Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models
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Anne-Christine Wong Te Fong1, Parames Thavasu2,4, Sladjana Gagrica3, Karen E. Swales2,4, Martin O. Leach1, Sabina C. Cosulich3, Yuen-Li Chung1 and Udai Banerji4
1Cancer 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
3IMED Oncology, AstraZeneca, Cancer Research UK Cambridge Institute, Cambridge, UK
4Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, UK
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
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.
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