Administrative Core

三阴性乳腺癌（TNBC）占所有乳腺癌的10-20%，是最具侵袭性的一种。转移性TNBC患者的死亡风险很高1,2，尽管采用了标准治疗化疗，如爱瑞布林（一种抑制微管动力学的软胆碱类似物）。之前，我们发现selinexor （KPT-330）是一种有效的输出素-1抑制剂，在TNBC细胞和患者来源的异种移植物（PDXs）中与eribulin协同作用。基于这些研究，我们启动了一项联合selinexor和eribulin的Ib期试验，并扩展到TNBC （NCT02419495）。TNBC剂量扩大组总有效率为10.5% (n = 19)；然而，两名患者有特殊的反应，证实持久的部分反应，在过渡到单药selinexor后长期维持。我们现在建议研究这种组合的作用机制。我们假设，对pdx和患者样本的综合分析将深入了解伊立布林和selinexor对治疗效果的个体贡献，以及潜在的预测因素和反应的药效学标志物，从而有助于设计使用伊立布林作为化疗主干的后续试验，特别是将通过实验治疗临床试验网络（ETCTN）启动的伊立布林加或不加selinexor的随机II期试验。为此，我们将(a)研究selinexor是否能增强伊立布林在伊立布林/selinexor试验中建立的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)比较有反应者和无反应者的pdx和患者样本的基线分子特征；(c)比较有反应者和无反应者在单药艾瑞布林或赛力那索和联合用药后PDXs的药效学变化；(d)比较pdx的药效学变化以及治疗前和治疗后患者样本的匹配。拟议的研究代表了PDXNet/ETCTN博士之间的合作。Funda Meric-Bernstam和Senthilkumar Damodaran，这与我们的长期目标是一致的，即利用pdx和分子谱来确定合理的联合疗法，以改善TNBC的预后，并确定可以从这些疗法中受益的患者。综上所述，我们希望更好地了解(a) selinexor是否能提高伊瑞布林的疗效，(b) PDX的疗效和药效学变化是否与患者的观察结果相关，以及(c)哪些肿瘤特征与反应相关。

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.