Abstract CT138: Translating preclinical observations to the clinic: Combination of the dual m-TORC1/2 inhibitor AZD2014 and paclitaxel in ovarian and lung cancer
Authors: Thavasu Parames , Wong Te Fong Anne-Christine LF , Jimenez Rodriguez Begona , Basu Bristi , Turner Alison , Hall Emma , Yap Timothy A. , Banerjee Susana , Leach Martin , de Bono Johann S. , Chung Yuen-Li , Banerji Udai 
Published: August 2015

Abstract
Background: We have previously immunomagnetically separated cancer cells from ascites samples of patients with ovarian cancer who went on to receive chemotherapy. We reported that a raised p-S6K in cancer cells was associated with chemoresistance (Carden C, et al, Mol Cancer Ther 2012;11:1609-17). We hypothesized that combining chemotherapy with a novel dual m-TORC1/2 inhibitor would be effective in this setting.
Methods: We studied apoptosis induced by paclitaxel (P), AZD2014 (A) and the combination (C) on 2 ovarian (A2780Cis, SKOV3), 2 lung (PC9, H520), 2 breast (MCF7, SKBR3) and 1 endothelial cell line (HUVEC) by quantifying cleaved-PARP using ELISA. We further investigated the effects of each drug and the combination on tumor growth and signal transduction (pSer473-AKT, p-S6) with a combination of P (20 mg/kg/week) and A (50 mg/kg/3 days/week) in 2 xenograft models (A2780Cis and H520). We also designed an investigator-initiated clinical trial of the combination of P 80 mg/m2/week in combination with an escalating dose of A administered twice a day in 2 schedules (2/7 and 3/7 started concomitantly with the P infusions). Radiological response was measured by RECIST and clinical benefit (CB) defined as progression at 14 weeks or later.
Results: There was a major increase in apoptosis induction, as determined by c-PARP levels quantitation, in 3/6 cancer cell lines and the endothelial cell line HUVEC when A was added to P when compared to P alone utilizing concentrations of both drugs at GI50 and 5 x GI50 for 24 hrs. Additive growth inhibition was observed in both xenograft models after 2 weeks of combination treatment with tumor volume increased by 281 ± 98% with the combination (p&lt;0.05), 557 ± 22% in vehicle-controls (V), 420 ± 156% with A alone and 726 ± 182% with P alone in A2780Cis xenografts; and by 196 ± 44% with the combination (p&lt;0.02), 382 ± 51% with V, 276 ± 52% with A and 509 ± 116% with P in the H520 xenografts. There was a reduction in pSer473-AKT and p-S6 levels in xenografts treated in the A and C arms in both models. The recommended phase II dose of the clinical trial is 80 mg/m2/week of P and 50 mg bd 3/7 of A. Within the clinical trial 7 patients with heavily pre-treated ovarian cancer have had 3 partial responses (PR) with 4 of 6 having CB. Furthermore, in a subset of patients with squamous NSCLC pre-treated with docetaxel, 2 of 5 PRs with significant intra-tumoral cavitation were reported, with 3/3 having CB. The clinical trial is currently expanding in ovarian cancer and squamous NSCLC cohorts.
Conclusions: The combination of P+A is effective in preclinical ovarian and lung cancer models, with additive growth inhibition and apoptosis seen. Promising drug combination antitumor activity has also been reported in heavily pre-treated patients with ovarian cancer and squamous NSCLC in an ongoing clinical trial.
Citation Format: Parames Thavasu, Anne-Christine LF Wong Te Fong, Begona Jimenez Rodriguez, Bristi Basu, Alison Turner, Emma Hall, Timothy A. Yap, Susana Banerjee, Martin Leach, Johann S. de Bono, Yuen-Li Chung, Udai Banerji. Translating preclinical observations to the clinic: Combination of the dual m-TORC1/2 inhibitor AZD2014 and paclitaxel in ovarian and lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT138. doi:10.1158/1538-7445.AM2015-CT138