Effects of the DRD2/3 antagonist ONC201 and radiation in glioblastoma

He, Ling; Bhat, Kruttika; Ioannidis, Angeliki; Zhang, Le; Nguyen, Nhan; Allen, Joshua E.; Nghiemphu, Phioanh L.; Cloughesy, Timothy F.; Liau, Linda M.; Kornblum, Harley I.; Pajonk, Frank

doi:10.1016/j.radonc.2021.05.027

Cited by 17 publications

(14 citation statements)

References 43 publications

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“…Furthermore, we verified the changes in the RNA expression levels of these candidate genes after irradiation ( Figure 6 C). Because the RNA samples in GEO dataset GSE153982 were extracted 48 h after 4 Gy irradiation [ 29 ], we treated GBM cell lines with the same dose in this study. After irradiation for 48 h, the RNA expression levels of F3 and MMP14 were increased in the three cell lines, which was consistent with the results of our bioinformatics analysis of “Radio_genes” ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

MMP14 Contributes to HDAC Inhibition-Induced Radiosensitization of Glioblastoma

Zhou

Liu

Wang

et al. 2021

IJMS

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Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.

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Section: Resultsmentioning

confidence: 99%

MMP14 Contributes to HDAC Inhibition-Induced Radiosensitization of Glioblastoma

Zhou

Liu

Wang

et al. 2021

IJMS

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“…Because of the limited data of adverse side effects, and unique mechanism of action, several open trials have explored the potential for synergistic benefit of Onc201 in conjunction with RT, chemotherapy, checkpoint inhibitors and targeted agents to potentiate therapy response and target separate mechanisms of resistance ( 118 ). Thus far, pre-clinical in vivo data has yielded promising responses though clinical trial results have yet to be reported ( 111 , 119 ).…”

Section: Novel Therapiesmentioning

confidence: 99%

Review: Neurological Complications From Therapies for Pediatric Brain Tumors

2022

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Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.

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“…DRD5 modulates DRD2 signaling negatively and, thus, weakens the ONC201 drug effect [ 203 ]. Moreover, ONC201 enhances radiation and the TMZ effect in GBM cell lines [ 163 ]. Chlorpromazine synergizes with TMZ in reducing the viability and cloning efficiency of GBM cells and inducing cell death [ 166 ].…”

Section: The Influence Of Neurotransmitters On Gbm and Potential Ther...mentioning

confidence: 99%

Neurotransmitters: Potential Targets in Glioblastoma

Huang

Chen

Liang

et al. 2022

Cancers

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For decades, glioblastoma multiforme (GBM), a type of the most lethal brain tumor, has remained a formidable challenge in terms of its treatment. Recently, many novel discoveries have underlined the regulatory roles of neurotransmitters in the microenvironment both physiologically and pathologically. By targeting the receptors synaptically or non-synaptically, neurotransmitters activate multiple signaling pathways. Significantly, many ligands acting on neurotransmitter receptors have shown great potential for inhibiting GBM growth and development, requiring further research. Here, we provide an overview of the most novel advances concerning the role of neurotransmitters in the normal neural and the GBM microenvironments, and discuss potential targeted drugs used for GBM treatment.

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Effects of the DRD2/3 antagonist ONC201 and radiation in glioblastoma

Cited by 17 publications

References 43 publications

MMP14 Contributes to HDAC Inhibition-Induced Radiosensitization of Glioblastoma

MMP14 Contributes to HDAC Inhibition-Induced Radiosensitization of Glioblastoma

Review: Neurological Complications From Therapies for Pediatric Brain Tumors

Neurotransmitters: Potential Targets in Glioblastoma

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