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Updated: Feb 13, 2026
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine
Maria Tsoli1, Jie Liu1, Laura Franshaw1
1Targeted Therapies Research Program, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
Insights
This study investigated PENAO, a novel compound targeting mitochondria, for treating Diffuse Intrinsic Pontine Gliomas (DIPG). Combination therapy with PENAO and temsirolimus showed promise by inducing oxidative stress and apoptosis in DIPG cells.
Area of Science:
- Oncology
- Mitochondrial Biology
- Pediatric Neuro-oncology
Background:
- Diffuse Intrinsic Pontine Gliomas (DIPG) are aggressive pediatric brain tumors with no effective treatments.
- DIPG exhibits resistance to apoptosis and involves metabolic reprogramming and redox disruption.
- Mitochondria play a critical role in these cellular processes, making them a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of PENAO, a novel mitochondrial inhibitor targeting adenine nucleotide translocase (ANT), against DIPG.
- To investigate the combined effect of PENAO with the mTOR inhibitor temsirolimus on DIPG cells.
- To elucidate the molecular mechanisms underlying the combination therapy's action.
Main Methods:
- DIPG neurosphere cultures were used to assess sensitivity to PENAO and combination therapy.
- Mitochondrial function, oxidative stress, and apoptosis were analyzed.
- Key signaling pathways including PI3K/AKT/mTOR, HSP90, and AMPK were investigated.
- In vivo orthotopic DIPG models were employed to evaluate anti-tumor effects.
Main Results:
- DIPG cells express high levels of ANT2 and are sensitive to PENAO, inducing oxidative stress.
- Co-treatment with PENAO and temsirolimus enhanced apoptotic effects in DIPG cells.
- The combination therapy inhibited the PI3K/AKT/mTOR pathway, HSP90, and activated AMPK.
- In vivo studies showed marginal anti-tumor effects, potentially due to poor blood-brain barrier (BBB) penetration.
Conclusions:
- PENAO, in combination with temsirolimus, represents a promising therapeutic strategy for DIPG by targeting mitochondrial function and inducing apoptosis.
- Further research is warranted to develop strategies that improve BBB penetration for effective in vivo treatment of DIPG.
Abstract:
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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