Administrative Core

行政核心

• 批准号: 10708299
• 负责人: Jack Roth
• 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/10708299
• 关键词: Administrative; Core

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.

三阴性乳腺癌 (TNBC) 占所有乳腺癌的 10-20%，是最具侵袭性的乳腺癌之一。尽管采用艾日布林（一种抑制微管动力学的软海绵素类似物）等标准化疗，转移性 TNBC 患者仍面临很高的死亡风险1,2。此前，我们发现 selinexor (KPT-330) 是一种有效的 Exportin-1 抑制剂，在 TNBC 细胞和患者来源的异种移植物 (PDX) 中与艾日布林具有协同作用。基于这些研究，我们启动了结合 selinexor 和艾日布林的 Ib 期试验，并在 TNBC 中进行扩展 (NCT02419495)。 TNBC 剂量扩展的总体缓解率为 10.5%（n = 19）；然而，两名患者出现了特殊的反应，并证实有持久的部分反应，并且在转用单药 selinexor 后仍能长期维持。我们现在建议研究这种组合的作用机制。我们假设，PDX 和患者样本的综合分析将深入了解艾日布林和 selinexor 对治疗效果的个体贡献，以及潜在的反应预测因子和药效标记物，从而有助于设计使用艾日布林作为化疗骨干的后续试验，特别是通过实验治疗学启动的艾日布林联合或不联合 selinexor 的随机 II 期试验。 临床试验网络（ETCTN）。为此，我们将 (a) 研究 selinexor 是否增强艾日布林在艾日布林/selinexor 试验期间建立的 TNBC PDX 中的疗效，以及联合用药在 PDX 中的疗效是否与临床疗效相关； (b) 比较 PDX 以及来自应答者和非应答者的患者样本的基线分子特征； (c) 比较单药艾日布林或 selinexor 以及组合后应答者和无应答者 PDX 的药效学变化； (d) 比较 PDX 以及匹配的治疗前和治疗中患者样本的药效学变化。拟议的研究代表了 PDXNet/ETCTN 博士之间的合作。 Funda Meric-Bernstam 和 Senthilkumar Damodaran 的研究结果与我们的长期目标是一致的，即利用 PDX 和分子分析来确定可改善 TNBC 结果的合理联合疗法，并确定可以从此类疗法中受益的患者。综上所述，我们希望更好地了解（a）selinexor 是否可以提高艾日布林的疗效，（b）PDX 疗效和药效学变化是否与患者中观察到的情况相关，以及（c）哪些肿瘤特征与反应相关。