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

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.