ESTRO 2024 - Abstract Book

S5323

Radiobiology - Tumour biology

ESTRO 2024

Zi-Lu Huang 1,2 , Zhi-Gang Liu 3 , Qi Lin 4 , Ya-Lan Tao 2 , Xinzhuoyun Li 1 , Patricia Baxter 3 , Jack MF Su 3 , Adekunle M. Adesina 5 , Chris Man 3 , Murali Chintagumpala 3 , Wan Yee Teo 3 , Yuchen Du 1 , Yun-Fei xia 6 , Xiao-Nan li 1 1 Northwestern University Feinberg School of Medicine, Pediatrics, Chicago, USA. 2 Sun Yat-Sen University Cancer Center, Radiation Oncology, Guangzhou, China. 3 Baylor College of Medicine, Pediatrics Baylor College of Medicine, Huston, USA. 4 Sun Yat-sen University, Pharmacology, Guangzhou, China. 5 Texas Children’s Hospital, Pathology, Huston, USA. 6 Sun Yat-Sen University Cancer Center, Radiation Oncology, Guangzhou, USA

Purpose/Objective:

Purpose: To discover new mechanisms of radiation resistance of pediatric high-grade gliomas (pHGG) in patient derived orthotopic xenograft (PDOX) animal models.

Material/Methods:

Experimental Design: A panel 6 PDOX models with or without DNA mismatch repair (MMR) deficiency were irradiated locally at 2 Gy/day for 5 days. Animal survival times were examined by log-rank analysis and correlated with spatial (tumor core vs. invasion) and temporal (acute and long-term) changes of DNA damage (γH2AX), cell proliferation (Ki 67), mitotic catastrophe, apoptosis (cleaved caspase-3), mitochondria biogenesis, as well as cell cycle quiescence and self-renewal regulators of putative glioma stem (CD133+ and CD15+) cells.

Results:

Results: Fractionated radiation resulted in extension of survival time (<10%) in 4/6 PDOX models (P<0.05) and widespread γH2AX positivity in >95% tumor cells in tumor core and >85% in the invasive foci, accompanied by ~30% apoptotic and mitotic catastrophic cell death. The model with DNA mismatch repair deficiency (IC-1406pHGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. In the surviving cells of two treated models, significant increase of mitochondria numbers, activated COX IV expression and reactive oxygen species were detected. Flow cytometric examination uncovered the exit of quiescence as a novel cause of post-radiation CD133+ tumor cells accumulation and identified activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes as molecular mediators.

Conclusion:

Conclusion: We identified the activation of mitochondrial biogenesis and the exit of quiescence of glioma stem cell as new mechanisms of radiation-resistance in PDOX models and proposed new strategies to reverse radio-resistance in pHGG.

Keywords: mitochondrial, orthotopic xenograft, glioma