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而提交的- 20-272.本补充建议旨在揭示协同机制，并制定优化的 微管破坏剂、艾日布林和PI 3 K抑制剂的组合在患者源性肿瘤中的方案 乳腺癌的异种移植（PDX）模型。这项工作将作为一项国家合作进行， 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，博士。 位于圣路易斯的华盛顿大学的Ma已经证明，艾日布林和PI 3 K抑制剂的组合 copanlisib极大地延长了八种三阴性乳腺癌PDX模型的无进展生存期 （TNBC）。这一新概念目前正在转移性TNBC患者中进行临床试验 （NCT 04345913）。她的发现令人惊讶，因为到目前为止，PI 3 K抑制剂的益处仅限于 ER+ PIK 3CAmt乳腺癌。并根据其作用机制，探讨了艾日布林的最佳给药时机， 将在拟定工作中测定PI 3 K抑制剂。这项补充奖励将延长工作， 研究项目1在乳腺癌PDX模型中测试PI 3 K抑制剂组合，并揭示 微管破坏剂、艾日布林和PI 3 K抑制剂的组合的协同作用机制， copanlisib. Wulf博士的母公司R 01提案，标题为“PI 3 K抑制剂治疗晚期 PIK 3CA突变型乳腺癌（1 R 01 CA 226776）”计划开发PI 3 K抑制剂（PI 3 Ki）组合， PIK 3CA突变型乳腺癌患者。PIK 3CA突变型乳腺癌可以用alpelisib靶向治疗， 最近FDA批准的PI 3 K-一种与雌激素联合广泛用于转移性疾病的抑制剂 受体阻断在这个项目中，我们假设PI 3 K抑制是一种代谢干预，如果应用 策略性地在微管破坏后，可以加深和延长用微管 干扰药物，广泛用于治疗转移性乳腺癌。我们将采用体外成像技术， 代谢组学研究和18 FDG-葡萄糖和13 C-丙酮酸的体内成像，以深度探测糖酵解， 对化疗、PI 3 K抑制及其组合的反应，并测试这些成像方式是否可以 预测答案。华盛顿大学的研究小组（Cynthia Ma博士，医学肿瘤学和临床前小鼠工作，Dr. Kooresh Shogi（定量PET成像），Cornelius von Morze博士（定量MRI成像）和 BIDMC/波士顿（Gerburg Wulf博士，临床前机制研究和Aaron Grant博士，13 C- 丙酮酸成像）已经建立了一个MTA，用于转移PDX模型，并将每两个月召开一次会议， 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.