Inhibition of the NOTCH pathway using γ-secretase inhibitor RO4929097 has limited antitumor activity in established glial tumors

Dantas‐Barbosa, Carmela; Bergthold, Guillaume; Daudigeos-Dubus, Estelle; Blockus, Heike; Boylan, John F.; Ferreira, Cristina; Puget, Stéphanie; Abély, M.; Vassal, Gilles; Grill, Jacques; Geoerger, Birgit

doi:10.1097/cad.0000000000000190

Cited by 28 publications

(22 citation statements)

References 54 publications

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“…In a previous study, the GSI treatment in patent ductus arteriosus has been indicated to inhibit the downstream targets of Notch pathway, including HES1, HES2, and HES5 . Additionally, GSI treatment also down‐regulates the NOTCH1 effector genes HES1 and HEY1 in established glial tumors . We also reached a favorable result that GSI, inhibited the proliferation and promoted the apoptosis of breast cancer cells.…”

Section: Discussionsupporting

confidence: 54%

Retracted: Inhibition of Notch signaling pathway enhanced the radiosensitivity of breast cancer cells

Peng

Xiao-lin

Ran

et al. 2018

J of Cellular Biochemistry

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This study aimed to investigate the effect of inhibiting the Notch signaling pathway on the radiosensitivity of breast cancer cells. Human breast cancer cell lines (MCF-7 and T47D) were selected and treated with radiation of different doses. Cells were treated with Gamma secretase inhibitor (GSI) to analyze the effects of GSI on the Notch signaling, which were detected by Immunofluorescence assay, RT-qPCR, and Western blot analysis. Besides, Transwell assay, Scratch test, colony formation assay, MTT assay, and flow cytometry were conducted to show the effects of GSI on the invasion and migration, survival fraction, cell viability, and apoptosis of MCF-7 and T47D cells after radiation therapy. Moreover, cell transfection with a dominant negative mutant of RBPJ, the key transcription factor of Notch signaling pathway, were also applied to show the inhibition of Notch signaling pathway. Initially, we found that the 4 Gy radiation activated Notch signaling pathway, and enhanced the invasion and migration of MCF-7 and T47D cells. However, GSI inhibited the Notch signaling pathway, and reversed the enhancement of radiation on the migration and invasion, promoted the enhancement of apoptosis and inhibition of proliferation of MCF-7 and T47D cells induced by radiation. Except that, we also determined that GSI and dnRBPJ suppressed the upregulation of Notch signaling after radiation therapy. Our study demonstrated that inhibition of the Notch signaling pathway enhanced the radiosensitivity of breast cancer cells, which may provide evident for a beneficial adjuvant therapy in the breast cancer treatment.

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Section: Discussionsupporting

confidence: 54%

Retracted: Inhibition of Notch signaling pathway enhanced the radiosensitivity of breast cancer cells

Peng

Xiao-lin

Ran

et al. 2018

J of Cellular Biochemistry

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“…One explanation could be the contribution of NOTCH inhibition in the tumor microenvironment possibly by disrupting tumor angiogenesis [23] or blocking endothelial to tumor cell signaling [24–25], which was not addressed in this study. Our findings are in agreement with previous results showing the enhanced therapeutic effect of combined GSI with TMZ ( in vitro and ex vivo ) or GSI with RT ( in vitro and in vivo ) compared to each treatment alone [16, 24, 26]. While these findings are important to move NOTCH inhibitors forward as GBM therapeutics, contribution of GSI to current standard of care treatment (TMZ + RT) has never been reported to the best of our knowledge.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2016

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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.

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“…Using 3D organotypic tumor explants, we demonstrated Notch inhibition via a gamma-secretase inhibitor (GSI) is associated with a decrease in GSCs, as well as a decrease in endothelial cells (11). We also demonstrated that combination treatment of tumor explants with Notch inhibition and radiation was more effective than either treatment alone, suggesting a synergistic effect (11, 15). These findings formed the scientific rationale for the design of the present trial.…”

Section: Introductionmentioning

confidence: 70%

Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial

Shimizu

Hovinga

et al. 2016

Clinical Cancer Research

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Background High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed anti-angiogenic role. Methods In this phase 0/I trial, 21 patients with newly-diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the maximum tolerated dose, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuro-imaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment. Results Treatment was well tolerated and no dose-limiting toxicities were observed. Immunohistochemistry of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes and an increase in VEGF-dependent angiogenic factors. Conclusion The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has variable blood-brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clinicaltrials.gov.NCT01119599

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Inhibition of the NOTCH pathway using γ-secretase inhibitor RO4929097 has limited antitumor activity in established glial tumors

Cited by 28 publications

References 54 publications

Retracted: Inhibition of Notch signaling pathway enhanced the radiosensitivity of breast cancer cells

Retracted: Inhibition of Notch signaling pathway enhanced the radiosensitivity of breast cancer cells

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

Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial

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