دورية أكاديمية
The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.
| العنوان: | The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance. |
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| المؤلفون: | Nardone, Agostina, Weir, Hazel, Delpuech, Oona, Brown, Henry, De Angelis, Carmine, Cataldo, Maria Letizia, Fu, Xiaoyong, Shea, Martin J, Mitchell, Tamika, Veeraraghavan, Jamunarani, Nagi, Chandandeep, Pilling, Mark, Rimawi, Mothaffar F, Trivedi, Meghana, Hilsenbeck, Susan G, Chamness, Gary C, Jeselsohn, Rinath, Osborne, C Kent, Schiff, Rachel |
| بيانات النشر: | Springer Science and Business Media LLC //dx.doi.org/10.1038/s41416-018-0354-9 Br J Cancer |
| سنة النشر: | 2019 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Animals, Breast Neoplasms, Cell Proliferation, Cinnamates, Drug Resistance, Neoplasm, Estradiol, Estrogens, Female, Fulvestrant, Heterografts, Humans, Indoles, MCF-7 Cells, Mice, Neoplasms, Hormone-Dependent, Receptors, Estrogen, Tamoxifen |
| الوصف: | BACKGROUND: The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations. METHODS: Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models. RESULTS: In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance. CONCLUSIONS: These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/300281Test |
| DOI: | 10.17863/CAM.47355 |
| الإتاحة: | https://doi.org/10.17863/CAM.47355Test https://www.repository.cam.ac.uk/handle/1810/300281Test |
| حقوق: | Attribution 4.0 International (CC BY) ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.6763D799 |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.47355 |
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