Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models.
Wong Te Fong, A-C
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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 <i>in vitro</i> and <i>in vivo</i> ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel (<i>n =</i> 12) studied. A cisplatin- resistant model (A2780Cis) was studied <i>in vitro</i> and <i>in vivo</i>. 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 (<i>p</i> = 0.03) caused by the combination and not paclitaxel or vistusertib alone. <i>In vivo</i>, we observed a significant increase in apoptosis (cleaved PARP measured by immunohistochemistry; <i>p</i> = 0.0003). Decreases in phospholipid and bioenergetic metabolites were studied using magnetic resonance spectroscopy and significant changes in phosphocholine (<i>p</i> = 0.01), and ATP (<i>p</i> = 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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Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
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Oncotarget, 2017, 8 (69), pp. 113874 - 113884