Abstract P5-20-03: Understanding pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors

Abstract

Abstract PI3K inhibitors have shown promise for the treatment of anti-estrogen-resistant breast cancers. Current PI3K inhibitor treatment regimens incompletely and transiently inhibit the pathway in carcinomas, and are accompanied by adverse effects in patients. We found that different periods of PI3K inhibition (12, 24, 36 h) potentiated anti-estrogen-induced apoptosis and inhibition of proliferation to similar extents in cultured ER+ cells. We thus hypothesized that short-term, complete inhibition of PI3K will have a greater anti-tumor effect and reduced systemic toxicity than 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. (18.6 uM and 20.7 uM, respectively), and decreased to a plateau phase after 1 h that was maintained for 8 h with low dose (6.8-10.7 uM) and 23 h with high dose (7.9-15 uM). We performed MCF-7 tumor pharmacokinetic analyses with low and high doses, and with 2 low doses administered 12 hours apart. Tumor GDC-0941 levels peaked after 9 h (1.6 uM with low-dose; 16.9 uM with high-dose). The second low dose increased tumor drug concentrations to 3.2 uM at 9 h after the second dose, compared to 1.6 uM at 9 h after the first dose. After 48 h, tumor drug concentrations decreased to 0 uM with low dose, and to 4.5 uM with high dose. Mice bearing MCF-7 tumors were treated with fulvestrant (5 mg/wk). Three days later, GDC-0941 was administered to assess pharmacodynamic effects. Phospho-AKT and -S6 levels (markers of PI3K and mTORC1 activities, respectively) were maximally suppressed after 1 h and 3 h of high- and low-dose treatments, respectively, returned to baseline within 16 h after low-dose treatment, and remained suppressed for 36 h following high-dose treatment. PARP cleavage (marker of apoptosis) occurred within 1 h and 3 h of high- and low-dose treatments, and increased over time. Re-treatment of mice with low-dose GDC-0941 after 12 h induced continued inhibition of PI3K and mTORC1 for 9-12 h, suggesting that BID low-dose treatment may be sufficient to continually inhibit PI3K. Comparison of high-dose and low-dose BID tumors showed that these treatments induced similar amounts of PI3K inhibition and PARP cleavage at 21-24 h. Mice bearing MCF-7 or fulvestrant-resistant T47D/FR tumors were treated with vehicle, fulvestrant, GDC-0941 (100 mg/kg QD 5 d/wk; 100 mg/kg BID 3 d/wk, 800 mg/kg QW), or combinations of fulvestrant and GDC-0941. Drug combinations induced tumor regression, fulvestrant did not affect tumor growth, high-dose GDC-0941 QW slowed tumor growth, and low-dose GDC-0941 QD or BID appreciably inhibited tumor growth. However, there was no significant difference among doses and schedules of GDC-0941 in the context of a fulvestrant backbone in either tumor model. These data suggest that transient/metronomic (QD, BID) and chronic/infrequent (QW) PI3K inhibition may provide similar anti-tumor efficacy in combination with an anti-estrogen. However, these tumor growth data conflict with cell fate data indicating that high-dose GDC-0941 induced much more apoptosis than low-dose GDC-0941. Ongoing studies will reveal how different schedules of PI3K inhibition shape tumor biology. Citation Format: Wei Yang, Jennifer R Bean, Lloye Dillon, Laurent Salphati, Jodie Pang, Xiaolin Zhang, Michelle Nannini Pepe, Todd W Miller. Understanding pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-20-03.