Therapeutic Targeting of the Notch Pathway in Glioblastoma Multiforme

Gersey, Zachary C.; Osiason, Adam D.; Bloom, Laura; Shah, Sumedh S.; Thompson, John W.; Bregy, Amadé; Agarwal, Nitin; Komotar, Ricardo J.

doi:10.1016/j.wneu.2019.07.180

Cited by 31 publications

(31 citation statements)

References 75 publications

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“…NOTCH1 pro ciency is hence a key mechanism for the resilience of cells in the PVN, rstly by allowing population of that niche and secondly by being prerequisite for the protective properties of this speci c microenvironment. In line with our results outlined here, many publications demonstrate a growth-inhibitory effect of NOTCH1 downregulation 44,46,47,48,49,50 . The differences regarding response to cytotoxic therapies 46,47,48,49,50 might be explained by the different models used and their TM-pro cient phenotype.…”

Section: Discussionsupporting

confidence: 92%

“…In line with our results outlined here, many publications demonstrate a growth-inhibitory effect of NOTCH1 downregulation 44,46,47,48,49,50 . The differences regarding response to cytotoxic therapies 46,47,48,49,50 might be explained by the different models used and their TM-pro cient phenotype. Our data suggests that NOTCH1 is an important mediator of the resistance of perivascular tumor cells and the resistance promoting effects of NOTCH1 downregulation can be attributed to the induction of TMs.…”

Section: Discussionsupporting

confidence: 92%

“…Our data suggests that NOTCH1 is an important mediator of the resistance of perivascular tumor cells and the resistance promoting effects of NOTCH1 downregulation can be attributed to the induction of TMs. The latter might not be re ected in all models: especially cultivation under serum-containing conditions, which were used for many studies on NOTCH1 in glioblastoma 49 , leads to TM-de cient tumors 17 .…”

Section: Discussionmentioning

confidence: 99%

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Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

Jung

Osswald

Ratliff

et al. 2020

Preprint

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Abstract Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches could be determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitated resistance against cytotoxic effects of radiotherapy and chemotherapy - independently of each other, but with additive effects. Perivascular glioblastoma cells were particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depended on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induced resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

Jung

Osswald

Ratliff

et al. 2020

Preprint

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“…Aside from breast cancer, lung cancer, ACC and possibly colorectal cancer, cell-autonomous activating Notch mutations in solid tumours are less common than haematological cancers. However, upregulation of wild-type Notch receptors and ligands, and aberrant Notch signalling is frequently observed in various tumours including melanoma [ 86 ], gastric cancer [ 87 ], ovarian cancer [ 88 ], prostate cancer [ 89 , 90 ], pancreatic cancer [ 91 , 92 ], hepatocellular carcinoma [ 93 , 94 , 95 ], glioma [ 40 , 96 , 97 ] and rare tumours such as cholangiocarcinoma [ 98 ] and desmoid tumours [ 99 ]. Notch gene alterations may play a role in a subset of these cancer cases; however, such mutations are yet to be identified.…”

Section: Notch In Cancer: An Overviewmentioning

confidence: 99%

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

Moore

Annett

McClements

et al. 2020

Cells

104

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Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.

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“…The Notch signaling pathways are highly evolutionarily conserved, and are crucial for cell differentiation, proliferation, migration, and tumor angiogenesis [64][65][66] . Notch homologous proteins-Notch1, Notch2, Notch3, and Notch4-are 300-kD single-pass transmembrane proteins that include a Notch intracellular domain (NICD) and an extracellular domain (NECD) [66] . The Notch pathway is activated via the binding of one of the ligand families, Delta-like (Dll-3 and Dll-4) and Jagged (Jagged-1 and -2), to the NECD via direct cell-to-cell contact [66] .…”

Section: Targeting Notchmentioning

confidence: 99%

Novel approaches to combat chemoresistance against glioblastomas

Towner¹,

Zalles²,

Saunders³

et al. 2020

CDR

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The poor prognosis of glioblastoma multiforme (GBM) patients is in part due to resistance to current standard-ofcare treatments including chemotherapy [predominantly temozolomide (TMZ; Temodar)], radiation therapy and an anti-angiogenic therapy [an antibody against the vascular endothelial growth factor (bevacizumab; Avastin)], resulting in recurrent tumors. Several recurrent GBM tumors are commonly resistant to either TMZ, radiation or bevacizumab, which contributes to the low survival rate for GBM patients. This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance. One of these therapeutic options is a small molecule called OKlahoma Nitrone 007 (OKN-007), which was discovered to inhibit the transforming growth factor β1 pathway, reduce TMZ-resistance and enhance TMZ-sensitivity. OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients. Another novel target is ELTD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1; alternatively known as ADGRL4, Adhesion G protein-coupled receptor L4), which we used a monoclonal antibody against, where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model. Notch 1 is known to be associated with chemoresistance in GBM. Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway, nuclear factor-κB, the hepatocyte/scatter factor (c-MET), the epidermal growth factor receptor, and the tumor microenvironment.

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Therapeutic Targeting of the Notch Pathway in Glioblastoma Multiforme

Cited by 31 publications

References 75 publications

Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

Novel approaches to combat chemoresistance against glioblastomas

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