用小分子抑制剂靶向 RNA 螺旋酶 DDX3X 治疗乳腺癌骨转移

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2024-09-19 DOI:10.1016/j.canlet.2024.217260

Paul T. Winnard Jr. , Farhad Vesuna , Guus M. Bol , Kathleen L. Gabrielson , Georgia Chenevix-Trench , Natalie D. ter Hoeve , Paul J. van Diest , Venu Raman

{"title":"用小分子抑制剂靶向 RNA 螺旋酶 DDX3X 治疗乳腺癌骨转移","authors":"Paul T. Winnard Jr. , Farhad Vesuna , Guus M. Bol , Kathleen L. Gabrielson , Georgia Chenevix-Trench , Natalie D. ter Hoeve , Paul J. van Diest , Venu Raman","doi":"10.1016/j.canlet.2024.217260","DOIUrl":null,"url":null,"abstract":"<div><div>Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":null,"pages":null},"PeriodicalIF":9.1000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment\",\"authors\":\"Paul T. Winnard Jr. , Farhad Vesuna , Guus M. Bol , Kathleen L. Gabrielson , Georgia Chenevix-Trench , Natalie D. ter Hoeve , Paul J. van Diest , Venu Raman\",\"doi\":\"10.1016/j.canlet.2024.217260\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.</div></div>\",\"PeriodicalId\":9506,\"journal\":{\"name\":\"Cancer letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.1000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0304383524006554\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304383524006554","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

乳腺癌骨转移患者只有有限的姑息治疗策略，需要有效的药物治疗。在乳腺癌患者的数据中，高水平的 RNA 螺旋酶 DDX3 与总生存率低和骨转移有关。因此，我们的目标是利用 DDX3 的小分子抑制剂 RK-33 在小鼠乳腺癌骨转移模型中靶向 DDX3。经组织学证实的活体成像显示，与安慰剂处理的小鼠相比，RK-33 处理的小鼠群中没有出现骨转移。我们从小鼠的骨转移病灶中生成了一个细胞系，发现该细胞系和一个源自患者的骨转移细胞系对传统化疗药物产生了抗药性，但对 RK-33 没有抗药性。最后，在乳腺癌患者的骨转移样本中观察到了不同水平的 DDX3。总之，这项研究表明，DDX3 是乳腺癌骨转移的相关临床靶点，RK-33 可以安全有效地治疗这些患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment

Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.