A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma

PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型

• 批准号: 10413236
• 负责人: Alan P. Fields
• 金额: $ 35.08万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413236
• 关键词: 3q26; Alleles; Auranofin; Biochemical; Biogenesis; Bioinformatics; Biological Markers; Biology; Cancer Etiology; Cell Line; Cells; Cessation of life; Characteristics; Chromosomes; Clinical; Combined Modality Therapy; Data; Development; Diagnosis; Drug Combinations; Enterobacteria phage P1 Cre recombinase; Erinaceidae; Event; Exhibits; Genes; Genetic; Genetic Engineering; Genetic Recombination; Genetic Transcription; Genetically Engineered Mouse; Genomics; Growth; Histologic; Human; In Vitro; Keratin; Knock-in; Knowledge; Lesion; Lung; Lung Adenocarcinoma; Lung Neoplasms; MEKs; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Morphology; Mus; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Prognosis; Proteins; Recurrence; Resources; Ribosomal DNA; Ribosomal RNA; Ribosomes; Signal Transduction; Specific qualifier value; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; TP53 gene; Testing; Therapeutic; Transgenes; United States; World Health Organization; base; cancer diagnosis; cell growth; cell transformation; clinically relevant; conditional knockout; design; druggable target; early detection biomarkers; efficacy evaluation; improved; improved outcome; in vivo; inhibitor; lung lesion; mouse model; neoplastic cell; new therapeutic target; notch protein; novel; novel drug combination; novel therapeutic intervention; novel therapeutics; overexpression; pharmacodynamic biomarker; pre-clinical; predictive marker; premalignant; programs; promoter; recombinant adenovirus; response; self-renewal; small molecule inhibitor; stem cells; treatment response; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

Project Abstract Lung cancer is the number one cause of cancer death in the United States. Non-small cell lung cancer (NSCLC), which accounts for the majority (80%) of lung cancer diagnoses, is divided into two major sub-types, lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LUSC). New therapeutic strategies targeting major oncogenic drivers of LADC have led to improved response rates and patient survival. However, due to a lack of well-characterized, validated, and therapeutically-actionable oncogenic drivers, similar therapeutic advances for LUSC have not been forthcoming. Genomic analysis of primary human LUSC reveals that the most prevalent recurrent genetic alterations in LUSC are concurrent loss of TP53 and copy number gains (CNGs) at chromosome 3q26 (>85-90%). These genetic alterations are observed in both precancerous lesions and early-stage LUSC, indicating they are early promotive events in LUSC tumorigenesis. Our previous studies have demonstrated that the 3q26 genes, PRKCI, SOX2 and ECT2 are coordinately co-amplified and functionally collaborate to maintain the transformed phenotype of LUSC cells. PKCι, the protein product for PRKCI, directly phosphorylates and regulates the oncogenic function of SOX2 and ECT2 in LUSC cells. Furthermore, our preliminary data demonstrate that: 1) overexpression of SOX2, PRKCI and ECT2, in the context of Trp53 loss, is sufficient to transform mouse lung basal stem cells (LBSCs), a major cell of origin for LUSC, and drive formation of tumors with malignant LUSC characteristics; 2) PKCι-SOX2 signaling activates a master transcriptional program specifying lineage-restricted lung squamous transformation; 3) PKCι-ECT2 signaling functions to increase the proliferative potential of LUSC cells through control of MEK-ERK signaling and enhanced ribosome biogenesis; and 4) both human LUSC cell lines with 3q26 CNGs and SOX2, PRKCI and ECT2 transformed LBSCs are sensitive to the growth inhibitory effects of Auranofin (ANF), a potent PKCι inhibitor, and to small molecule inhibitors of oncogenic PKCι-SOX2 and PKCι-ECT2 driven effector pathways including Hedgehog, WNT, NOTCH, MEK-ERK and rRNA synthesis. Based on these data we hypothesize that: 1) PRKCI, SOX2 and ECT2 represent cooperative multigenic drivers of LUSC tumorigenesis; and 2) combined treatment with ANF and inhibitors of PKCι-SOX2 and PKCι-ECT2 effector pathways will synergistically inhibit transformed growth of LUSC tumors. These hypotheses will be tested through completion of two interrelated specific aims designed to: 1) evaluate the efficacy of novel drug combinations that target oncogenic PKCι effector pathways; and 2) characterize a novel genetically- tractable mouse model for PRKCI-driven LUSC. Successful completion of these studies will facilitate the design of novel therapeutic strategies to improve outcomes for patients with LUSC. Furthermore, our novel clinically-relevant genetically-engineered LUSC mouse model will enhance our understanding of LUSC biology, characterize LUSC initiation and progression from preneoplastic lesions to malignant LUSC, identify markers for early LUSC diagnosis and develop and test novel targeted therapies for improved treatment of LUSC.

