Washington University PDX Development and Trial Center

项目摘要 此申请是为了响应资助机会公告(FOA)PA- 20-272。这一补充建议旨在揭示协同作用的机制，并开发优化的 患者来源的微管干扰剂、埃布林和PI3K抑制剂的联合治疗方案 异种移植(PDX)乳腺癌模型。这项工作将作为两个国家之间的合作进行 圣路易斯的华盛顿大学和波士顿的BIDMC/哈佛医学院。在她的临床前工作中，Dr。 圣路易斯华盛顿大学的马教授已经证明，灯盏花素和PI3K抑制剂的组合 Copanlisib显著延长了8种PDX三阴性乳腺癌模型的无进展生存期 (TNBC)。这一新概念现在正被推广到转移性TNBC患者的临床试验中 (NCT04345913)。她的发现令人惊讶，因为到目前为止，PI3K抑制剂的益处仅限于 ER PIK3CAmt乳腺癌。灯盏花素的确切作用机制及最佳给药时机 PI3K-抑制剂将在拟议的工作中确定。这项补充奖励将把工作扩展到 研究项目1在乳腺癌PDX模型中测试PI3K抑制剂组合并发现 微管破碎剂、灯盏花素和PI3K抑制剂联合的协同作用机制 科帕尼西布。 Wulf博士的父母R01建议题为“PI3K-抑制剂治疗晚期糖尿病的新用途” PIK3CA-突变乳腺癌(1R01CA226776)“计划开发PI3K-抑制物(PI3Ki)组合用于 PIK3CA突变乳腺癌患者。PIK3CA-突变乳腺癌可以用alpelisib，a 最近FDA批准的PI3K-一种现在广泛用于与雌激素联合用于转移环境的抑制剂 受体阻断。在这个项目中，我们假设PI3K抑制是一种代谢干预，如果应用的话 在微管破裂后采取战略性措施，可以加深和延长微管获得的缓解 广泛用于治疗转移性乳腺癌的颠覆性药物。我们将使用体外成像和 ~(18)FDG-葡萄糖和~(13)C-丙酮酸~(13)C-葡萄糖深探头糖酵解代谢组学及体内显像 对化疗的反应、PI3K抑制以及它们的组合和测试这些成像方式是否可以 预测反应。华盛顿大学的团队(Cynthia Ma博士，内科肿瘤学和临床前老鼠工作，Dr.Cynthia Ma，Dr. Koresh Shogi(定量PET成像)，Cornelius von Morze博士(定量MRI成像)和at BIDMC/Boston(Gerburg Wulf博士，临床前机械学研究；Aaron Grant博士，13C- 丙酮酸成像)已经建立了用于转移PDX模型的MTA，并将每两个月召开一次会议，以 让这个补充项目在一年内完成。

Project Summary This application is being submitted in response to the Funding Opportunity Announcement (FOA) PA- 20-272. This supplemental proposal seeks to uncover the mechanism of synergy and develop an optimized regimen of the combination of a microtubule-disrupting agent, eribulin, and a PI3K-inhibitor in patient-derived xenograft (PDX) models of breast cancer. The work will be conducted as a national collaboration between Washington University in St. Louis and BIDMC/Harvard Medical School in Boston. In her pre-clinical work, Dr. Ma at Washington University in St. Louis has shown that the combination of eribulin and the PI3K-inhibitor copanlisib greatly extends progression-free survival in eight PDX models of triple negative breast cancer (TNBC). This novel concept is now being carried forward into a clinical trial in patients with metastatic TNBC (NCT04345913). Her discovery was surprising as PI3K-inhibitor benefit so far had been restricted to ER+PIK3CAmt breast cancer. The exact mechanism and, based on the mechanism, best timing of eribulin and PI3K-inhibitor will be determined in the proposed work. This supplemental award will extend the work in Research Project 1 in testing PI3K inhibitor combinations in breast cancer PDX models and to uncover mechanisms of synergy for the combination of microtubule disrupting agent, eribulin, and the PI3K inhibitor, copanlisib. Dr. Wulf's Parent R01 Proposal entitled “Novel Uses for PI3K-inhibitors for the Treatment of Advanced PIK3CA-mutant Breast Cancer (1R01CA226776)” is slated to develop PI3K-inhibitor (PI3Ki) combinations for patients with PIK3CAmutant breast cancer. PIK3CA-mutant breast cancer can be targeted with alpelisib, a recent FDA-approved PI3K-an inhibitor now widely used in the metastatic setting in conjunction with estrogen receptor blockade. In this project, we hypothesize that PI3K-inhibition is a metabolic intervention that, if applied strategically following microtubule disruption, can deepen and prolong remissions obtained with microtubule disrupting drugs, which are widely used to treat metastatic breast cancer. We will employ in vitro imaging and metabolomic studies and in vivo imaging with 18FDG-glucose and 13C-pyruvate to deep-probe glycolysis in response to chemotherapy, PI3K-inhibition and their combination and test if these imaging modalities can predict responses. The team at WashU (Dr. Cynthia Ma, medical oncology and preclinical mouse work, Dr. Kooresh Shogi (quantitative PET-imaging), Dr. Cornelius von Morze (quantitative MRI imaging) and at BIDMC/Boston (Dr. Gerburg Wulf, pre-clinical mechanistic studies and Dr. Aaron Grant, pioneer in 13C- pyruvate imaging) have established a MTA for transfer of the PDX models and will conference bi-monthly to make this supplemental project happen within a year.