Toward Clinical Trial: AXL-STAT3 Targeting of Lung Tumor Microenvironments

走向临床试验：AXL-STAT3 靶向肺肿瘤微环境

• 批准号: 10660429
• 负责人: Josephine A Taverna
• 金额: $ 47.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660429
• 关键词: A549; Aftercare; Binding; Biological; Biological Assay; Biopsy; CD34 gene; Cancer Patient; Cancer cell line; Cell Line; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Collaborations; Combined Modality Therapy; Communication; Communities; Comparison arm; Complex; Correlative Study; Data; Dependence; Distant Metastasis; Dose; Drug Targeting; Ecosystem; Enzyme-Linked Immunosorbent Assay; Epithelium; Fibroblasts; Growth; Heterogeneity; Hybrids; IL6ST gene; Immunofluorescence Immunologic; Immunologics; Implant; In Vitro; Interleukin-11; Investigation; JAK1 gene; Knock-out; Lung; Lung Adenocarcinoma; Lung Neoplasms; Macrophage; Malignant - descriptor; Malignant neoplasm of lung; Maximum Tolerated Dose; Mediating; Mesenchymal; Modeling; Molecular Profiling; Mus; Neoplasm Circulating Cells; Non-Malignant; Oncoproteins; Organoids; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phase Ib Trial; Phenotype; Population; Prediction of Response to Therapy; Production; Progression-Free Survivals; Receptor Protein-Tyrosine Kinases; Resistance; STAT3 gene; Safety; Signal Transduction; Stimulus; System; Therapeutic; Toxic effect; Translating; Transplantation; Tumor Burden; Xenograft Model; Xenograft procedure; cancer therapy; cell type; cytokine; design; drug testing; effective therapy; epithelial to mesenchymal transition; experimental study; human subject; humanized mouse; improved; in vivo; indexing; inhibitor; innovation; insight; knock-down; liquid biopsy; lung cancer cell; lymph nodes; mimicry; molecular marker; monocyte; mouse model; neoplastic cell; novel; paracrine; peripheral blood; phase 2 study; precision medicine; preclinical study; predictive marker; prevent; programs; prospective; recruit; response; restraint; secondary endpoint; small hairpin RNA; stemness; survival outcome; targeted treatment; treatment strategy; treatment stratification; tumor; tumor growth; tumor microenvironment; tumor xenograft; tumorigenic

ABSTRACT Dynamic lung tumor microenvironments (TMEs) contain a myriad of cell subtypes, each providing a unique functionality in support of malignant growth. To prepare a metastatic niche, a tight signaling network must be present to coordinate the delivery and sharing of co-stimulatory signals among malignant and non-malignant cell populations. AXL and STAT3 cascades are critical components of intra- and intercellular signaling networks, as they translate multiple external stimuli into specific cellular responses. Single cell profiling of lung tumors reveals that AXL collaborates with STAT3 to generate a unified tumor ecosystem that promotes hybrid epithelial-to- mesenchymal transition (EMT), pro-tumorigenic remodeling of fibroblasts and M2 polarization of macrophages. Disruption of AXL-STAT3 network not only compromises this co-dependency in lung cancer cells implanted in xenograft mice, but also limits the tumor cells' ability to conscript supportive host cells to form a symbiotic community. We hypothesize that combined targeting of AXL-STAT3 network disrupts the communication among diverse cell subtypes, thereby inhibiting lung tumor growth and metastatic spread. In Aim 1a, we will conduct knockdown and knockout experiments in lung cancer, fibroblast and monocytic cell lines to explore the relationship between AXL-STAT3 pathway and macrophage differentiation in co-culture systems. We will demonstrate that AXL-STAT3 network in lung cancer cells and fibroblasts exerts a paracrine effect via IL-11 secretion on macrophages to sustain STAT3 signaling for M2 polarization and stemness mimicry. In Aim 1b, in vivo drug testing of AXL and JAK inhibitors in CD34+ humanized NSGTM-SGM3 mouse xenograft models will evaluate AXL-STAT3 drug targeting effects on host cell recruitment, hybrid EMT phenotypes, macrophage plasticity and pro-tumorigenic remodeling of stromal fibroblasts. In Aim 2, we propose a phase Ib/II study to determine safety and efficacy of dubermatinib (AXL inhibitor) and momelotinib (JAK inhibitor) in patients with metastatic lung adenocarcinoma. In Aim 2a, a Bayesian Optimal Interval design will identify the MTD of momelotinib in combination with dubermatinib with a target toxicity rate 30% in 18 patients. In Aim 2b, we will conduct a prospective phase II, single-arm comparison of progression free survival in 26 patients treated with combination dubermatinib and momelotinib versus an historical control. Correlative studies include pre- and post- treatment paired lung tumor and liquid biopsies to determine if combined treatment can disrupt AXL-STAT3 signaling network in malignant and non-malignant cell populations and reprogram aggressive tumor microenvironments. AXL-STAT3 targeting to restrain TMEs is a promising therapeutic strategy in patients with advanced lung adenocarcinoma. This R01 proposal will address an important question regarding the efficacy of combination treatment with AXL inhibitor and JAK inhibitor (for STAT3 signaling blockade) in lung cancer patients and will provide a treatment stratification model based on intercellular crosstalk between AXL-STAT3 signaling for an extended clinical trial.

抽象的 动态肺肿瘤微环境 (TME) 包含多种细胞亚型，每种亚型都提供独特的功能 支持恶性生长的功能。为了准备转移生态位，必须有一个紧密的信号网络 协调恶性和非恶性细胞之间共刺激信号的传递和共享 人口。 AXL 和 STAT3 级联是细胞内和细胞间信号网络的关键组成部分， 它们将多种外部刺激转化为特定的细胞反应。肺部肿瘤的单细胞分析揭示 AXL 与 STAT3 合作生成一个统一的肿瘤生态系统，促进混合上皮细胞 间充质转化 (EMT)、成纤维细胞的促肿瘤重塑和巨噬细胞的 M2 极化。 AXL-STAT3 网络的破坏不仅会损害植入肺癌细胞的这种相互依赖性 异种移植小鼠，但也限制了肿瘤细胞征召支持性宿主细胞形成共生的能力 社区。我们假设 AXL-STAT3 网络的联合靶向会破坏通信 不同细胞亚型之间的相互作用，从而抑制肺肿瘤的生长和转移扩散。在目标 1a 中，我们将 在肺癌、成纤维细胞和单核细胞系中进行敲除和敲除实验，以探索 共培养系统中 AXL-STAT3 通路与巨噬细胞分化的关系。我们将 证明肺癌细胞和成纤维细胞中的 AXL-STAT3 网络通过 IL-11 发挥旁分泌作用 巨噬细胞分泌以维持 M2 极化和干性拟态的 STAT3 信号传导。在目标 1b 中， CD34+ 人源化 NSGTM-SGM3 小鼠异种移植模型中 AXL 和 JAK 抑制剂的体内药物测试将 评估 AXL-STAT3 药物靶向对宿主细胞募集、混合 EMT 表型、巨噬细胞的影响 基质成纤维细胞的可塑性和促肿瘤重塑。在目标 2 中，我们提出了一项 Ib/II 期研究 确定 dubermatinib（AXL 抑制剂）和 momelotinib（JAK 抑制剂）在患有以下疾病的患者中的安全性和有效性 转移性肺腺癌。在目标 2a 中，贝叶斯最优区间设计将确定 MTD momelotinib 与 dubermatinib 联合治疗，18 名患者的目标毒性率为 30%。在目标 2b 中，我们将 对 26 名接受过治疗的患者进行无进展生存期的前瞻性 II 期单臂比较 杜贝马替尼和莫洛替尼联合用药与历史对照的比较。相关研究包括事前和事后 治疗将肺肿瘤和液体活检配对，以确定联合治疗是否可以破坏 AXL-STAT3 恶性和非恶性细胞群中的信号网络并重新编程侵袭性肿瘤 微环境。 AXL-STAT3 靶向抑制 TME 是一种有前景的治疗策略 晚期肺腺癌。该 R01 提案将解决一个有关功效的重要问题 AXL 抑制剂和 JAK 抑制剂（用于 STAT3 信号阻断）联合治疗肺癌患者 并将提供基于 AXL-STAT3 信号传导之间细胞间串扰的治疗分层模型 进行扩展的临床试验。