项目摘要 肺癌是美国癌症死亡的头号原因。非小细胞肺癌 非小细胞肺癌(NSCLC)占肺癌诊断的大部分(80%)，分为两大亚型， 肺腺癌(LADC)和肺鳞癌(LUSC)。新的靶向治疗策略 LADC的主要致癌驱动因素导致了应答率和患者存活率的提高。然而，由于 缺乏具有良好特征、经过验证和可用于治疗的致癌驱动因素，类似的治疗方法 LUSC的进展还没有到来。原代人LUSC基因组分析显示 LUSC中最常见的反复遗传改变是TP53的同时丢失和拷贝数增加 (CNGs)位于染色体3q26(&gt；85-90%)。这些基因改变在两种癌前病变中都能观察到。 和早期LUSC，表明它们是LUSC肿瘤发生的早期促进事件。我们之前的研究 已经证明3q26基因、PRKCI、SOX2和ECT2是协同共扩增的，并且 功能协作以维持LUSC的转化表型。PKCι，蛋白产品 PRKCI，直接磷酸化并调节SOX2和ECT2在LUSC细胞中的致癌功能。 此外，我们的初步数据表明：1)SOX2、PRKCI和ECT2在肺癌组织中过表达。 Trp53缺失的背景下，足以转化小鼠肺基本干细胞(LBSCs)，LBSCs是 2)PKCι-SOX2信号通路激活一种 指定谱系限制性肺鳞状细胞转化的主转录程序；3)蛋白激酶Cι-ect2 通过调控MEK-ERK信号增强LUSC增殖潜能的信号功能 和增强的核糖体生物发生；4)3q26 CNGs和SOX2，PRKCI的人LUSC细胞系 ECT2转化的LBSCs对金诺芬(ANF)的生长抑制作用敏感 PKCι抑制剂，以及致癌的PKCι-SOX2和PKCι-ECT2驱动效应的小分子抑制剂 途径包括Hedgehog、WNT、Noch、MEK-ERK和rRNA合成。基于这些数据，我们 假设：1)PRKCI、SOX2和ECT2代表LUSC的协同多基因驱动因素 肿瘤发生；2)心钠素与PKCι-SOX2和PKCι-ECT2抑制剂联合治疗 效应通路将协同抑制LUSC肿瘤的转化生长。这些假设将 通过完成两个相互关联的特定目标进行测试，这些目标旨在：1)评估小说的效果 针对致癌的PKCι效应通路的药物组合；以及2)表征一种新的遗传学- PRKCI驱动的LUSC的易驯服的小鼠模型。成功完成这些研究将有助于 设计新的治疗策略以改善LUSC患者的预后。此外，我们的小说 临床相关的基因工程LUSC小鼠模型将增强我们对LUSC生物学的理解， 描述LUSC从癌前病变到恶性LUSC的发生和发展，确定标志物 用于LUSC的早期诊断，并开发和测试新的靶向疗法以改进LUSC的治疗。