotherapy, and chemotherapy are the main treatments for BC, even though the latter are often not aways successful because of the common side effects and the damage caused to healthy tissues and organs. Aggressive and metastatic BCs are difficult to treat, thus new studies are needed in order to find new therapies and strategies for managing these diseases. In this review, we intend to give an overview of studies in this field, presenting the data from the literature concerning the classification of BCs and the drugs used in therapy for the treatment of BCs, along with drugs in clinical studies.

/pdf/targeting-breast-cancer-an-overlook-on-current-strategies-hzz4skqa.pdf

Targeting Breast Cancer: An Overlook on Current Strategies

The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model. 

SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer.

Purpose of review: Due to the findings of current studies and the approval of novel substances for the therapy of hormone-receptor-positive breast cancer patients, the established standards of endocrine treatment are changing. The purpose of this review is to give an overview of the history of endocrine treatment, to clarify its role in the present standard of care, and to discuss the possibilities of improvement. Recent findings: Tamoxifen, aromatase inhibitors, and fulvestrant are the main drugs that have been used for decades in the therapy of hormone-receptor-positive breast cancer patients. However, since a relevant number of women suffer at some point from disease recurrence or progression, several novel substances are being investigated to overcome resistance mechanisms by interfering with certain signaling pathways, such as the PI3K/AKT/mTOR or the CDK4/6 pathways. mTOR and CDK4/6 inhibitors were the first drugs approved for this purpose and many more are in development. Summary: Endocrine treatment is one of the best tolerable cancer therapies available. Continuous investigation serves to improve patients’ outcomes and modernize the current standard of care. Considering the resistance mechanisms and substances analyzed against these, endocrine treatment of hormone-receptor-positive breast cancer is on the brink of a new era.

Naiba Nabieva

Papers

Endocrine Treatment for Breast Cancer Patients Revisited-History, Standard of Care, and Possibilities of Improvement.