NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

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.

Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer

“…In our study, PyClone analysis suggested that cells harboring NOTCH1 mutations were sensitive to radiation, whereas those harboring EGFR and MGA mutations were resistant to radiation. Recent studies suggest that activation of the NOTCH signaling pathway is related to radiation resistance in tumor cells (19)(20)(21). OncodriveROLE, a machine learning-based approach, indicated that the NOTCH1 p.Cys1374Tyr mutation, as detected in our study, is a "loss-of-function" mutation (22,23).…”

Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance

“…Yet in the context of drug treatment, this promotion of a slow-cycling state may have the untoward consequence of conferring resistance. The Notch-dependency of the refractory GSC state may thus portend opportunities for combination therapy, some of which are now being explored in pre-clinical and early clinical studies (Cenciarelli et al, 2014; Xu et al, 2016; Yahyanejad et al, 2016) .…”

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

“…Notch-1 and its ligands are overexpressed in many GBM cell lines and primary tumors and activation of this pathway contributes to CSC survival and proliferation (Purow et al, 2005; Kanamori et al, 2007). A recent study confirmed that Notch blockade combined with a standard-of-care treatment has an anti-CSC effect and provides an improved survival benefit for GBM patients as well as new insights for further clinical studies (Yahyanejad et al, 2016). …”