Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Andrew, S.; Tarapore, Rohinton; Hall, Matthew D; Shonka, Nicole; Gardner, Sharon; Umemura, Yoshie; Sumrall, Ashley; Khatib, Ziad; Mueller, Sabine; Kline, Cassie; Zaky, Wafik; Khatua, Soumen; Weathers, Shiao Pei; Odia, Yazmín; Niazi, Toba; Daghistani, Doured; Cherrick, Irene; Korones, David N.; Karajannis, Matthias A.; Kong, Xiao Tang; Minturn, Jane E.; Waanders, Angela J.; Arillaga-Romany, Isabel; Batchelor, Tracy T.; Wen, Patrick Y.; Merdinger, Krystal; Schalop, Lee; Stogniew, Martin; Allen, Joshua E.; Oster, Wolfgang; Mehta, Minesh P.

doi:10.1007/s11060-019-03271-3

Cited by 141 publications

(107 citation statements)

References 23 publications

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“…Recent preclinical and clinical data have hinted at an efficacy of ONC201 in several solid cancers including GBM [21][22][23]25,27 . Originally identified as an inducer of TRAIL, ONC201 inhibits D2-like dopamine receptors DRD2 and DRD3 and activates the mitochondrial protease ClpP, a key player in the mitochondrial unfolded protein response 52,53 .…”

Section: Discussionmentioning

confidence: 99%

“…Originally identified as an inducer of TRAIL, ONC201 inhibits D2-like dopamine receptors DRD2 and DRD3 and activates the mitochondrial protease ClpP, a key player in the mitochondrial unfolded protein response 52,53 . So far, clinical trials using ONC201 against GBM have shown pharmacodynamic activity in biomarker-defined recurrent GBM patients, as well as in pediatric and adult H3 K27M-mutant glioma 22,26,27 .…”

Section: Discussionmentioning

confidence: 99%

“…This results in dual inactivation of Akt/ERK signaling that drives Foxo3a-mediated TRAIL gene induction to promote pro-apoptotic and anti-proliferative effects in tumor cells, but not in normal cells [16][17][18][19][20] . With p53-independency, low toxicity and excellent penetration of the BBB, ONC201 is currently being evaluated in multiple clinical trials for select advanced malignancies, including myeloma, leukemia, lymphoma, endometrial cancer, high grade glioma, and other solid tumors [21][22][23][24][25][26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Bhat

Ioannidis

et al. 2020

Preprint

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BackgroundGlioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation.MethodsUsing patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self - renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment with ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells.ConclusionsOur findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBM in vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.Key points- Combined treatment of ONC201 and radiation exhibit anti-tumor effects on cells from primary and recurrent GBM- Combined treatment significantly prolongs survival in vivo- Combined treatment potentially targets the quiescent GBM cell populationImportance of the StudyThe survival rates for patients with GBM are unacceptably low and novel treatment approaches are needed. This study provides evidence that a combination of radiation and the dopamine receptor antagonist ONC201 significantly prolongs survival in mouse models of glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Bhat

Ioannidis

et al. 2020

Preprint

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“…Recent reports in the literature have suggested an anti-tumor activity of dopamine receptor type 2 antagonists against glioblastoma (18-21) and dopamine receptors have been found to be expressed in various tumor types including glioblastoma (22). However, the anti-tumor efficacy of dopamine receptor antagonists as single agents was found to be limited in preclinical (23) and clinical studies (24).…”

Section: Discussionmentioning

confidence: 99%

Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

Saki

Bhat

Cheng

et al. 2020

Preprint

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Background Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

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“…We recently found that initial in vitro testing of serous EC cell lines with ONC201 resulted in signi cant inhibition of cellular proliferation, induction of apoptosis, as well as anti-metastatic effects (22). The results from several phase I and II clinical trials showed that ONC201 is clinically active and exceptionally well-tolerated with favorable pharmacokinetics, pharmacodynamics and clinical bene t in advanced cancers including lymphoma, glioblastoma and ECs (17,(23)(24)(25)(26). ONC201 has demonstrated durable objective responses in patients with H3 K27M mutant gliomas and FDA has granted Fast track designation to this investigational agent (26,27).…”

Section: Introductionmentioning

confidence: 99%

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Pierce

Fang

Yin

et al. 2020

Preprint

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BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometriod and serous EC specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes.. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. ConclusionONC201 has anti-proliferative and anti-tumorigenic effects in endometrial cancer cells and mouse model, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

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Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Cited by 141 publications

References 23 publications

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

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