Details

Autor(en) / Beteiligte

• Wong Te Fong, Anne-Christine
• Thavasu, Parames
• Gagrica, Sladjana
• Swales, Karen E
• Leach, Martin O
• Cosulich, Sabina C
• Chung, Yuen-Li
• Banerji, Udai

Titel

Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models

Ist Teil von

• Oncotarget, 2017-12, Vol.8 (69), p.113874-113884

Ort / Verlag

United States: Impact Journals LLC

Erscheinungsjahr

2017

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 and ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel ( 12) studied. A cisplatin- resistant model (A2780Cis) was studied and . 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 ( = 0.03) caused by the combination and not paclitaxel or vistusertib alone. , we observed a significant increase in apoptosis (cleaved PARP measured by immunohistochemistry; = 0.0003). Decreases in phospholipid and bioenergetic metabolites were studied using magnetic resonance spectroscopy and significant changes in phosphocholine ( = 0.01), and ATP ( = 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.