ONC201: a new treatment option being tested clinically for recurrent glioblastoma

Ralff, Marie D.; Lulla, Amriti R.; Wagner, Jessica; El‐Deiry, Wafik S.

doi:10.21037/tcr.2017.10.03

Cited by 37 publications

(36 citation statements)

References 28 publications

(31 reference statements)

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“…Our observations are in accordance with previous studies highlighting the role of ONC201 in mediating ER stress response in breast cancer cells [12,44] and high-grade central nervous system glioblastoma [45]. However, in these studies, the observed ER stress response was primarily due to Gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates genes that are associated with energy metabolism.…”

Section: Discussionsupporting

confidence: 93%

Comparative Transcriptome Analyses of Metastatic and Non-Metastatic Colorectal Cancer Cells Delineate Differential Mechanisms of CHOP Upregulation in Response to ONC201 Treatment

Madhoun¹,

Haddad²,

Al-Tarrah³

et al. 2020

Preprint

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The imipramine ONC201 exerts a novel anti-proliferative activity over a wide spectrum of cancer cell types. ONC201 activates integrated stress response pathway that is associated with induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We questioned whether the ONC201/CHOP crosstalk is regulated by diverse signaling pathways in non-metastatic versus metastatic cancer cell lines. Therefore, the Dukes' type B colorectal adenocarcinoma non-metastatic (SW480) and metastatic (LS-174T) cell lines were treated with ONC201. Cell proliferation and apoptosis were evaluated by MTT assay, flow cytometry analysis, gene expression was assessed by Affymetrix microarray, and key regulatory proteins were validated by Western blot assays. Unlike LS-174T cells, SW480 cells were resistant to ONC201 treatment. Gene ontology pathway enrichment analysis of differentially expressed genes revealed substantial differences between LS-174T and SW480 responsiveness to ONC201 treatment. In both cell lines, CHOP expression was upregulated in response to ONC201 treatment, however, its upstream regulatory mechanisms were not identical. Although, PERK, ATF6 and IRE1 ER-stress pathways were found to upregulated CHOP in both cell types, the BAK/BAX pathway was a notable regulator of CHOP in the metastatic LS-174T cells alone. In addition, CHOP RNA splicing profiles were varied between the two cell lines, which was further modified in response to ONC201 treatments. In conclusion, we delineated the signaling mechanisms regulating the expression of CHOP in non-metastatic versus metastatic colorectal cells in response to ONC201 treatment. The observed differences were related to cellular plasticity and metabolic reprogramming.

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Section: Discussionsupporting

confidence: 93%

Comparative Transcriptome Analyses of Metastatic and Non-Metastatic Colorectal Cancer Cells Delineate Differential Mechanisms of CHOP Upregulation in Response to ONC201 Treatment

Madhoun¹,

Haddad²,

Al-Tarrah³

et al. 2020

Preprint

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“…ONC201 inhibits the phosphorylation of AKT and ERK pathways, leading to the dephosphorylation of transcription factor FOXO3A, and thus transcription of pro-apoptotic death receptor ligand TRAIL. Through a stress response activation ONC201 is involved in EIF2α phosphorylation and increases DR5 expression [ 221 , 222 ] Based on the the first results using ONC201 in monotherapy which showed that the treatment was well tolerated and that ONC201 may have single agent activity in GBM [ 223 ], a phase II clinical trial was started on GBM with H3 K27M mutation (NCT02525692). It showed that ONC201 can be used regardless of age or location [ 216 ].…”

Section: Results-glioblastoma Targeted Therapiesmentioning

confidence: 99%

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Silva

Mercier

Étienne-Selloum

et al. 2021

Cancers

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Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.

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“…Glioblastoma (GBM) is an incurable brain cancer with an incidence of 3.2/100 000 [1]. Biomarker-driven targeted therapy has proven effective in many cancer types and seems promising in GBM based on case stories with specific aberrations [2][3][4]. This includes gene fusions that have resulted in approval of tropomyosin receptor kinase (TRK) inhibitors for TRK fusion-positive cancers, regardless of histology [5,6].…”

Section: Introductionmentioning

confidence: 99%

Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

et al. 2020

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Glioblastoma (GBM) is an incurable brain tumor for which new treatment strategies are urgently needed. Next-generation sequencing of GBM has most often been performed retrospectively and on archival tissue from both diagnostic and relapse surgeries with limited knowledge of clinical information, including treatment given. We sought to investigate the genomic composition prospectively in treatment-na€ ıve patients, searched for possible targetable aberrations, and investigated for prognostic and/or predictive factors. A total of 108 newly diagnosed GBM patients were included. Clinical information, progression-free survival, and overall survival (OS) were noted. Tissues were analyzed by whole-exome sequencing, single nucleotide polymorphism (SNP) and transcriptome arrays, and RNA sequencing; assessed for mutations, fusions, tumor mutational burden (TMB), and chromosomal instability (CI); and classified into GBM subgroups. Each genomic report was discussed at a multidisciplinary tumor board meeting to evaluate for matching trials. From 111 consecutive patients, 97.3% accepted inclusion in this study. Eighty-six (77%) were treated with radiation therapy/temozolomide (TMZ) and adjuvant TMZ. One NTRK2 and three FGFR3-TACC3 fusions were identified. Copy number alterations in GRB2 and SMYD4 were significantly correlated with worse median OS together with known clinical variables like age, performance status, steroid dose, and O6-methyl-guanine-DNA-methyl-transferase status. Patients with CI-median or TMB-high had significantly worse median OS compared to CI-low/high or TMB-low/median. In conclusion, performing genomic profiling at diagnosis enables evaluation of genomic-driven therapy at the first progression. Furthermore, TMB-high or CI-median patients had worse median OS, which can support the possibility of offering experimental treatment already at the first line for this group.

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ONC201: a new treatment option being tested clinically for recurrent glioblastoma

Cited by 37 publications

References 28 publications

Comparative Transcriptome Analyses of Metastatic and Non-Metastatic Colorectal Cancer Cells Delineate Differential Mechanisms of CHOP Upregulation in Response to ONC201 Treatment

Comparative Transcriptome Analyses of Metastatic and Non-Metastatic Colorectal Cancer Cells Delineate Differential Mechanisms of CHOP Upregulation in Response to ONC201 Treatment

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

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