University of Texas PDX Development and Trial Center

德克萨斯大学 PDX 开发和试验中心

• 批准号: 10580478
• 负责人: Senthilkumar Damodaran
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580478
• 关键词: Biological Markers; Biopsy; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Patient; Cessation of life; Clinical; Clinical Trials; Clinical Trials Network; Collaborations; Combined Modality Therapy; Development; Dose; Drug Combinations; Goals; In Vitro; Individual; Institution; Investigational Therapies; Lead; Microtubules; Modeling; Molecular; Molecular Profiling; Outcome; Patient Recruitments; Patient Selection; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase Ib Trial; Randomized; Research Personnel; Sampling; Testing; Texas; Treatment Efficacy; Universities; Vertebral column; analog; base; chemotherapy; clinical efficacy; co-clinical trial; design; exportin 1 protein; follow-up; high risk; improved; inhibitor; insight; interest; malignant breast neoplasm; partial response; patient derived xenograft model; pharmacodynamic biomarker; phase I trial; phase II trial; pre-clinical; predictive marker; relapse risk; response; response biomarker; standard of care; triple-negative invasive breast carcinoma; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-039. Triple negative breast cancer (TNBC) accounts for 10-20% of all breast cancers, and is one of the most aggressive. Patients with metastatic TNBC are at high risk of death1,2 despite standard-of-care chemotherapies such as eribulin, a halichondrin analogue that inhibits microtubule dynamics. Previously, we found that selinexor (KPT-330), a potent inhibitor of exportin-1, synergizes with eribulin in TNBC cells and patient-derived xenografts (PDXs). Based on these studies, we launched a Phase Ib trial combining selinexor and eribulin, with expansion in TNBC (NCT02419495). Overall response rate was 10.5% in TNBC dose expansion (n = 19); however, two patients had exceptional responses with confirmed durable partial response, maintained long-term after transitioning to single-agent selinexor. We now propose to investigate the mechanism of action of this combination. We hypothesize that integrated analysis of PDXs and patient samples will give insights into the individual contributions of eribulin and selinexor to treatment efficacy, and into potential predictors and pharmacodynamic markers of response that can facilitate the design of follow-up trials using eribulin as chemotherapy backbone, in particular a randomized Phase II trial of eribulin with and without selinexor, to be launched through the Experimental Therapeutics Clinical Trial Network (ETCTN). To this end, we will (a) investigate whether selinexor enhances the efficacy of eribulin in TNBC PDXs established during the eribulin/selinexor trial, and whether efficacy of the combination in PDXs correlate with clinical efficacy; (b) compare baseline molecular features in PDXs and patient samples from responders and nonresponders; (c) compare pharmacodynamic changes in PDXs from responders and nonresponders following single-agent eribulin or selinexor and combination; and (d) compare pharmacodynamic changes in PDXs and in matching pre-treatment and on-treatment patient samples. The proposed study represents a PDXNet/ETCTN collaboration between Drs. Funda Meric-Bernstam and Senthilkumar Damodaran, and is consistent with our long-term goal to leverage PDXs and molecular profiling to identify rational combination therapies that will improve TNBC outcomes, as well as to identify patients who can benefit from such therapies. Taken together, we expect to better understand (a) whether selinexor improves efficacy of eribulin, (b) whether PDX efficacy and pharmacodynamic changes correlate with what is seen in patients, and (c) what tumor features correlate with response.

项目总结/摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 22-039.三阴性乳腺癌（TNBC）占所有乳腺癌的10-20%，并且是最常见的乳腺癌之一。 咄咄逼人尽管接受了标准化疗，转移性TNBC患者仍有较高的死亡风险1，2 例如艾日布林，一种抑制微管动力学的软海绵素类似物。之前我们发现selinexor （KPT-330）是一种强效的输出蛋白-1抑制剂，与艾日布林在TNBC细胞和患者来源的异种移植物中具有协同作用 （PDXs）。基于这些研究，我们启动了一项Ib期试验，将selinexor和eribulin联合使用， 在TNBC（NCT 02419495）中。在TNBC剂量扩展中的总体响应率为10.5%（n = 19）;然而，两个 患者有特殊的反应，证实持久的部分反应，维持长期后， 过渡到单药赛灵克斯我们现在建议调查这一行动的机制 组合.我们假设，PDX和患者样本的综合分析将使我们深入了解 艾日布林和赛林克斯对治疗疗效的个体贡献，以及潜在的预测因子， 反应的药效学标志物，可以促进使用艾日布林作为 化疗骨干，特别是艾日布林与和不与赛林克斯的随机II期试验， 实验治疗临床试验网络（ETCTN）。为此，我们将（a） 研究赛林克斯是否增强艾日布林在TNBC PDX中的功效， 艾日布林/司林克斯试验，以及该组合在PDX中的功效是否与临床功效相关;（B） 比较来自应答者和非应答者的PDX和患者样品中的基线分子特征;（c） 比较单药治疗后应答者和非应答者的PDX的药效学变化 艾日布林或赛灵克斯和组合;和（d）比较PDX和匹配的PDX中的药效学变化。 治疗前和治疗中的患者样品。拟议的研究代表了PDXNet/ETCTN Funda Meric-Bernardian博士和Senthilkumar Damodaran博士之间的合作，并与我们的合作一致。 长期目标是利用PDX和分子特征分析来确定合理的联合治疗， 改善TNBC结果，以及确定可以从这种疗法中受益的患者。综合起来看， 我们期望更好地理解（a）赛林克斯是否改善艾日布林的功效，（B）PDX功效和 药效学变化与患者中所见相关，以及（c）哪些肿瘤特征与 反应