Both N- and C-terminal transactivation functions of DNA-bound ERα are blocked by a novel synthetic estrogen ligand

Yamamoto, Yasuhiko; Wada, Osamu; Takada, Ichiro; Yogiashi, Yoshiko; Shibata, Jiro; Yanagisawa, Junn; Kitazato, Kenji; Kato, Shigeaki

doi:10.1016/j.bbrc.2003.10.178

Cited by 27 publications

(22 citation statements)

References 40 publications

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“…Our work, as well as that of others (8,9,11,12 ), would predict that second-line AIs would not help, whereas an antiestrogen might. ESR1 mutations certainly may be actionable for clinical decisionmaking to switch from tamoxifen to fulvestrant, or to other drugs, e.g., TAS-108 (SR16234), which in cell models overcomes "tamoxifen resistance" due to the ESR1 mutation p.D351Y (37 ). In fact, some commercial companies are already starting to offer ESR1 mutation genotyping (as cfDNA analysis by blood draw, i.e., the Guardant 360 commercial blood test).…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

et al. 2015

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BACKGROUND Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a “liquid biopsy.” METHODS We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α–positive metastatic breast cancer who were receiving systemic therapy. Selected mutations were validated using droplet digital PCR (ddPCR). RESULTS Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. ddPCR analysis was more sensitive than NGS and identified 6 additional baseline cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA of 1 primary patient who was thought to have metastatic disease but was clear by scans. CONCLUSIONS Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

et al. 2015

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“…TAS-108 has been shown to be a strong binding ligand to estrogen receptor with recruitment of a specific cofactor to estrogen receptor ␤ (15). It was shown that TAS-108 acts with molecular mechanisms that are different from those of tamoxifen or SERD (16). TAS-108 showed tissue-selective agonist activity in the bone and cardiovascular systems (17).…”

Section: Introductionmentioning

confidence: 99%

A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer

Blakely

Buzdar

Chang

et al. 2004

Clinical Cancer Research

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Purpose: TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer.Experimental Design: TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course.Results: A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1-2. TAS-108 had no effect on endometrial thickness based on trans-vaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4 -60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean C max ranged from 2.8 to 21.0 ng/mL and AUC 0-t from 15.1 to 148.7 ng⅐h/mL, this showed a linear correlation with the dose.Conclusions: TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.

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“…Additionally, TAS-108 has shown antagonistic effects on a mutant ERa reported to have a tamoxifen-resistant phenotype and preliminarily shown to have antitumor activity against tamoxifen-and AI-resistant cell lines. (8) TAS-108 has also shown fewer estrogenic effects on the uterus than tamoxifen in animal models. (6) Furthermore, a preclinical study suggested possible positive effects of TAS-108 on BMD.…”

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confidence: 99%

Randomized phase II study of three doses of oral TAS‐108 in postmenopausal patients with metastatic breast cancer

et al. 2012

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This randomized phase II study was intended to identify the optimal dose of TAS-108, a novel steroidal antiestrogen, for the treatment of breast cancer in postmenopausal Japanese women. The potential clinical effects of TAS-108 on the uterus, bone, serum lipids, and hormones were also investigated. Postmenopausal women with hormone receptor-positive metastatic breast cancer who had previously received one or two endocrine therapies were randomly assigned to one of the three possible dose levels of 80 or 120 mg/day). Oral TAS-108 was given daily, and the efficacy and safety of the three doses were evaluated. A total of 97 patients (33, 32, and 32 in the 40-, 80-, and 120-mg groups, respectively) were treated with TAS-108. The clinical benefit rate was 30.3% for the 40-mg, 25.0% for the 80-mg, and 25.0% for the 120-mg group. The 40-mg group achieved the prespecified target threshold. TAS-108 at all dose levels was well tolerated and appeared to have no harmful effects in terms of the variables examined in this study. We conclude that the optimal dose of TAS-108 among the three doses is 40 mg, once daily, for further studies. JAPIC Clinical Trials Information number: Japic CTI -121754. (Cancer Sci 2012; 103: 1708-1713 A romatase inhibitors have been widely used as first-line endocrine therapeutic agents for postmenopausal patients with HR-positive breast cancer and also adjuvant therapy in postmenopausal women with early breast cancer.(1,2) However, tamoxifen showed equivalent disease-free survival compared with AIs in patients with low tumor values of Ki-67 in an adjuvant trial, (3) and it has also been reported that tamoxifen holds potential for sequential treatment of postmenopausal patients with MBC progressing after AI treatment.(4) Therefore, tamoxifen still remains an important treatment option in HR-positive breast cancer. However, due to its estrogen-like effects on the uterus, tamoxifen has been associated with the risk of developing endometrial cancer, (5) which has been an important motivating factor in the development of new types of antiestrogen with different pharmacologic profiles.A novel steroidal antiestrogenic compound, TAS-108 binds strongly to ERa and ERb with a mechanism of action unlike tamoxifen, (6) and in humans is mainly metabolized by CYP3A4 enzymes in the liver.(7) TAS-108 shows pure antagonistic activity as it blocked both the N-terminal AF-1 and C-terminal AF-2 transactivation functions of ERa, abolished the recruitment of co-activators, but promoted the recruitment of co-repressors and allowed normal DNA binding. Additionally, TAS-108 has shown antagonistic effects on a mutant ERa reported to have a tamoxifen-resistant phenotype and preliminarily shown to have antitumor activity against tamoxifen-and AI-resistant cell lines.(8) TAS-108 has also shown fewer estrogenic effects on the uterus than tamoxifen in animal models. (6) Furthermore, a preclinical study suggested possible positive effects of TAS-108 on BMD. (9) Several phase I studies were carried out in the USA involving postm...

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Both N- and C-terminal transactivation functions of DNA-bound ERα are blocked by a novel synthetic estrogen ligand

Cited by 27 publications

References 40 publications

Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer

Randomized phase II study of three doses of oral TAS‐108 in postmenopausal patients with metastatic breast cancer

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