Abstract 5512: Pharmacodynamic analysis of PI3K inhibition in breast tumors: A model to improve early clinical investigation of novel agents

Abstract

Abstract PI3K inhibitors have shown promise for the treatment of anti-estrogen-resistant breast cancers. Dose determination in clinical studies is often performed in a dose-escalation fashion until toxicities are observed; however, this approach does not provide information on target inhibition or allow optimization of scheduling for maximal anti-cancer effects. Current PI3K inhibitor treatment regimens incompletely and transiently inhibit the pathway in carcinomas, and are accompanied by adverse effects in patients. We hypothesize that short-term, complete inhibition of PI3K will have a greater anti-tumor effect and reduced adverse effects than chronic, partial inhibition. Through detailed analysis of the timing and magnitude of drug effects on tumor biology, drug doses and schedules may be optimized during early clinical development to improve anti-tumor effects in subsequent trials. Pharmacokinetic analysis of the 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 GDC-0941 (6.8-10.7 uM) and for 23 h with high-dose GDC-0941 (7.9-15 uM). Thus, GDC-0941 appears to be retained in a tissue compartment and slowly released back into plasma over time. Mice bearing MCF-7 tumors were treated with the anti-estrogen fulvestrant (5 mg) for three days, and then low- or high-dose GDC-0941, or 2 low doses of GDC-0941 12 hours apart, to assess pharmacodynamic effects and tumor cell response. PARP cleavage (marker of apoptosis) occurred within 1 h and 3 h of high- and low-dose treatments, respectively, and apoptosis increased over time. Phosphorylated AKT and S6 levels (markers of PI3K and mTORC1 activities) were maximally suppressed after 1 h and 3 h of high- and low-dose treatments, respectively, and returned to baseline within 16 h after low-dose treatment. In vitro analysis revealed that PI3K inhibition induced upregulation of growth factor receptors upstream of PI3K, indicating a requirement for sustained and robust PI3K inhibition. Re-treatment of mice with low-dose GDC-0941 after 12 h induced continued inhibition of PI3K and mTORC1 for >9 h, suggesting that twice daily low-dose treatment may be sufficient to continually inhibit PI3K. In contrast, high-dose GDC-0941 suppressed PI3K and mTORC1 for >24 h. Analysis of these doses and schedules on tumor growth is ongoing. Citation Format: Wei Yang, Jennifer R. Bean, Lloye Dillon, Laurent Salphati, Michelle Nannini, Todd W. Miller. Pharmacodynamic analysis of PI3K inhibition in breast tumors: A model to improve early clinical investigation of novel agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5512. doi:10.1158/1538-7445.AM2014-5512