Optimization of PI3K-inhibitors to augment the efficacy of microtubule-disrupting chemotherapy

优化 PI3K 抑制剂以增强微管破坏化疗的疗效

基本信息

批准号：
10326434
负责人：
GERBURG M WULF
金额：
$ 12.5万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326434
关键词：
Address Administrative Supplement Aldehyde-Lyases Antineoplastic Agents Birds Boston Breast Cancer Cell Cell division Cells Citric Acid Cycle Clinical Trials Collaborations Cytoskeleton Detection Development Disease Disease remission Endocrine Enzymes Estrogen Receptors Estrogen receptor negative Estrogen receptor positive Exposure to FDA approved Funding Opportunities Glucose Glycolysis Grant Human Resources Image In Vitro Institution Intervention Kinetics Lead Magnetic Resonance Imaging Malignant Neoplasms Massachusetts Measures Medical Oncology Metabolic Metastatic breast cancer Methods Microtubule stabilizing agent Microtubules Mus Mutation Names Nodal PIK3CA gene Paclitaxel Parents Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Pharmacodynamics Positron-Emission Tomography Progression-Free Survivals Protocols documentation Pyruvate Pyruvate Metabolism Pathway Reagent Recording of previous events Regimen Research Research Personnel Resistance Schedule Signal Transduction Specificity Techniques Technology Telephone Testing Time Universities Washington Work alpelisib base cancer therapy chemotherapy clinically relevant fluorodeoxyglucose glucose metabolism imaging modality in vivo in vivo imaging inhibitor/antagonist interest malignant breast neoplasm medical schools metabolomics mouse model mutant novel patient derived xenograft model pre-clinical preclinical imaging predicting response quantitative imaging response symposium synergism therapy resistant treatment response triple-negative invasive breast carcinoma tumor heterogeneity

项目摘要

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-21-009. 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 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 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. Our Parent Proposal is slated to develop PI3K-inhibitor (PI3Ki) combinations for patients with PIK3CA- mutant breast cancer. PI3Kinase is a nodal point of the intracellular signaling machinery that drives cell division of breast cancer cells. PIK3CA-mutant breast cancer can be targeted with alpelisib, a recent FDA-approved PI3K-a inhibitor now widely used in the metastatic setting in conjunction with estrogen receptor blockade. Our Supplemental Proposal is an extension of Aim 2, To determine in vivo if the metabolic changes induced by PI3K- inhibition are predictive of cancer treatment responses and of Aim 3, To determine in vivo if time-staggered PI3K- inhibition can enhance the efficacy of antineoplastic treatments for endocrine-resistant PIK3CA-mutant BC of our Parent Proposal. 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.

本申请是为了响应被确定为 NOT- 的特殊利益通知 (NOSI) 而提交的 CA-21-009。该补充提案旨在揭示协同机制并开发优化的在 PDX 模型中使用微管破坏剂、艾日布林和 PI3K 抑制剂的组合方案乳腺癌。这项工作将作为圣路易斯华盛顿大学之间的全国合作进行。圣路易斯和波士顿 BIDMC/哈佛医学院。华盛顿大学马博士在临床前工作中圣路易斯的研究表明，艾日布林和 PI3K 抑制剂 copanlisib 的组合大大延长了八种 TNBC PDX 模型的无进展生存期。这个新颖的概念现在正在被发扬光大转移性 TNBC 患者的临床试验 (NCT04345913)。作为 PI3K 抑制剂，她的发现令人惊讶迄今为止，获益仅限于 ER+PIK3CAmt 乳腺癌。确切的机制，并基于机制，艾日布林和 PI3K 抑制剂的最佳时机将在拟议的工作中确定。我们的家长提案计划为 PIK3CA- 患者开发 PI3K 抑制剂 (PI3Ki) 组合突变乳腺癌。 PI3激酶是驱动细胞分裂的细胞内信号传导机制的节点乳腺癌细胞。 PIK3CA 突变乳腺癌可以用 alpelisib 来治疗，alpelisib 是 FDA 最近批准的一种药物 PI3K-a 抑制剂现已广泛用于与雌激素受体阻断联合治疗转移性疾病。我们的补充提案是目标 2 的延伸，以确定体内 PI3K- 是否会引起代谢变化抑制可预测癌症治疗反应和目标 3，以确定体内时间交错的 PI3K- 抑制可以增强内分泌耐药 PIK3CA 突变 BC 的抗肿瘤治疗效果我们的家长提案。在这个项目中，我们假设 PI3K 抑制是一种代谢干预，如果应用的话战略性地继微管破坏后，可以加深和延长微管获得的缓解- 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和使用 18FDG-葡萄糖和 13C-丙酮酸进行代谢组学研究和体内成像，以深度探测糖酵解对化疗、PI3K 抑制及其组合的反应，并测试这些成像方式是否可以预测回应。华盛顿大学团队（Cynthia Ma 博士、医学肿瘤学和临床前小鼠工作、Kooresh Shogi 博士（定量 PET 成像，Cornelius von Morze 博士（定量 MRI 成像）和 BIDMC/波士顿（Dr. Cornelius von Morze） Gerburg Wulf（临床前机制研究）和 Aaron Grant 博士（13C-丙酮酸成像先驱）建立了一个用于 PDX 模型转让的 MTA，并将每两个月举行一次会议以使其成为补充项目在一年内发生。