Abstract P6-13-22: Pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors
Authors: W Yang, J Bean, S Hosford, D Lloye, S Liu, L Salphati, J Pang, X Zhang, M Nannini, TW Miller
Journal: Cancer Research (2016)

Abstract PI3K inhibitors have shown promise for the treatment of anti-estrogen-resistant ER+ breast cancers. Current PI3K inhibitor treatment regimens may incompletely and transiently inhibit the pathway in carcinomas, and are accompanied by significant adverse effects in patients. We hypothesized that short-term, complete inhibition of PI3K will have a greater anti-tumor effect and reduce systemic toxicity compared to chronic, partial inhibition. Pharmacokinetic analysis of the orally available pan-PI3K inhibitor GDC-0941 at low (100 mg/kg) and high (800 mg/kg) doses in mice revealed that plasma levels peaked after 15-30 min, and decreased below the limit of detection within 24 h (low dose) and 72 h (high dose), respectively. Administering 2 doses at 100 mg/kg 12 h apart provided continuous drug exposure. Drug pharmacokinetics in MCF-7 tumors was similar. Mice bearing s.c. MCF-7 tumors were treated with the anti-estrogen fulvestrant (fulv; 5 mg/wk) three days before GDC-0941 treatment to assess pharmacodynamic effects. Phospho-AKT and -S6 levels (markers of PI3K and mTORC1 activities, respectively) were inversely correlated with tumor drug concentrations. Mice bearing MCF-7, fulv-resistant T47D/FR, or HCC-003 patient-derived xenografts were treated with vehicle, fulv, GDC-0941 (100 mg/kg QD 5 d/wk; 100 mg/kg BID 3 d on/4 d off; 800 mg/kg QW), or combinations. Tumor growth curves indicated that different schedules of PI3K inhibition with fulv similarly induced tumor regression. Molecular analysis of MCF-7 tumors showed that fulv plus GDC-0941 QW induced 30.14% apoptosis (assessed by TUNEL) at 48 h, which dropped to baseline (2.72%) at 72 h. Fulv plus GDC-0941 BID induced 18.27% apoptosis at 24 h, and maintained apoptosis rate near 10% until 96 h (when GDC-0941 washed out), which is a rate similar to that observed with fulv plus GDC-0941 QD. Fulv plus GDC-0941 QW decreased cell proliferation (assessed by geminin and Ki67 staining) from 34.89% (baseline) to 11.46%, which rebounded to 60.54% at the time of GDC-0941 washout (at 96 h). Fulv plus GDC-0941 QD or BID modestly decreased cell proliferation to 28.84% and 24.32%, respectively, after 24 h, which returned to baseline after 36 h and 72 h, respectively, then maintained the level for a week. Temporal analysis of PI3K signaling revealed that fulv plus GDC-0941 QW and BID maximally decreased phospho-AKT levels after 3 h, which returned to baseline within 48 h and 72 h, respectively. With fulv + GDC-0941 QD, phospho-AKT levels decreased after 3 h, but rebounded to baseline within 24 h. These results indicate that 2 approaches to PI3K inhibition provide similar anti-tumor efficacy: 1) complete/intermittent (QW) PI3K inhibition induces a burst of apoptosis with a rebound in cell proliferation after drug clearance; and 2) metronomic/repeated (QD) PI3K inhibition repeatedly induces a smaller amount of apoptosis without significantly affecting cell proliferation. These findings may inform clinical testing of PI3K inhibitors to maximize therapeutic index. Citation Format: Yang W, Bean J, Hosford S, Lloye D, Liu S, Salphati L, Pang J, Zhang X, Nannini M, Miller TW. Pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-22.