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

• 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
• 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

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.

该申请是根据特殊利益通知（NOSI）提交的 CA-21-009。该补充提议旨在揭示协同作用的机制，并开发出优化的 在PDX模型中，微管破坏剂，eribulin和PI3K抑制剂的组合方案 乳腺癌。这项工作将作为圣华盛顿大学之间的国家合作进行。 波士顿的路易斯和比德姆/哈佛医学院。在她的临床前工作，华盛顿大学的MA博士 在圣路易斯中 TNBC八个PDX模型中的无进展生存期。现在，这个新颖的概念正在将 转移性TNBC患者（NCT04345913）的临床试验。作为PI3K抑制剂，她的发现令人惊讶 到目前为止，益处仅限于ER+PIK3CAMT乳腺癌。确切的机制，并基于 在拟议的工作中，将确定机制，eribulin和PI3K抑制剂的最佳时机。 我们的父母建议计划为PIK3CA-患者开发PI3K抑制剂（PI3KI）组合 突变乳腺癌。 PI3Kinase是驱动细胞分裂的细胞内信号传导机制的淋巴结点 乳腺癌细胞。 PIK3CA突变乳腺癌可以用Alpelisib（最近的FDA批准）靶向 PI3K-A抑制剂现已与雌激素受体阻滞结合在转移环境中广泛使用。我们的 补充建议是AIM 2的扩展，以确定体内是否由PI3K-诱导的代谢变化 抑制是预测癌症治疗反应和目标3的预测，以确定体内时间耗时的PI3K- 抑制可以增强抗塑性治疗对内分泌耐药性PIK3CA突变BC的疗效 我们的父母建议。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，可以加深并延长用微管获得 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的反应是否可以预测 回答。 Washu的团队（MA Cynthia博士，医学肿瘤学和临床前老鼠工作，Kooresh Shogi博士 （定量宠物成像，Cornelius von Morze博士（定量MRI成像）和BIDMC/Boston（博士 Gerburg Wulf，临床前机械研究和Aaron Grant博士，13C-丙酮酸成像的先驱） 建立了用于转移PDX模型的MTA，并将每两个月会议以使这种补充 项目发生在一年之内。