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

本申请是为了回应特别利益通知（NOSI）而提交的，该通知被确定为不- CA-21-009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抑制剂的组合的方案 乳腺癌这项工作将作为华盛顿大学和圣路易斯大学之间的一项全国性合作进行。 路易斯和BIDMC/哈佛医学院在波士顿。在临床前工作中，华盛顿大学的马博士 已经表明艾日布林和PI 3 K抑制剂copanlisib的组合大大延长了 在TNBC的八个PDX模型中的无进展存活率。这一新颖的概念现在正被推进到一个 转移性TNBC患者的临床试验（NCT 04345913）。她的发现是令人惊讶的PI 3 K抑制剂 迄今为止，受益仅限于ER+ PIK 3CAmt乳腺癌。确切的机制，并根据 机制，艾日布林和PI 3 K抑制剂的最佳时机将在拟议的工作中确定。 我们的母公司计划为PIK 3CA患者开发PI 3 K抑制剂（PI 3 Ki）组合- 突变型乳腺癌PI 3激酶是驱动细胞分裂的细胞内信号机制的节点 乳腺癌细胞。PIK 3CA突变型乳腺癌可以用最近FDA批准的alpelisib靶向治疗 PI 3 K-a抑制剂现在广泛用于与雌激素受体阻断剂结合的转移性环境中。我们 补充建议是目标2的扩展，以确定体内由PI 3 K-1诱导的代谢变化是否与目标2中的代谢变化相关。 抑制是癌症治疗反应和目标3预测，为了在体内确定时间交错的PI 3 K- 抑制可以增强内分泌抗性PIK 3CA突变BC的抗肿瘤治疗的功效。 我们的家长提案在这个项目中，我们假设PI 3 K抑制是一种代谢干预，如果应用 策略性地跟随微管破坏，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， 对化疗的反应，PI 3 K抑制及其组合，并测试这些成像方式是否可以预测 应答 华盛顿大学的团队（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. Gerburg Wulf，临床前机制研究和Aaron Grant博士，13 C-丙酮酸成像的先驱） 为PDX型号的转移建立了MTA，并将每两个月召开一次会议， 项目在一年内完成。

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.