Abstract
Glioblastoma multiforme (GBM) is the most common malignant brain tumor 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 resistance and intrinsic or acquired 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. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.
Highlights
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults
We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner
We investigated for the first time the efficacy of a clinically approved NOTCH inhibitor (RO4929097) in tumor control when combined with RTonly, TMZ -only and RT + TMZ treatment groups in a 2D and 3D spheroid model in vitro as well as in an orthotopic GBM mouse model
Summary
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Multimodal treatment of surgery followed by radiotherapy (RT) and chemotherapy using temozolomide (TMZ) extends the two-year median survival rate of patients from 10%with radiotherapy alone to 27% when combined with temozolomide [1]. In GBM, a subpopulation of radiation resistant tumor cells expressing neural stem cell markers such as CD133 with high proliferative and self-renewal capacity have been shown to contribute to tumor recurrence. These cells are often referred to as glioma stem cells [6,7]. Conventional chemoradiotherapy appears to effectively remove the bulk of tumor cells, while leaving many GBM stem cells alive, driving treatment resistance and tumor relapse It appears that eradication of these cells is needed to augment treatment efficacy and outcome
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