Abstract 3604: Effect of a new oral SERD AZD9496 on ER mediated signaling in xenograft model of postmenopausal breast cancer
Authors: Sabnis Gauri J. , Kazi Armina , Schech Amanda , Yu Stephen , Golubeva Olga , Brodie Angela 
Published: July 2017

Abstract
Aromatase inhibitors (AIs) have made significant improvements in the treatment outcomes of patients with breast cancer. However, tumors may eventually acquire resistance. One of the proposed mechanisms of resistance to AIs is overexpression of ERα and cross-talk of ERα with growth factor receptors. Studies including our own have shown that downregulation of ER with fulvestrant may provide benefit in the treatment of AI-resistant breast cancer. Fulvestrant has been employed in the clinic as either first or second line treatment for ER positive breast cancers alone or in combination with AIs. Studies have suggested that further escalation of dose may provide further benefit. However, dose escalation of fulvestrant which is administered via intramuscular injection is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active SERD (selective estrogen receptor downregulator), AZD9496 was developed. We evaluated the effect of AZD9496 on the growth of hormone sensitive and anastrozole resistant breast cancer tumors using MCF-7Ca xenograft model of postmenopausal breast cancer. Mice bearing xenografts of MCF-7Ca were then treated with fulvestrant (1 mg/d-sc) or AZD9496 (5 mg/kg/d-po), alone or in combination with anastrozole (200μg/d-sc) for 23 weeks. Tumors were measured weekly and growth rate was calculated. AZD9496 was significantly better at inhibiting the growth of tumors compared to control (p&lt;0.001) and anastrozole (p=0.04) while being equally effective as fulvestrant (p&gt;0.99). In the second study, efficacy of AZD9496 was evaluated on against anastrozole resistant MCF-7Ca xenografts. Tumors were treated with anastrozole (200μg/d) for 13 weeks. During this time, the tumors initially regressed but eventually began to grow and had doubled in volume. At this time-point, they were regrouped to receive second line treatment. Single agent AZD9496 was marginally significant compared to continued anastrozole treatment (p=0.07). Nevertheless, second line treatment with AZD9496 was equally effective as fulvestrant (p=0.36). AZD9496 treatment was also equally effective in reducing the expression of ERα protein in MCF-7Ca xenografts as fulvestrant. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was not significantly different from mice that were treated with androstenedione (p=0.99). Furthermore, AZD9496 did not decrease the expression of ERα in the uterus, confirming its selectivity for mammary ERα. AZD9496 treatment was also able to reduce intratumoral aromatase activity. However, it was not due to direct inhibition of the enzyme, but due to reduction in ERα mediated signaling. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its oral bioavailability, selectivity for mammary ER, and ability to reduce aromatase activity while being equally effective as fulvestrant.
Citation Format: Gauri J. Sabnis, Armina Kazi, Amanda Schech, Stephen Yu, Olga Golubeva, Angela Brodie. Effect of a new oral SERD AZD9496 on ER mediated signaling in xenograft model of postmenopausal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3604. doi:10.1158/1538-7445.AM2017-3604