RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
ONC201 或 ONC206 与恩杂鲁胺或达洛鲁胺在去势抵抗性前列腺癌临床前研究中的协同联合治疗
英文原题：Synergistic combination therapy with ONC201 or ONC206, and enzalutamide or darolutamide in preclinical studies of castration-resistant prostate cancer.
查看英文原题
Synergistic combination therapy with ONC201 or ONC206, and enzalutamide or darolutamide in preclinical studies of castration-resistant prostate cancer.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
雄激素受体（AR）信号通路是前列腺癌治疗的靶点，可使用非甾体类抗雄激素（NSAA）如恩杂鲁胺和阿帕鲁胺治疗晚期疾病患者。转移性去势抵抗性前列腺癌（mCPRC）产生耐药性后对治疗变得难治，限制了患者的总生存期。达罗他胺是一种新型下一代雄激素受体信号抑制剂，已获 FDA 批准用于非转移性去势抵抗性前列腺癌（nmCRPC）。Imipridone ONC201/TIC10 是首创小分子 imipridone，可激活整合应激反应（ISR），上调 TNF 相关凋亡诱导配体（TRAIL），在临床前模型中单药或与恩杂鲁胺联合对 CRPC 具有活性。
我们假设 imipridone 与雄激素受体信号阻断剂如达罗他胺联合可能在抗 mCRPC 细胞抗肿瘤疗效方面产生协同作用。mCRPC 细胞系 22RV1、LNCaP、DU145 和 PC3 分别以 imipridone ONC201、ONC206、阿帕鲁胺、达罗他胺或恩杂鲁胺单药或联合处理。ONC201 或 ONC206 与雄激素受体信号阻断剂的联合在 mCRPC 细胞中显示出协同效应。ONC201 与达罗他胺或恩杂鲁胺的联合降低了 LNCaP 细胞中的 PSA 水平，并在 LNCaP 和 22RV1 细胞系中诱导了 ATF4。在体外，无论 AR 状态或去势敏感性如何，达罗他胺均与 ONC201 产生协同作用。流式细胞术分析显示，接受 ONC201 及 ONC201 与达罗他胺联合治疗的小鼠瘤内 NK 细胞增加。在治疗组中还观察到 NK 细胞内 TRAIL 激活增加的趋势。ONC201和darolutamide在22RV1 CRPC模型中显示出体内抗肿瘤效果。
我们的结果促使进一步开展imipridones ONC201或ONC206与enzalutamide或darolutamide联合用于治疗去势抵抗性晚期或转移性前列腺癌的转化和临床研究。
展开英文摘要原文
Androgen receptor (AR) signaling is a target in prostate cancer therapy and can be treated with non-steroidal anti-androgens (NSAA) including enzalutamide, and apalutamide for patients with advanced disease. Metastatic castration-resistant prostate cancer (mCPRC) develop resistance becomes refractory to therapy limiting patient overall survival.
Darolutamide is a novel next-generation androgen receptor-signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC). Imipridone ONC201/TIC10 is first-in-class small molecule imipridone that activates the integrated stress response (ISR), upregulates TNF-related apoptosis-inducing ligand (TRAIL) and has activity against CRPC alone or in combination with enzalutamide in preclinical models.
We hypothesized that combination of imipridones with androgen receptor signaling blockers such as darolutamide may synergize in anti-tumor efficacy against mCRPC cells. mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with imipridones ONC201, ONC206, apalutamide, darolutamide, or enzalutamide as single agents or in combinations. Combinations of ONC201 or ONC206 and androgen receptor signaling blockers demonstrated synergistic effects in mCRPC cells.
Combinations of ONC201 and darolutamide or enzalutamide reduced PSA levels in LNCaP cells and induced of ATF4 in both LNCaP and 22RV1 cell lines. Darolutamide synergized with ONC201 regardless of AR status or castration sensitivity in vitro .
Flow cytometric analysis showed increased intra-tumoral NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. ONC201 and darolutamide demonstrated anti-tumor effects in vivo in the 22RV1 CRPC model.
Our results prompt further translational and clinical studies with imipridones ONC201 or ONC206 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer.
论文信息
- 作者
- Wu LJ、Pinho-Schwermann M、Zhou L、Zhang L、Huntington KE、Malpass R、Seyhan AA、Carneiro BA
- 单位
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University Providence, RI 02903, USA.United States
- 期刊
- American journal of cancer research2024
- 原文标识
- PubMed 39803644 · DOI 10.62347/VJMW4904
在 PubMed 查看 → 出版商原文（DOI） 全文 PDF（PMC）· 可下载 治疗专题与资料阅读指南 资料来源与翻译说明 报告译文或资料问题 →