以多巴胺受体 D2 为靶点的子宫内膜癌治疗新策略。
Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer.
机构信息
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China.
出版信息
J Exp Clin Cancer Res. 2021 Feb 8;40(1):61. doi: 10.1186/s13046-021-01842-9.
BACKGROUND
ONC201 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.
METHODS
Cell 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. LKB1p53 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 endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer.
RESULTS
Increasing 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 LKB1/p53 mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice.
CONCLUSION
ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, 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.
背景
ONC201 是一种多巴胺受体 D2（DRD2）拮抗剂，通过 ClpP 激活抑制肿瘤生长，诱导整合应激反应通路和与细胞生长抑制相关的线粒体事件，目前正在实体瘤和血液恶性肿瘤的临床试验中进行研究。在这项研究中，我们研究了 ONC201 在子宫内膜癌细胞系和子宫内膜癌基因工程小鼠模型中的抗肿瘤作用。
方法
通过 MTT 和集落形成测定评估细胞增殖。通过 Cellometer 评估细胞周期和细胞凋亡。使用粘附、Transwell 和划痕愈合测定评估侵袭能力。LKB1p53 子宫内膜癌小鼠模型喂食对照低脂饮食或高脂肪饮食以模拟饮食诱导的肥胖。肿瘤发生后，用安慰剂或 ONC201 治疗小鼠。代谢组学和脂质组学用于鉴定 ONC201 在小鼠子宫内膜肿瘤中的肥胖依赖性作用。用免疫组织化学分析人子宫内膜样腺癌和浆液性癌标本中的 DRD2 表达。从癌症基因组图谱（TCGA）数据库比较子宫内膜癌的四个分子亚型之间的 DRD2 mRNA 表达。
结果
子宫内膜癌中 DRD2 表达的增加与分级、浆液组织学和分期显著相关，并且与无进展生存期和总生存期更差相关。与其他亚型相比，在 Copy Number High（CNH）亚型中发现更高的 DRD2 mRNA 表达。ONC201 抑制子宫内膜癌细胞增殖，诱导细胞周期 G1 期阻滞，引起细胞应激和凋亡，并降低细胞侵袭。饮食诱导的肥胖促进子宫内膜肿瘤生长，而 ONC201 在肥胖和瘦 LKB1/p53 小鼠中表现出抗肿瘤作用。代谢组学分析表明，ONC201 逆转了肥胖驱动的脂质生物合成上调，并降低了肥胖和瘦小鼠中的蛋白质生物合成。
结论
ONC201 在子宫内膜癌细胞和子宫内膜癌转基因小鼠模型中具有抗肿瘤作用，并且在人浆液性和子宫内膜样子宫内膜癌中均检测到 DRD2 表达。这些研究支持通过 ONC201 拮抗 DRD2 作为一种有前途的治疗策略，用于子宫内膜癌，该策略已在浆液性和子宫内膜样子宫内膜癌患者中显示出药效学活性和临床获益。
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