OC-0238: Akt1 facilitates DNA double-strand breaks repair through a direct physical interaction with DNA-PKcs
Radiotherapy and Oncology
Purpose or Objective: Glioblastoma multiforme (GBM) is the most common malignant brain tumour in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation and TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The Notch signaling pathway is expressed and active in human glioblastoma and Notch inhibitors attenuate tumor growth in vivo in xenograft models.
... xenograft models. Here, we investigate the efficacy of a clinically (FDA) approved γ-secretase inhibitor (GSI) RO4929097 in tumor control in combination with standard care of treatment (TMZ+RT) in an orthotopic glioma tumour model. Material and Methods: Treatment efficacy in vitro was tested in 2D cultures using proliferation and clonogenic survival assays. 3D sphere assays were used as a model for pharmacological treatment response with quantification of spheroid growth delay in the different different treatment arms. Flow cytometry was used to detect cells expressing stem cell markers. Luciferase-expressing U87 cells were intracranially injected into the brain of CD-1 mice. Tumor volume was quantified using contrast-enhanced microCT and bioluminescence imaging. Animals received TMZ (ip), RO4929097 (GSI, orally) or radiation (RT, 8Gy) alone or in combination. RT dose was calculated and prescribed using SmART-Plan software with two 5-mm parallel-opposed beams placed at the center of the tumour. Results: GSI in combination with RT and TMZ attenuated tumour cell proliferation, clonogenic survival as well as glioma spheroid growth. The expression of glioma stem cell markers SOX2 and CD133 was blocked by single or combined treatments with Notch inhibitors in vitro. Using our image guided micro-CT and radiotherapy platform in vivo, a significant growth delay was observed in GSI-, RT-and TMZonly treated groups compared to the control group. Standard of care treatment (RT + TMZ) or addition of GSI to either TMZ or RT irradiation resulted in a significant growth delay and prolonged survival. Strikingly, the longest tumour growth delay together with an increase in median survival was observed in mice treated with the triple combination (GSI+RT+TMZ), with 1 out of 4 mice showing tumour cure. Conclusion: We show in an orthotopic glioblastoma mouse model that adding a clinically approved Notch inhibitor to the TMZ/RT standard of care results in a significant growth delay and increased overall survival. The observed therapeutic benefit is promising for clinical translation in order to increase survival in patients bearing glioblastoma with active Notch signaling.