Identification of a novel targetable cancer stem cell regulator promoting cancer progression and metastasis in non-small cell lung cancer

鉴定一种新型靶向癌症干细胞调节剂，促进非小细胞肺癌的癌症进展和转移

基本信息

批准号：
10907315
负责人：
Hui-Kuan Lin
金额：
$ 40.09万
依托单位：
DUKE UNIVERSITY
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：
2023-02-09 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10907315
关键词：
Accounting Attenuated CD47 gene CRISPR/Cas technology Cancer Patient Cancer cell line Cell membrane Cells Clinical Data Drug resistance Endowment Epidermal Growth Factor Receptor Genetic Goals Immune Immune Evasion Immune signaling Immunity Immunotherapy Impairment Integral Membrane Protein Knock-in Mouse Knowledge LATS1 gene Ligands Light Lung Adenocarcinoma Macrophage Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Organoids PD-1/PD-L1 Patients Phagocytosis Phagocytosis Induction Phosphotransferases Platinum Population Process Prognosis Property Protein Family Protein Phosphatase 2A Regulatory Subunit PR53 Regulation Reporting Resistance Role Sampling Signal Transduction Survival Rate Technology Testing Thrombospondin 1 Tumor Escape Tumor Stem Cells Xenograft procedure anti-PD-1 cancer cell cancer initiation cancer stem cell cancer therapy chemotherapy cytokine empowerment humanized mouse immune checkpoint blockers immunoregulation innovation insight lung cancer cell mouse genetics mouse model neoplastic cell novel overexpression patient derived xenograft model pharmacologic recruit resistance mechanism response standard of care stem cell function stem cell population survival outcome targeted treatment therapeutically effective therapy resistant transcriptomics transmission process tumor tumor progression tumorigenesis

项目摘要

Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer. The 5- year survival rate is about 14% for stage IIIA NSCLC, while it is about 5% for stage IIIB. However, once NSCLC has reached to the stage IV and metastasized to different places, it is very difficult to treat. The 5- year survival rate for stage IV NSCLC is just about 1%. Targeted therapy such as anti-EGFR or anti-ALK is the frontline treatment for advanced NSCLC with EGFR or ALK mutations, while platinum-based chemotherapy is the first line treatment for advanced NSCLC without targetable mutations. Interestingly, recent studies suggest that anti-PD1/PDL1 immunotherapy is a new and effective strategy for advanced NSCLC. While NSCLC patients initially show great benefit from these treatments, the response is only transient with relatively short duration likely due to acquiring resistant mechanisms. Identification of novel and effective therapeutic strategies is therefore an urgent need for advanced NSCLC with metastasis. A small cell population with CSC properties contributes to cancer initiation, progression and metastasis as well as drug resistance in various cancers such as NSCLC, but an effective strategy to eliminate CSCs is currently lacking, representing an unmet clinical need for CSC and NSCLC targeting. While CSCs possess immune escape properties, it is unclear how non-CSC cancer cells accounting for the majority of total cancer cell populations could also resist from immune cell attack. The goal of this study is to characterize a novel and unique CSC population in NSCLC and its regulatory mechanisms that can be harnessed for developing a novel effective strategy for advanced NSCLC and/or for overcoming the resistance to current standard of care. Our study identifies a novel druggable regulator localized in cell membrane for maintaining CSCs, cancer progression and metastasis of NSCLCs and its overexpression predicts poor survival outcome NSCLC patients. Genetically or pharmacologically targeting this newly identified regulator attenuates oncogenic signal for maintain CSC properties and immune escape leading to cancer progression and metastasis of NSCLC. We hypothesized that a unique cell population with CSC properties existed in cancer can transmit an oncogenic and immune escape signal to non-CSC cancer cells, thereby endowing bulk cancer cells with immune escape properties. We proposed three specific aims, which are highly supported by our innovative preliminary results, to further characterize the roles and underlying mechanisms of this novel regulator and its ligand as well as their targeting in regulating CSCs, progression and metastasis of NSCLC. Our proposal is highly original and significant, as we have proposed a breakthrough concept, identified a novel checkpoint blocker with CSC and immune escape properties and utilized cutting technologies including unbiased transcriptomics, Cas9/CRISPR editing, patient-derived organoids, patient derived xenograft (PDX) models, and humanized mice and genetic knockin mouse models with intact immunity to validate our provocative hypothesis and concept. Our study has revolutionized and significantly advanced our understanding of CSC and cancer-immune regulation, but also offers a new paradigm and strategy for targeting advanced NSCLC.

非小细胞肺癌（NSCLC）约占所有肺癌的85％。这 5- 年生存率大约 IIIIA阶段NSCLC的14％，而这是 IIIB期5％。但是，一次 NSCLC已经到达IV阶段并转移到不同的地方，很难治疗。这 5- 第四阶段的年生存率 NSCLC是大约1％。诸如抗EGFR或抗Antal的靶向疗法是晚期NSCLC的一线治疗使用EGFR或ALK突变，而基于铂的化学疗法是晚期治疗 NSCLC无目标突变。有趣的是，最近的研究表明抗PD1/PDL1免疫疗法是高级NSCLC的新策略。而NSCLC患者最初从中显示出很大的好处治疗，响应仅是瞬时的瞬态，可能是由于获得抗性而引起的机制。因此，识别新颖有效的治疗策略是迫切需要先进的 NSCLC具有转移。具有CSC特性的小细胞种群有助于癌症的启动，进展 NSCLC等各种癌症中的转移以及耐药性，但有效的策略是消除目前缺乏CSC，代表了对CSC和NSCLC靶向的未满足的临床需求。而CSC拥有免疫逃生特性，尚不清楚非CSC癌细胞如何考虑总癌细胞的大多数种群还可以抵抗免疫细胞攻击。这项研究的目的是表征一个新颖而独特的 NSCLC中的CSC人群及其监管机制可以利用，以开发新的有效高级NSCLC和/或克服当前护理标准的阻力的策略。我们的研究鉴定出一种在细胞膜中定位于维持CSC，癌症进展和 NSCLC及其过表达的转移预测，NSCLC患者的存活率差。遗传或在药理上针对这种新确定的调节剂减弱致癌信号以维持CSC 特性和免疫逃逸导致NSCLC的癌症进展和转移。我们假设一个癌症中存在具有CSC特性的独特细胞种群可以传播致癌和免疫逃生向非CSC癌细胞发出信号，从而赋予具有免疫逃生特性的大量癌细胞。我们提出了我们的创新初步结果支持了三个具体目标，这些目标是进一步的特征这种新型调节器及其配体的角色和基本机制以及对调节的靶向 NSCLC的CSC，进展和转移。正如我们提出的那样，我们的建议是高度原始和重要的一个突破性概念，确定了具有CSC和免疫逃生特性的新型检查点阻滞剂，利用切割技术，包括无偏的转录组学，CAS9/CRISPR编辑，患者衍生的器官，患者衍生的异种移植（PDX）模型以及人源化的小鼠和遗传敲击素小鼠模型具有完整的免疫力来验证我们的挑衅性假设和概念。我们的研究彻底改变了显着提高了我们对CSC和癌症免疫调节的理解，但也提供了新的范式和针对高级NSCLC的策略。