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- 年生存率约为 IIIA 期 NSCLC 为 14%，而该比例约为 IIIB 期为 5%。然而，有一次 NSCLC已达到IV期而且转移到异地，治疗起来非常困难。这 5- IV期的年生存率非小细胞肺癌是大约只有1%。抗EGFR或抗ALK等靶向治疗是晚期NSCLC的一线治疗 EGFR 或 ALK 突变，而铂类化疗是晚期晚期患者的一线治疗没有靶向突变的非小细胞肺癌。有趣的是，最近的研究表明抗 PD1/PDL1 免疫疗法是治疗晚期 NSCLC 的一种新的有效策略。虽然 NSCLC 患者最初表现出从这些药物中获益匪浅治疗时，反应只是短暂的，持续时间相对较短，可能是由于获得了耐药性机制。因此，迫切需要确定新颖有效的治疗策略伴有转移的非小细胞肺癌。具有 CSC 特性的小细胞群有助于癌症的发生和进展和转移以及各种癌症（例如非小细胞肺癌）的耐药性，但消除这些癌症的有效策略目前 CSC 缺乏，这表明 CSC 和 NSCLC 靶向的临床需求尚未得到满足。虽然 CSC 拥有免疫逃逸特性，目前尚不清楚非 CSC 癌细胞如何占总癌细胞的大多数人群还可以抵抗免疫细胞的攻击。本研究的目的是描述一种新颖且独特的特征 NSCLC 中的 CSC 群体及其调控机制可用于开发新的有效药物晚期非小细胞肺癌和/或克服对当前护理标准的耐药性的策略。我们的研究鉴定出一种位于细胞膜上的新型可药物调节剂，用于维持 CSC、癌症进展和 NSCLC 的转移及其过度表达预示着 NSCLC 患者的生存结果较差。遗传或药理学上针对这一新发现的调节剂可减弱致癌信号以维持 CSC 特性和免疫逃逸导致非小细胞肺癌的癌症进展和转移。我们假设一个癌症中存在的具有 CSC 特性的独特细胞群可以传递致癌和免疫逃逸向非 CSC 癌细胞发出信号，从而赋予大量癌细胞免疫逃逸特性。我们提议三个具体目标得到了我们创新性初步结果的大力支持，以进一步表征这种新型调节剂及其配体的作用和潜在机制以及它们在调节中的靶向 CSC、NSCLC 的进展和转移。正如我们所提议的那样，我们的提案具有高度原创性和重要意义一个突破性的概念，确定了一种具有 CSC 和免疫逃逸特性的新型检查点阻断剂，利用切割技术，包括无偏转录组学、Cas9/CRISPR 编辑、源自患者的类器官、患者来源的异种移植 (PDX) 模型以及人源化小鼠和基因敲入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增进了我们对 CSC 和癌症免疫调节的理解，同时也提供了一个新的范例以及针对晚期 NSCLC 的策略。