Version 1
: Received: 10 July 2024 / Approved: 10 July 2024 / Online: 11 July 2024 (08:34:42 CEST)
How to cite:
Kuchařová, Z.; Kortmann, R.-D.; Glasow, A.; Patties, I. Antitumor Activity of Radiation Therapy Combined With Checkpoint Kinase Inhibition in SHH/p53-Mutated Human Medulloblastoma. Preprints2024, 2024070903. https://doi.org/10.20944/preprints202407.0903.v1
Kuchařová, Z.; Kortmann, R.-D.; Glasow, A.; Patties, I. Antitumor Activity of Radiation Therapy Combined With Checkpoint Kinase Inhibition in SHH/p53-Mutated Human Medulloblastoma. Preprints 2024, 2024070903. https://doi.org/10.20944/preprints202407.0903.v1
Kuchařová, Z.; Kortmann, R.-D.; Glasow, A.; Patties, I. Antitumor Activity of Radiation Therapy Combined With Checkpoint Kinase Inhibition in SHH/p53-Mutated Human Medulloblastoma. Preprints2024, 2024070903. https://doi.org/10.20944/preprints202407.0903.v1
APA Style
Kuchařová, Z., Kortmann, R. D., Glasow, A., & Patties, I. (2024). Antitumor Activity of Radiation Therapy Combined With Checkpoint Kinase Inhibition in SHH/p53-Mutated Human Medulloblastoma. Preprints. https://doi.org/10.20944/preprints202407.0903.v1
Chicago/Turabian Style
Kuchařová, Z., Annegret Glasow and Ina Patties. 2024 "Antitumor Activity of Radiation Therapy Combined With Checkpoint Kinase Inhibition in SHH/p53-Mutated Human Medulloblastoma" Preprints. https://doi.org/10.20944/preprints202407.0903.v1
Abstract
Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Current therapy results in poor prognosis for high-risk SHH/p53-mutated MB, emphasizing the importance of more effective therapeutic strategies. Here, we investigated potential radiosensitizing effects of checkpoint kinase inhibitors (Chk-i) prexasertib (Chk1/2) and SAR-020106 (Chk1) in human SHH/p53-mutated MB in vitro and in vivo. UW228 and DAOY cells were treated with Chk-i and irradiation (RT). Metabolic activity, proliferation, and apoptosis was determined at d3, long-term clonogenicity at d14. DNA damage was assessed after 1, 24, and 72 h. Patient-derived SHH/p53-mutated, luciferase-transfected MB cells were implanted orthotopically into NSG mice (d0). Fractionated therapy (daily, d7-11) was applied. Body weight (BW) was documented daily, tumor growth weekly, and proliferation at d42. In vitro, Chk-i exhibited dose-dependent reduction of metabolic activity, proliferation, and clonogenicity, and enhancement of apoptosis. Combination with RT showed additive antitumor effects and enhanced residual DNA damage. In vivo, tumor growth was delayed by Chk-i alone. Low-dose prexasertib enhanced RT-induced tumor growth inhibition (37-fold) and reduced proliferating cells, high-dose prexasertib and SAR-020106 showed opposite effects (n=3, n.s.). BW assessments revealed that the treatment was well tolerated. Our data indicate a benefit of Chk-i in combination with RT in SHH/p53-mutated MB. However, high-dose Chk-i may compromise the RT effect, possibly by its anti-proliferative activity. Furthermore, we demonstrate for the first time the antitumor activity of the Chk1-specific inhibitor SAR-020106 in the murine brain.
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
