Identifying Mechanisms of Sox2-Driven Squamous Cell Lung Cancer

识别 Sox2 驱动的鳞状细胞肺癌的机制

• 批准号: 9066602
• 负责人: Trudy Gale Oliver
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066602
• 关键词: Accounting; Automobile Driving; Basal Cell; Biological; Biological Markers; Biological Models; Cancer Etiology; Cancer Patient; Carcinogens; Cells; Cessation of life; Colon Carcinoma; Critical Pathways; DNA Sequence Alteration; Data; Development; Disease; Drug Combinations; Early identification; FGFR2 gene; FRAP1 gene; Fibroblast Growth Factor Receptors; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Health; Histopathology; Human; IGF2 gene; In Vitro; Lung; Lung Neoplasms; Maintenance; Malignant neoplasm of lung; Malignant neoplasm of prostate; Manuscripts; Mission; Modeling; Mus; Mutation; Neurosecretory Systems; Oncogenic; Outcome; PI3K/AKT; Pathway interactions; Patients; Preclinical Drug Evaluation; Preparation; Proteins; Public Health; Publishing; Quality of life; RNA Sequences; Recurrence; Research; STK11 gene; Signal Pathway; Signaling Protein; Smoking; Squamous Cell; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Staging; Survival Rate; System; Testing; The Cancer Genome Atlas; Tumor Suppressor Genes; United States; United States National Institutes of Health; Virus; Work; alveolar type II cell; base; cancer cell; cell type; drug testing; exome sequencing; human disease; improved; in vivo; in vivo Model; innovation; kinase inhibitor; malignant breast neoplasm; mouse model; new therapeutic target; next generation sequencing; novel; novel therapeutics; overexpression; pre-clinical; promoter; small molecule inhibitor; targeted treatment; therapeutic biomarker; therapeutic target; tool; transcription factor; treatment strategy; tumor; tumor DNA; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Squamous cell carcinoma (SCC) is the second most common subtype of lung cancer and is responsible for over 40,000 deaths each year in the United States alone. SCC has a survival rate of 15% and unlike the other major subtype of lung cancer, there are currently no approved targeted therapies for SCC. Recently, The Cancer Genome Atlas sequenced 178 human SCCs and identified numerous genetic alterations that may serve as valuable therapeutic targets. Because SCC is highly associated with smoking, the genetic mutation rate is one of the highest of all tumor types, making it difficult to distinguish "driver" from "passenger" mutations. Clearly, a major unmet need for the treatment of SCC is the identification of new therapeutic targets and treatment strategies. The transcription factor Sox2 is one of the most commonly altered genes in SCC, amplified in 23% and overexpressed in 60-90% of human SCCs. However, Sox2's function and key target genes in lung SCC are unclear. In addition, there are currently no targeted therapies that inhibit this transcription facor. We recently developed a novel mouse model of SCC driven by Sox2 expression that highly resembles the human disease at the level of histopathology, biomarker expression and pathway activation. This model will be a useful tool to identify novel therapeutic targets and biomarkers, elucidate mechanisms of tumor progression, identify the cell(s) of origin, and test novel therapies and drug combinations in SCC. The objective of this study is to use this novel mouse model and human lung cancer cells to identify pathways critical for Sox2-driven SCC and to elucidate the cell(s) of origin for SCC in vivo. We hypothesize that mouse tumors (since not exposed to carcinogen) will have fewer genetic alterations than the human disease and thereby serve as a biological filter to identify important pathways driven by or cooperating with Sox2. Based on preliminary in vitro and in vivo data, we predict that Sox2 drives targetable pathways that are critical for tumor initiation and/or maintenance. Given that Sox2-driven SCCs express markers of basal cells, we predict that Sox2 either arises in basal cells or transforms other lung cell types to a basal cell identity. To test these hypotheses, we will: 1) use next-generation sequencing to identify conserved genetic changes between mouse and human SCC, 2) test the impact of inhibiting key pathways in Sox2-expressing human lung cancer cells, and 3) use our bicistronic lentiviral system with cell type-specific promoters to determine which lung cell type functions as the cell(s) of origin for Sox2-driven SCC in vivo. This approach is innovative because we will employ a novel mouse model of SCC that highly recapitulates the human disease. This research is significant because lung cancer is the leading cause of cancer death in the United States and there are currently no targeted therapies approved for SCC. A better understanding of the critical pathways and cellular origins of SCC will impact the treatment and survival of patients with this intractable disease.

描述（由申请人提供）：鳞状细胞癌（SCC）是第二常见的肺癌亚型，仅在美国每年就有超过40,000人死亡。SCC的生存率为15%，与其他主要亚型肺癌不同，目前还没有批准的针对SCC的靶向治疗方法。最近，癌症基因组图谱对178个人类SCCs进行了测序，并确定了许多可能作为有价值的治疗靶点的遗传改变。由于SCC与吸烟高度相关，其基因突变率是所有肿瘤类型中最高的之一，因此很难区分“驱动”突变和“乘客”突变。显然，治疗SCC的一个主要未满足的需求是确定新的治疗靶点和治疗策略。转录因子Sox2是SCC中最常见的改变基因之一，23%的人SCC扩增，60-90%的人SCC过表达。然而，Sox2在肺SCC中的功能和关键靶基因尚不清楚。此外，目前还没有抑制这种转录因子的靶向治疗方法。我们最近开发了一种由Sox2表达驱动的新型SCC小鼠模型，该模型在组织病理学、生物标志物表达和途径激活水平上与人类疾病高度相似。该模型将是一个有用的工具，用于鉴定新的治疗靶点和生物标志物，阐明肿瘤进展机制，鉴定起源细胞，以及测试SCC的新疗法和药物组合。本研究的目的是利用这种新的小鼠模型和人类肺癌细胞来鉴定sox2驱动的SCC的关键途径，并阐明体内SCC的起源细胞。我们假设小鼠肿瘤（因为没有暴露于致癌物）将比人类疾病有更少的遗传改变，从而作为一个生物过滤器来识别由Sox2驱动或与Sox2合作的重要途径。基于初步的体外和体内数据，我们预测Sox2驱动对肿瘤起始和/或维持至关重要的靶向通路。鉴于Sox2驱动的SCCs表达基底细胞标志物，我们预测Sox2要么在基底细胞中出现，要么将其他肺细胞类型转化为基底细胞身份。为了验证这些假设，我们将：1)使用下一代测序来鉴定小鼠和人类SCC之间的保守遗传变化，2)测试抑制表达sox2的人肺癌细胞的关键途径的影响，以及3)使用我们的双电子慢病毒系统与细胞类型特异性启动子来确定哪种肺细胞类型作为体内sox2驱动的SCC的起源细胞。这种方法是创新的，因为我们将采用一种高度概括人类疾病的新型SCC小鼠模型。这项研究意义重大，因为肺癌是美国癌症死亡的主要原因，目前还没有批准针对SCC的靶向治疗。更好地了解SCC的关键途径和细胞起源将影响这种难治性疾病患者的治疗和生存。