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Br J Cancer. 2018 Dec 17. doi: 10.1038/s41416-018-0354-9. [Epub ahead of print]

The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.

Author information

1
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.
2
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02210, USA.
3
Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
4
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
5
Quantitative Biology, Discovery Science, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
6
Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
7
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA.
8
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA. rschiff@bcm.edu.
9
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. rschiff@bcm.edu.
10
Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. rschiff@bcm.edu.

Abstract

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, likeĀ 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.

PMID:
30555156
DOI:
10.1038/s41416-018-0354-9

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