Abstract B10: Noninvasive pharmacodynamic markers of the dual mTORC1/2 inhibitor AZD2014 in combination with paclitaxel, in cisplatin-resistant ovarian carcinoma xenografts

• DOI: 10.1158/1557-3125.metca15-b10
• Publication Date: 2016-05-20T08:53:21Z
• Authors: Anne-Christine LF...; Efthymia Papaevan...; Martin O. Leach; Udai Banerji; Yuen-Li Chung

Abstract Background: The PI3K/AKT/mTOR pathway is known to regulate glucose metabolism, proliferation and apoptosis, hence the inhibition of mTOR expected have impact on these important mechanisms tumor growth survival. Studies cancer metabolism following reported date only been carried out allosteric inhibitors which selectively inhibit activity mTORC1. metabolic changes associated with dual mTORC1 2 inhibitions remain unknown. AZD2014 a mTORC1/2 inhibitor. aims this study are (i) examine effects alone in combination paclitaxel, (ii) develop non-invasive pharmacodynamic (PD) biomarker for response. Methods: We investigated (A: 50mg/kg/3 days/week po), paclitaxel (P: 20mg/kg/1 day/week ip) (A+P: same doses) growth, signal transduction (pSer473-AKT, pSer240/244-S6) apoptosis (cleaved PARP) cisplatin resistant ovarian (A2780CisR) carcinoma xenograft model weeks treatment. Metabolic profiles A2780CisR extracts after treatment were also measured by high resolution vitro 1H- 31P-MRS. In order early PD markers response, vivo 1H-MRS before 3 days performed. Results: Growth molecular response- Following two treatment, volumes xenografts increased 280±100% A+P (p<0.05; compared vehicle-controls (V)), 420±160% A (not significant V (ns)), 730±180% P (ns) 560±20% V. Reduced pSer473-AKT pSer240/244-S6 protein levels cleaved-PARP expression observed A- A+P-treated consistent induction respectively. 31P-MRS extracts- Similar increases branched-chain amino acids (p<0.03), glutamine (p<0.002), tyrosine (p<0.0001), phenylalanine (p<0.02) (p<0.03) found tumors when Significant decreases phosphocholine (PC, p<0.002), glycero-phosphocholine (GPC, phosphoethanolamine (PE, p<0.02) ATP (p<0.003), together reduced choline kinase, seen tumors. An increase threonine was P- 1H-MRS- reduction phospholipid metabolites GPC PE) confirmed decrease ratio total choline/water (p=0.04) at time-point Conclusions: effective preclinical tumors, additive apoptosis. Very few P-treated non-phospholipid previous findings where similar (1). caused PC (associated kinase expression) other choline-related may potential as surrogate determining response (1) Lin et al. Cell Symposia: Angiogenesis, Regulation, Cancer Biology association VIB, Belgium 2012. This work supported CR-UK EPSRC Imaging Centre MRC Department Health (England) grants C1060/A10334 C1060/A16464, NHS funding NIHR Biomedical Research Centre. MOL an Senior Investigator. Citation Format: Anne-Christine LF Wong Te-Fong, Efthymia Papaevangelou, Martin O. Leach, Udai Banerji, Yuen-Li Chung. Noninvasive inhibitor cisplatin-resistant xenografts. [abstract]. In: Proceedings AACR Special Conference: Metabolism Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Res 2016;14(1_Suppl):Abstract nr B10.