Clémentine Fulbert1, Stéphan Chabardès2,3,4, David Ratel5. 1. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France. clementine.fulbert@gmail.com. 2. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France. 3. Neurosurgery Department, CHU Grenoble Alpes, 38000, Grenoble, France. 4. Univ. Grenoble Alpes, Inserm U1216, Grenoble Institut des Neurosciences, 38000, Grenoble, France. 5. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France. david.ratel@cea.fr.
Abstract
PURPOSE: Glioblastoma is the most common malignant brain tumor, currently treated by surgery followed by concomitant radiotherapy and temozolomide-based chemotherapy. Despite these treatments, median survival is only 15 months as a result of tumor recurrence in the resection margins. Here, we propose therapeutic hypothermia - known to have neuroprotective effects - as an adjuvant treatment to maintain residual glioblastoma cells in a dormant state, and thus prevent tumor recurrence. METHODS: In vitro experiments were performed on healthy tissue with primary human astrocytes, and four human glioblastoma cell lines: A172, U251, U87, and T98G. We explored the adjuvant potential of moderate hypothermia (28 °C) by studying the reversibility of its inhibitory effects on cell proliferation and comparing them to currently used temozolomide. RESULTS: Moderate hypothermia reduced healthy cell growth, but also inhibited glioblastoma cell proliferation even after rewarming. Indeed, hypothermic preconditioning duration strongly enhanced inhibitory effects from 35% after 3 days to 100% after 30 days. In contrast, moderate (28 °C) and severe (23 °C) preconditioning induced similar results. Finally, moderate hypothermia had more uniform inhibitory effects than temozolomide, which reduced proliferation by between 15% and 95%, and also potentiated the effects of the latter. CONCLUSION: Moderate hypothermia shows promise as an adjuvant therapy for glioblastoma through its inhibition of cell proliferation beyond direct conditioning and potentiation of the effects of chemotherapy. If in vivo preclinical results corroborate our findings, therapeutic hypothermia applied at the resection margins could probably inhibit tumor growth, delay tumor recurrence and reduce inter-patient variability.
PURPOSE: Glioblastoma is the most common malignant brain tumor, currently treated by surgery followed by concomitant radiotherapy and temozolomide-based chemotherapy. Despite these treatments, median survival is only 15 months as a result of tumor recurrence in the resection margins. Here, we propose therapeutic hypothermia - known to have neuroprotective effects - as an adjuvant treatment to maintain residual glioblastoma cells in a dormant state, and thus prevent tumor recurrence. METHODS: In vitro experiments were performed on healthy tissue with primary human astrocytes, and four human glioblastoma cell lines: A172, U251, U87, and T98G. We explored the adjuvant potential of moderate hypothermia (28 °C) by studying the reversibility of its inhibitory effects on cell proliferation and comparing them to currently used temozolomide. RESULTS: Moderate hypothermia reduced healthy cell growth, but also inhibited glioblastoma cell proliferation even after rewarming. Indeed, hypothermic preconditioning duration strongly enhanced inhibitory effects from 35% after 3 days to 100% after 30 days. In contrast, moderate (28 °C) and severe (23 °C) preconditioning induced similar results. Finally, moderate hypothermia had more uniform inhibitory effects than temozolomide, which reduced proliferation by between 15% and 95%, and also potentiated the effects of the latter. CONCLUSION: Moderate hypothermia shows promise as an adjuvant therapy for glioblastoma through its inhibition of cell proliferation beyond direct conditioning and potentiation of the effects of chemotherapy. If in vivo preclinical results corroborate our findings, therapeutic hypothermia applied at the resection margins could probably inhibit tumor growth, delay tumor recurrence and reduce inter-patient variability.
Entities:
Keywords:
Cancer treatment; Cell proliferation; Dormancy; Glioblastoma; Temozolomide; Therapeutic hypothermia