Great thread Jeff and I’m so glad to see this funding go to you! Well deserved!!!

10/ Takeaway👉
📌 1st study to identify OXPHOS/hypoxia signatures in DIPG models
📌 Targeting mitochondrial metabolism alleviates hypoxia & radiosensitizes in DIPG mouse models.
📌This approach has potential to enhance radiation therapy and inspire new treatment combo strategies

9/ We found increased expression of certain nuclear encoded OXPHOS related genes while other papers have shown decreased mitochondrial DNA and altered mitochondrial metabolism. There is more to be learned about DIPG mitochondria and how this impacts tumor cell behavior.

8/ Ongoing questions: So far, DIPG studies have highlighted mitochondrial differences compared to healthy tissues. But we still lack definitive data on what those differences are and how it impacts the tumor (are there more or less mitochondria? Do they function differently?)

7/ Unexpected: Phenformin also triggered changes in cholesterol pathways. This raises questions and maybe possibilities(?) for future drug combination strategies (e.g., phenformin + statins) to overcome resistance to mitochondrial inhibition. #CancerMetabolism

6/ Phenformin has risks in humans, including lactic acidosis, so is unlikely to be used clinically. But our findings pave the way for exploring safer mitochondrial-targeting drugs or combination therapies that target potential resistance pathways.

5/ We used phenformin, an older diabetes drug that was withdrawn from the market, to block mitochondrial OXPHOS in tumor cells and mouse models of DIPG.
We showed that in tumor spheroids hypoxia decreased.
In both cells and mouse models, radiosensitivity increased

4/ We wondered if we could target the mitochondria to:
✅ Deprive tumor cells of energy
✅ Lower oxygen consumption
✅ Reduce hypoxia
✅ Improve radiation sensitivity #Radiosensitization

3/ Hypoxia can make tumours more aggressive and resistant to radiation. Using clinical datasets, we identified hypoxia signatures in DIPG/DMG patient tumours and in DIPG mouse models. Tumours with ⬆️ hypoxia scores also had ⬆️ OXPHOS gene expression.

2/ We found patient-derived DIPG cell lines rely heavily on mitochondria for energy production via oxidative phosphorylation (OXPHOS). This consumes oxygen, potentially creating hypoxia. ⬇️#BrainTumor

1/ 🚨 Diffuse intrinsic pontine gliomas (#DIPG) are aggressive and deadly brain tumours affecting children. Surgery isn’t an option, and radiation therapy offers only temporary relief. Our goal was to identify ways to enhance the tumor kill effect of radiation🧵#CancerResearch