ESTRO 2023 - Abstract Book

S6

Saturday 13 May

ESTRO 2023

R. Bristow United Kingdom

Abstract not available

SP-0013 Physical personalisation of radiotherapy K. Bristow USA

Abstract not available

SP-0014 Frontiers in AI: Clinical impact beyond automation C. Grassberger USA

Abstract not available Symposium: Lipids and metabolomics in radiation response - An emerging paradigm in radioresistant cancers?

SP-0015 Deciphering the role of cholesterol in the radiation response of glioblastoma N. Gomez-Roman 1 1 University of Strathclyde, SIPBS, Glasgow, United Kingdom

Abstract Text Glioblastoma is the most common and most malignant primary brain tumour, with a dismal prognosis of less than 5% of patients surviving after 5 years. Treatment for glioblastoma comprises surgery, radiation, and chemotherapy with temozolomide. It has remained static for the last two decades due to the clinical failure of all molecular-targeted therapies tested, despite promising results in laboratory models of glioblastoma. In recent years, several publications have reported an association between high blood cholesterol levels and cancer onset, growth, metastasis, and therapeutic resistance, including in breast, prostate, and pancreatic cancer. The dependence of cancer cells on cholesterol may be used as an Achilles’ heel by targeting cholesterol to treat cancer cells and sensitise them to anticancer therapies. As with other cancers, glioblastoma cells rely heavily on cholesterol for growth, survival and treatment resistance. To assess the potential of targeting cholesterol for the treatment of glioblastoma, we performed a systematic analysis of the cytotoxic and radiosensitising activities of drugs targeting cholesterol pathways controlling cellular homeostasis using a three-dimensional human glioblastoma preclinical in vitro model that recapitulates clinical response. These included ITX 5061 (cholesterol uptake); the statins pitavastatin, simvastatin, fluvastatin, lovastatin, and AY9944 (cholesterol synthesis); LXR-623 (transcriptional control of cholesterol genes); evodiamine (cholesterol efflux); avasimibe, rubamaillin, and efavirenz (cholesterol esterification); and U18666A (intracellular cholesterol transport and trafficking). We identified robust cytotoxic effects on glioblastoma cells treated with the intracellular cholesterol transport inhibitor U18666A, followed by simvastatin, evodiamine, pitavastatin, AY9944, and fluvastatin (EC50 of 0.02, 0.6, 0.83, 0.9, 1.99, and 2.89 mM, respectively). An effect of cholesterol on the radiation sensitivity of glioblastoma was also observed: while cholesterol supplementation conferred radioprotection; cholesterol-lowering drugs pitavastatin and simvastatin conferred radiosensitisation. Increased DNA double-strand breaks and cells undergoing mitotic catastrophe were observed with radiation and pitavastatin treatment combined with radiation alone 24 hours after treatment. Statins treatment also induced changes in the cell cycle, with an increased proportion of cells in the G1 phase and fewer cells in S and G2 phases following treatment, either alone or in combination with radiation. Investigations into the mechanism(s) involved in statins’ cell cycle regulation are currently underway. Based on the cytotoxicity observed with the intracellular cholesterol transport and trafficking inhibitor U18666A, we have also identified a role for the cholesterol transport and trafficking pathway in glioblastoma patient survival. In particular, transcriptomic analysis using the TCGA and GTex datasets for cancer and normal tissue, respectively, demonstrated higher expression of mRNA and protein in tumour samples compared to normal tissues of genes involved in the trafficking of cholesterol across membrane contact sites between organelles, including STARD3NL, NPC2, TSPO, MOSPD1, 2, and 3, ATAD3, HECW2. An effect on survival was also observed, with a statistically significant correlation between high mRNA expression and worse survival for each gene. Furthermore, a cholesterol transport gene signature including STAR, STARD3, STARD3NL, NPC2, TSPO, HECW, MOSPD1, MOSPD2, and MOSPD3 exhibited statistically significantly worse survival in high vs low genes expression compared to single gene expression (log-rank p=4.4e-05, HR=2.1). Gene amplification of STARD3NL was also observed in over 15% of glioblastoma tumour samples. Further analysis demonstrated a correlation between high STARD3NL mRNA expression with worse survival in several GBM datasets. It is well known that high cholesterol levels are associated with the risk of different cancers and hamper therapeutic response. However, to date, how cholesterol exerts this effect remains uncertain. A better understanding of cholesterol homeostasis in cancer cells is needed to identify appropriate combinations and schedules, resulting in consistent clinical responses and ultimately improving patient outcomes. These preliminary findings place cholesterol trafficking as an alternative cancer-specific pathway for targeting cholesterol in glioblastoma, offering an exciting, novel therapeutic avenue for cancer treatment, warranting further investigation. SP-0016 Dopamine receptor antagonists, radiation, and cholesterol biosynthesis in mouse models of glioblastoma F. Pajonk USA Abstract not available