Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma
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Maria Tsoli1, Jie Liu1, Laura Franshaw1, Han Shen1, Cecilia Cheng1, MoonSun Jung2, Swapna Joshi1, Anahid Ehteda1, Aaminah Khan1, Angel Montero-Carcabosso3, Pierre J. Dilda4, Philip Hogg5 and David S. Ziegler1,6
1Targeted Therapies Research Program, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia
2Experimental Therapeutics Program, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia
3Preclinical Therapeutics and Drug Delivery Research Program, Department of Oncology, Hospital Sant Joan de Déu, Barcelona, Spain
4Biophytis, UPMC, BC94, Paris, France
5ACRF Centenary Cancer Research Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia
6Kids Cancer Centre, Sydney’s Children Hospital, Randwick, New South Wales, Australia
David S. Ziegler, email: [email protected]
Keywords: DIPG; paediatric brain tumour; mitochondria; mTOR; PDGFR
Received: August 08, 2017 Accepted: January 02, 2018 Published: January 08, 2018
Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted.
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