文章：

CB-103，一种首创的转录Notch抑制剂，在乳腺癌临床前模型中的疗效

The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer

原文发布日期：3 August 2023

DOI: 10.3390/cancers15153957

类型: Article

开放获取: 是

英文摘要：

Background: The efficacy of CB-103 was evaluated in preclinical models of both ER+ and TNBC. Furthermore, the therapeutic efficacy of combining CB-103 with fulvestrant in ER+ BC and paclitaxel in TNBC was determined. Methods: CB-103 was screened in combination with a panel of anti-neoplastic drugs. We evaluated the anti-tumor activity of CB-103 with fulvestrant in ESR1-mutant (Y537S), endocrine-resistant BC xenografts. In the same model, we examined anti-CSC activity in mammosphere formation assays for CB-103 alone or in combination with fulvestrant or palbociclib. We also evaluated the effect of CB-103 plus paclitaxel on primary tumors and CSC in a GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with a two-sided unpaired Students’t-test. A one-way or two-way ANOVA followed by Tukey’s post-analysis was performed to analyze the in vivo efficacy study results. The results: CB-103 showed synergism with fulvestrant in ER+ cells and paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, the endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone. Conclusion: our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.

摘要翻译： 

背景：在ER+和三阴性乳腺癌（TNBC）的临床前模型中评估了CB-103的疗效，并进一步确定了CB-103联合氟维司群治疗ER+乳腺癌、联合紫杉醇治疗TNBC的疗效。方法：将CB-103与一组抗肿瘤药物联合进行筛选。我们在ESR1突变（Y537S）型内分泌耐药乳腺癌异种移植模型中评估了CB-103联合氟维司群的抗肿瘤活性。在同一模型中，通过乳腺球形成实验检测了CB-103单药或联合氟维司群/帕博西尼的抗肿瘤干细胞活性。此外，在GSI耐药的三阴性乳腺癌模型HCC1187中评估了CB-103联合紫杉醇对原发肿瘤和肿瘤干细胞的影响。组间比较采用双侧非配对Student t检验，体内疗效研究结果采用单因素或双因素方差分析结合Tukey事后检验进行分析。结果：CB-103在ER+细胞中与氟维司群、在三阴性乳腺癌细胞中与紫杉醇均显示协同作用。在两个模型中，CB-103联合氟维司群或紫杉醇均能有效抑制乳腺球形成。在ESR1突变型内分泌耐药乳腺癌模型中，CB-103联合氟维司群显著降低肿瘤体积；在GSI耐药的三阴性乳腺癌模型中，CB-103联合紫杉醇较单用紫杉醇显著延缓肿瘤生长。结论：我们的数据表明，对于生物标志物确认Notch活性的内分泌耐药复发性乳腺癌，CB-103联合SERDs和/或CDKis；以及对于生物标志物确认Notch活性的三阴性乳腺癌，CB-103联合含紫杉醇化疗方案，均是值得临床研究的候选策略。

原文链接：

The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer