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

基本信息

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
项目类别：
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

项目摘要

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）包含无数的细胞亚型，每种可提供独特支持恶性增长的功能。要准备转移性利基，必须一个紧密的信号网络是存在以协调恶性和非恶性细胞中共同刺激信号的交付和共享人群。 AXL和STAT3级联是细胞内和细胞间信号网络的关键组成部分，AS 他们将多个外部刺激转化为特定的细胞反应。肺部肿瘤的单细胞分析显示 AXL与STAT3合作生成了一个统一的肿瘤生态系统，该系统促进了混合上皮到 - 间充质转变（EMT），成纤维细胞的促肿瘤重塑和巨噬细胞的M2极化。 AXL-STAT3网络的破坏不仅损害了植入的肺癌细胞中的这种共依赖性异种移植小鼠，但也限制了肿瘤细胞应征支持宿主细胞形成共生的能力社区。我们假设AXL-STAT3网络的结合靶向扰动了通信在各种细胞亚型中，从而抑制肺肿瘤的生长和转移性扩散。在AIM 1A中，我们将在肺癌，成纤维细胞和单核细胞系中进行敲低和敲除实验以探索共培养系统中AXL-STAT3途径与巨噬细胞分化之间的关系。我们将证明肺癌细胞中的AXL-STAT3网络和成纤维细胞在IL-11中发挥旁分泌作用巨噬细胞的分泌，以维持M2极化和干性模仿的STAT3信号传导。在AIM 1B中，在 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AIM 2中，我们提出了IB/II期研究确定Dubermatinib（AXL抑制剂）和Momelotinib（JAK抑制剂）的安全性和功效转移性肺腺癌。在AIM 2A中，贝叶斯最佳间隔设计将确定 Momelotinib与Dubermatinib结合使用，目标毒性率在18例患者中为30％。在AIM 2B中，我们将对26例患者进行了前瞻性II期，单臂比较杜贝马替尼和Momelotinib的组合与历史控制。相关研究包括前后治疗配对的肺肿瘤和液体活检以确定合并治疗是否会破坏AXL-STAT3 恶性和非恶性细胞种群中的信号网络，并重新编程侵袭性肿瘤微环境。 AXL-STAT3靶向限制TMES是一种有前途的治疗策略晚期肺腺癌。该R01提案将解决有关的重要问题用AXL抑制剂和JAK抑制剂（用于STAT3信号阻滞）的组合治疗肺癌患者并将基于AXL-STAT3信号之间的细胞间串扰提供治疗分层模型进行延长的临床试验。