Title: Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models
Abstract: // Anne-Christine Wong Te Fong 1 , Parames Thavasu 2, 4 , Sladjana Gagrica 3 , Karen E. Swales 2, 4 , Martin O. Leach 1 , Sabina C. Cosulich 3 , Yuen-Li Chung 1 and Udai Banerji 4 1 Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden, London, UK 2 Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK 3 IMED Oncology, AstraZeneca, Cancer Research UK Cambridge Institute, Cambridge, UK 4 Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, UK Correspondence to: Udai Banerji, email: [email protected] Keywords: mTORC1/2; vistusertib; AZD2014; chemo-resistance; ovarian cancer Received: August 03, 2017 Accepted: November 14, 2017 Published: December 06, 2017 ABSTRACT Activation of the PI3K/mTOR pathway has been shown to be correlated with resistance to chemotherapy in ovarian cancer. We aimed to investigate the effects of combining inhibition of mTORC1 and 2 using the mTOR kinase inhibitor vistusertib (AZD2014) with paclitaxel in in vitro and in vivo ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel ( n = 12) studied. A cisplatin- resistant model (A2780Cis) was studied in vitro and in vivo . We demonstrated inhibition of mTORC1 and mTORC2 by vistusertib and the combination by showing reduction in p-S6 and p-AKT levels, respectively. In the A2780CisR xenograft model compared to control, there was a significant reduction in tumor volumes ( p = 0.03) caused by the combination and not paclitaxel or vistusertib alone. In vivo , we observed a significant increase in apoptosis (cleaved PARP measured by immunohistochemistry; p = 0.0003). Decreases in phospholipid and bioenergetic metabolites were studied using magnetic resonance spectroscopy and significant changes in phosphocholine ( p = 0.01), and ATP ( p = 0.04) were seen in tumors treated with the combination when compared to vehicle-control. Based on this data, a clinical trial evaluating the combination of paclitaxel and vistusertib has been initiated (NCT02193633). Interestingly, treatment of ovarian cancer patients with paclitaxel caused an increase in p-AKT levels in platelet-rich plasma and it was possible to abrogate this increase with the co-treatment with vistusertib in 4/5 patients: we believe this combination will benefit patients with ovarian cancer.