The Prospective Value of Dopamine Receptors on Bio-Behavior of Tumor

Wang, Xu; Wang, Zhibin; Luo, Chao; Mao, Xiao‐Yuan; Li, Xi; Yin, Ji‐Ye; Zhang, Wei; Zhou, Honghao; Liu, Zhao‐Qian

doi:10.7150/jca.27780

Cited by 63 publications

(64 citation statements)

References 131 publications

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“…1 DRD2 Overexpression in Human Cancer. The indicated publications for each tumor type were identified through a PubMed search as of July 2020, as well as recent reviews of DRD2 in oncology [19] , [20] . …”

Section: Onc201 Mechanism Of Actionmentioning

confidence: 99%

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ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

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ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

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Section: Onc201 Mechanism Of Actionmentioning

confidence: 99%

“…Dopamine and dopamine receptors are secreted and expressed, respectively, by various immune cells. This includes NK and T-cells that can be targeted to modulate tumor immune response [20] , [43] , [44] . Dopamine inhibits NK cell effector function [44] , and DRD2 antagonism has been shown to activate NK cells [43] .…”

Section: Onc201 Mechanism Of Actionmentioning

confidence: 99%

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

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“…Although our understanding of the biology of dopamine receptor signaling in cancer progression is still rudimentary and sometimes controversial, mounting experimental and clinical evidence has indicated that the dysregulation of dopamine receptor signaling is associated with the progression of human cancers, including PCa (35,(57)(58)(59)(60). Some epidemiologic studies further suggested a correlation between psychotic disorders in which dopaminergic drugs are applied and the risk of cancer, of particular note, a reduced risk of PCa (61,62).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Effect and Mechanism of Action of Ergot Alkaloid Dihydroergocristine in Chemoresistant Prostate Cancer Cells

Bai

et al. 2020

Anticancer Res

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“…DRD2 has been shown to regulate many aspects of tumor behavior, including invasion and migration in cancer cells. Activation of DRD2 by the DRD2-speci c agonist BIM53097 inhibits tumoral pituitary cells migration and invasion by activating the co lin pathway in vitro (45,46). However, downregulation of DRD2 by tri uoperazine and haloperidol also results in decreased invasion and migration in prostate cancer cells, indicating the functional diversity of DRD2 and its downstream targets in different types of cancer (47).…”

Section: Discussionmentioning

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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The Prospective Value of Dopamine Receptors on Bio-Behavior of Tumor

Cited by 63 publications

References 131 publications

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

In Vitro Effect and Mechanism of Action of Ergot Alkaloid Dihydroergocristine in Chemoresistant Prostate Cancer Cells

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

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