Washington University PDX Development and Trial Center

华盛顿大学 PDX 开发和试验中心

• 批准号: 10371645
• 负责人: Li Ding
• 金额: $ 12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371645
• 关键词: Administrative Supplement; Aldehyde-Lyases; Antimitotic Agents; Award; Bioenergetics; Biophysical Process; Boston; Breast Cancer Cell; Cellular Metabolic Process; Citric Acid Cycle; Clinical Trials; Collaborations; Cytoskeleton; Detection; Development; Disease remission; Enzymes; Estrogen Receptors; Estrogen receptor positive; Exposure to; FDA approved; Funding Opportunities; Future; Glucose; Glycolysis; Grant; Image; In Vitro; Intervention; Kinetics; Laboratories; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Massachusetts; Measures; Medical Oncology; Metabolic; Metabolism; Metastatic breast cancer; Methods; Microtubule Stabilization; Microtubule stabilizing agent; Microtubules; Mus; Mutation; Nucleotide Biosynthesis; PIK3CA gene; Paclitaxel; Parents; Patient Transfer; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacodynamics; Positron-Emission Tomography; Process; Progression-Free Survivals; Protocols documentation; Pyruvate; Pyruvate Metabolism Pathway; Reagent; Recording of previous events; Regimen; Research; Research Personnel; Research Project Grants; Resistance; Schedule; Specificity; Techniques; Technology; Testing; Time; Universities; Washington; Work; alpelisib; animal imaging; base; chemotherapy; clinically relevant; design; fluorodeoxyglucose; glucose metabolism; imaging modality; in vivo; in vivo imaging; inhibitor/antagonist; malignant breast neoplasm; medical schools; metabolomics; mouse model; mutant; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; pre-clinical; preclinical imaging; predicting response; quantitative imaging; response; symposium; synergism; therapy resistant; triple-negative invasive breast carcinoma; tumor heterogeneity

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.

项目摘要 该申请是根据资金机会公告（FOA）PA-提交的 20-272。该补充提议旨在揭示协同作用的机制，并开发出优化的 在患者来源的微管破坏剂，eribulin和PI3K抑制剂的组合方案 异种移植（PDX）乳腺癌模型。这项工作将作为国家合作 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 圣路易斯华盛顿大学的硕士学位表明，艾里布林和PI3K抑制剂的组合 Copanlisib在八种三重阴性乳腺癌的PDX模型中极大地扩展了无进展的生存率 （TNBC）。现在，这个新颖的概念正在转移到转移性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， ER+PIK3CAMT乳腺癌。确切的机制，并基于机制，是eribulin和 PI3K抑制剂将在拟议的工作中确定。此补充奖励将扩大工作 研究项目1在乳腺癌PDX模型中测试PI3K抑制剂组合并发现 微管破坏剂，eribulin和PI3K抑制剂的协同机制 Copanlisib。 Wulf博士的父r01提案，标题为“用于治疗高级PI3K抑制剂的新颖用途 PIK3CA突变乳腺癌（1R01CA226776）都计划开发PI3K抑制剂（PI3KI）组合 PIK3Camutant乳腺癌患者。 PIK3CA突变乳腺癌可以用Alpelisib靶向 最近，FDA批准的PI3K-AN抑制剂现在与雌激素结合使用在转移环境中 接收器封锁。在这个项目中，我们假设PI3K抑制是一种代谢干预措施，如果应用 从策略性地遵循微管破坏，可以加深和延长用微管获得 破坏药物，这些药物被广泛用于治疗转移性乳腺癌。我们将使用体外成像和 代谢组学研究和体内成像18FDG-葡萄糖和13C-丙酮酸到深探针糖酵解 对化学疗法，PI3K抑制作用及其组合和测试是否可以反应 预测响应。 Washu的团队（Cynthia Ma博士，医学肿瘤学和临床前老鼠工作，博士 Kooresh Shogi（定量宠物成像），Cornelius von Morze博士（定量MRI成像）和AT BIDMC/BOSTON（Gerburg Wulf博士，临床前机械研究和Aaron Grant博士，13C-的先驱 丙酮酸成像）已经建立了用于转移PDX模型的MTA，并将每两月会议 使这个补充项目在一年内实现。