Article | Published:

Translational Therapeutics

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

British Journal of Cancer (2018) | Download Citation

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, 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.

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Acknowledgements

This study was supported in part by a research grant from AstraZeneca; by Susan G. Komen for the Cure: Promise Grant PG12221410 (to R.S. and C.K.O.); by a grant from the Breast Cancer Research Foundation BCRF-18-145; and by the NIH: SPORE Grants P50CA058183 and CA186784, and Cancer Center Grant P30CA125123.

Author information

Affiliations

  1. Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA

    • Agostina Nardone
    • , Carmine De Angelis
    • , Maria Letizia Cataldo
    • , Xiaoyong Fu
    • , Martin J. Shea
    • , Tamika Mitchell
    • , Jamunarani Veeraraghavan
    • , Chandandeep Nagi
    • , Meghana Trivedi
    • , Susan G. Hilsenbeck
    • , Gary C. Chamness
    • , C. Kent Osborne
    •  & Rachel Schiff
  2. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02210, USA

    • Agostina Nardone
    •  & Rinath Jeselsohn
  3. Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    • Hazel Weir
    • , Oona Delpuech
    •  & Henry Brown
  4. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    • Chandandeep Nagi
    • , C. Kent Osborne
    •  & Rachel Schiff
  5. Quantitative Biology, Discovery Science, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    • Mark Pilling
  6. Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    • Mothaffar F. Rimawi
    • , Meghana Trivedi
    • , C. Kent Osborne
    •  & Rachel Schiff
  7. Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA

    • Meghana Trivedi

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Contributions

All authors conceived and/or designed the work that led to the submission, acquired data, and/or played an important role in interpreting the results. All authors drafted or revised the manuscript. All authors approved the final version. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Competing interests

R.S. has received research funding (to institution) from AstraZeneca, Gilead, PUMA, and GlaxoSmithKline (GSK). She is a consulting/advisory committee member for Macrogenics, and Eli Lilly. C.K.O. has received research funding from AstraZeneca and GSK. He has been a member of advisory boards for Pfizer, Nanostring, Genentech, Tolmar Pharmaceuticals, and AstraZeneca. He is also a member of a DMC for Eli Lilly. M.F.R. has received research funding (to institution) from Pfizer and GSK. He is a consulting member for Genentech, Novartis, Daiichi Sankyo, and Macrogenics. R.J. received research funding from Pfizer. O.D. is an AstraZeneca employee. H.W., M.P., and H.B. are former AstraZeneca employees.

Ethical approval

All animal care was in accordance with institutional guidelines.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Rachel Schiff.

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DOI

https://doi.org/10.1038/s41416-018-0354-9