A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer

Lucki, Natasha C.; Villa, Genaro R.; Vergani, Naja; Bollong, Michael J.; Beyer, Brittney A.; Lee, Jae Woo; Anglin, Justin L.; Spangenberg, Stephan H.; Chin, Emily; Sharma, Amandeep; Johnson, Kevin C.; Sander, Philipp; Gordon, Perry; Skirboll, Stephen; Wurdak, Heiko; Schultz, Peter G.; Mischel, Paul S.; Lairson, Luke L.

doi:10.1073/pnas.1816626116

Cited by 26 publications

(36 citation statements)

References 43 publications

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“…Glioma, which is the most prevalent and aggressive primary intracranial tumor, accounts for almost 80% of brain tumors 1,2 . Conventional therapies for glioma include surgical resection, chemotherapy, and radiotherapy 3 .…”

Section: Introductionmentioning

confidence: 99%

Valproic Acid Enhanced Apoptosis by Promoting Autophagy Via Akt/mTOR Signaling in Glioma

Han

Cao

et al. 2020

Cell Transplant

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Glioma is the most common malignant tumor in the central nervous system with a poor median survival. Valproic acid (VPA), a widely used antiepileptic drug, has been found to have antitumor effects on gliomas, but its role still has not been determined. In this study, we investigated VPA-induced apoptotic and autophagic effects on human U251 and SNB19 cells by cell counting kit-8 assay, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick end labeling staining, western blots, and immunofluorescence assay in vitro, and then we further explored the role of autophagy in apoptosis by using the selective antagonist MHY1485. The data showed that VPA inhibited U251 and SNB19 glioma cells viability in a dose-dependent and time-dependent manner and induced apoptosis through the mitochondria-dependent pathway in vitro. In addition, VPA activated the Akt/mTOR pathway by decreasing their protein phosphorylation to promote cellular apoptosis. Surprisingly, the mTOR agonist MHY1485, causing a strong elevation of mTOR activity, partially reduced apoptosis ratio, which supposing that the autophagy of VPA is involved in the regulation of apoptosis. These findings suggest that VPA enhanced apoptosis by promoting autophagy via Akt/mTOR signaling in glioma, which could be further evaluated as a reliable therapy for glioma.

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Section: Introductionmentioning

confidence: 99%

Valproic Acid Enhanced Apoptosis by Promoting Autophagy Via Akt/mTOR Signaling in Glioma

Han

Cao

et al. 2020

Cell Transplant

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“…The existence of a stem cell population in glioblastoma is controversially discussed. Although computational work on single cell analytics of clinical specimens suggest that glioblastoma is composed of differentiated cells 2 , recent high profile published work of many others further supported the existence of stem cell-like populations in this disease, being regulated be the microenvironment 48 or specific metabolic 49 , 50 and cell cycle 51 , 52 programs. Inhibiting Notch pathway activity is a powerful strategy to target GSCs 5 , 6 and in experimental studies it has been shown to improve the efficiency of standard of care therapeutic Temozolomide 53 .…”

Section: Discussionmentioning

confidence: 99%

A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma

Khan

Tsiampali

et al. 2020

Sci Rep

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The Notch signaling network determines stemness in various tissues and targeting signaling activity in malignant brain cancers by gamma-secretase inhibitors (GSI) has shown promising preclinical success. However, the clinical translation remains challenging due to severe toxicity side effects and emergence of therapy resistance. Better anti-Notch directed therapies, specifically directed against the tumor promoting Notch receptor 1 signaling framework, and biomarkers predicting response to such therapy are of highest clinical need. We assessed multiple patient datasets to probe the clinical relevance Notch1 activation and possible differential distribution amongst molecular subtypes in brain cancers. We functionally assessed the biological effects of the first-in-human tested blocking antibody against Notch1 receptor (brontictuzumab, BRON) in a collection of glioma stem-like cell (GSC) models and compared its effects to genetic Notch1 inhibition as well as classical pharmacological Notch inhibitor treatment using gamma-secretase inhibitor MRK003. We also assess effects on Wingless (WNT) stem cell signaling activation, which includes the interrogation of genetic WNT inhibition models. Our computed transcriptional Notch pathway activation score is upregulated in neural stem cells, as compared to astrocytes; as well as in GSCs, as compared to differentiated glioblastoma cells. Moreover, the Notch signature is clinical predictive in our glioblastoma patient discovery and validation cohort. Notch signature is significantly increased in tumors with mutant IDH1 genome and tumors without 1p and 19q co-deletion. In GSCs with elevated Notch1 expression, BRON treatment blocks transcription of Notch pathway target genes Hes1/Hey1, significantly reduced the amount of cleaved Notch1 receptor protein and caused significantly impairment of cellular invasion. Benchmarking this phenotype to those observed with genetic Notch1 inhibition in corresponding cell models did result in higher reduction of cell invasion under chemotherapy. BRON treatment caused signs of upregulation of Wingless (WNT) stem cell signaling activity, and vice versa, blockage of WNT signaling caused induction of Notch target gene expression in our models. We extend the list of evidences that elevated Notch signal expression is a biomarker signature declaring stem cell prevalence and useful for predicting negative clinical course in glioblastoma. By using functional assays, we validated a first in man tested Notch1 receptor specific antibody as a promising drug candidate in the context of neuro oncology and propose biomarker panel to predict resistance and therapy success of this treatment option. We note that the observed phenotype seems only in part due to Notch1 blockage and the drug candidate leads to activation of off target signals. Further studies addressing a possible emergence of therapy resistance due to WNT activation need to be conducted. We further validated our 3D disease modeling technology to be of benefit for drug development projects.

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“…High grade gliomas represent a complex and devastating disease and are posing an unmet clinical need. These tumours resist multi-modal therapies and survival times are only 14 months on average (Gregory et al, 2020;Kadiyala et al, 2019;Lucki et al, 2019;Wen and Kesari, 2008). In recent years a lot of focus has been on the complex microenvironment of gliomas.…”

Section: Introductionmentioning

confidence: 99%

Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages

Mazzolini

Morisse

et al. 2021

Preprint

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SummaryMicroglia actively promote the growth of high-grade gliomas. Within the glioma microenvironment an activated (amoeboid) microglial morphology has been observed, however the underlying causes and the related impact on microglia functions and their tumour promoting activities is unclear. Using the advantages of the larval zebrafish model, we demonstrate that pre-neoplastic glioma cells have an immediate impact on microglial morphology and functions. Overexpression of human HRasV12 in proliferating domains of the larval brain induces an amoeboid morphology of microglia, increases microglial numbers and decreases their motility and phagocytic activity. RNA sequencing analysis revealed lower expression levels of the actin nucleation promoting factor wasla in microglia. Importantly, a microglia specific rescue of wasla expression restores microglial morphology and functions. This results in increased phagocytosis of pre-neoplastic cells and slows down tumour progression. In conclusion, we identified a mechanism that de-activates core microglial functions within the emerging glioma microenvironment.

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A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer

Cited by 26 publications

References 43 publications

Valproic Acid Enhanced Apoptosis by Promoting Autophagy Via Akt/mTOR Signaling in Glioma

Valproic Acid Enhanced Apoptosis by Promoting Autophagy Via Akt/mTOR Signaling in Glioma

A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma

Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages

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