title: AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.
abstract: Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom. Hazel.Weir@astrazeneca.com.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Weir
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Mandy
authors.initials: M
authors.lastname: Lawson
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Rabow
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Buttar
authors.affiliation: Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Rowena J
authors.initials: RJ
authors.lastname: Callis
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Curwen
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Camila
authors.initials: C
authors.lastname: de Almeida
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Hulse
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Donald
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Lyman J L
authors.initials: LJ
authors.lastname: Feron
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Galith
authors.initials: G
authors.lastname: Karoutchi
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: MacFaul
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moss
authors.affiliation: Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Pearson
authors.affiliation: Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Tonge
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.affiliation: Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Graeme E
authors.initials: GE
authors.lastname: Walker
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Zena
authors.initials: Z
authors.lastname: Wilson
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rowlinson
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Powell
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Sadler
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Richmond
authors.affiliation: Oncology iMed, AstraZeneca R&D Boston, Gatehouse Drive, Waltham, Massachusetts.
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.affiliation: H3 Biomedicine, Cambridge, Massachusetts.
authors.forename: Ermira
authors.initials: E
authors.lastname: Pazolli
authors.affiliation: Oncology iMed, AstraZeneca R&D Boston, Gatehouse Drive, Waltham, Massachusetts.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Mazzola
authors.affiliation: Oncology iMed, AstraZeneca R&D Boston, Gatehouse Drive, Waltham, Massachusetts.
authors.forename: Celina
authors.initials: C
authors.lastname: D'Cruz
authors.affiliation: Oncology iMed, AstraZeneca R&D Boston, Gatehouse Drive, Waltham, Massachusetts.
authors.forename: Chris
authors.initials: C
authors.lastname: De Savi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D051381:Rats; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000604573:AZD9496; D002934:Cinnamates; C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D007211:Indoles