用于肝细胞癌治疗的高效选择性CXCR4拮抗剂

StephenW

A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment
Jen-Shin Song, View ORCID ProfileChih-Chun Chang, View ORCID ProfileChien-Huang Wu, Trinh Kieu Dinh, Jiing-Jyh Jan, View ORCID ProfileKuan-Wei Huang, Ming-Chen Chou, Ting-Yun Shiue, View ORCID ProfileKai-Chia Yeh, View ORCID ProfileYi-Yu Ke, Teng-Kuang Yeh, View ORCID ProfileYen-Nhi Ngoc Ta, Chia-Jui Lee, Jing-Kai Huang, Yun-Chieh Sung, View ORCID ProfileKak-Shan Shia, and View ORCID ProfileYunching Chen

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PNAS March 30, 2021 118 (13) e2015433118; https://doi.org/10.1073/pnas.2015433118

    Edited by Michael Karin, University of California San Diego, La Jolla, CA, and approved February 4, 2021 (received for review July 23, 2020)

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Significance

A highly selective, safe, and potent CXCR4 antagonist, BPRCX807, has been designed and experimentally validated in various hepatocellular carcinoma models. Through combination therapy, it can synergize with either a kinase (e.g., sorafenib) or checkpoint inhibitor (e.g. anti–PD-1) to augment effectiveness of current anticancer treatments. With its unique mode of action, a new anticancer strategy for preventing cell migration and metastasis is provided.
Abstract

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti–PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.

    hepatocellular carcinomaCXCR4 receptorprogrammed cell death 1sorafenibtumor microenvironment

StephenW

用于肝细胞癌治疗的高效选择性CXCR4拮抗剂
宋仁信，查看ORCID配置文件Chih-Chun Chang，查看ORCID配置文件Chien-Huang Wu，Trinh Kieu Dinh，Jiing-Jyh Jan，查看ORCID配置文件HuangKuan-Wei Huang，周明辰，Shi Ting-Yun Shiue，查看ORCID配置文件是，查看ORCID配置文件Kei-Yu Ke，Teng-匡光，查看ORCID配置文件Yen-Nhi Ngoc Ta，李嘉-，黄静凯，Sung-Chieh Sung，查看ORCID配置文件Kak-Shan Shia，和查看ORCID配置文件Yuunching Chen

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PNAS 2021年3月30日118（13）e2015433118; https://doi.org/10.1073/pnas.2015433118

    由加利福尼亚大学圣地亚哥分校的迈克尔·卡林（Michael Karin）编辑，加利福尼亚，拉荷亚，并于2021年2月4日批准（已收到2020年7月23日的审查）

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意义

一种高选择性，安全且有效的CXCR4拮抗剂BPRCX807已在各种肝细胞癌模型中进行了设计和实验验证。通过联合治疗，它可以与激酶（例如索拉非尼）或检查点抑制剂（例如抗PD-1）协同作用，以增强当前抗癌治疗的有效性。凭借其独特的作用方式，提供了一种预防细胞迁移和转移的新抗癌策略。
抽象的

CXC 4型趋化因子受体（CXCR4）受体及其配体CXCL12在各种癌症中过表达，并介导肿瘤进展和低氧介导的对癌症治疗的抵抗力。尽管CXCR4拮抗剂与常规抗癌药合用时具有潜在的抗癌作用，但它们对CXCL12 / CXCR4下游信号传导途径的效力较弱和全身毒性已排除了临床应用。在此，已经设计并通过实验实现了被称为安全，选择性和有效的CXCR4拮抗剂的BPRCX807。在体外和体内肝细胞癌小鼠模型中，它可以通过减少肿瘤相关的巨噬细胞（TAM）浸润，将TAM重新编程为免疫刺激性，从而显着抑制原发性肿瘤生长，防止远处转移/细胞迁移，减少血管生成并正常化免疫抑制性肿瘤微环境。表型并促进细胞毒性T细胞浸润进入肿瘤。尽管单独使用BPRCX807可以像市售索拉非尼和抗PD-1一样有效地延长总体生存期，但在联合治疗中，二者可以协同作用，以进一步延长预期寿命并更有效地抑制远处转移。

    肝细胞癌CXCR4受体程序性细胞死亡1索非尼单抗或微环境

StephenW

https://www.pnas.org/content/pnas/118/13/e2015433118.full.pdf

lovesunshine

CXCR4居然跟PD1联系起来了，厉害，希望有进展。