Identifying Mechanisms of Sox2-Driven Squamous Cell Lung Cancer

识别 Sox2 驱动的鳞状细胞肺癌的机制

基本信息

批准号：
8751653
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
项目类别：
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/8751653
关键词：
Accounting Automobile Driving Basal Cell Biological Biological Markers Biological Models Cancer Etiology Cancer Patient Carcinogens Cells Cessation of life Colon Carcinoma Combination Drug Therapy Critical Pathways DNA Data Development Disease Early identification FGFR2 gene Fibroblast Growth Factor Receptors Gene Expression Profile Gene Mutation Gene Targeting Genes Genetic Genetic Transcription Genomics Goals Growth 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 Pathway Gene 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 FRAP1 protein human disease improved in vivo in vivo Model inhibitor/antagonist innovation kinase inhibitor malignant breast neoplasm mouse model new therapeutic target next generation sequencing novel overexpression pre-clinical promoter public health relevance small molecule therapeutic target tool transcription factor treatment strategy tumor tumor initiation tumor progression tumorigenesis

项目摘要

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，仅在美国每年就导致超过 40,000 人死亡。 SCC 的生存率为 15%，与肺癌的其他主要亚型不同，目前尚无批准的 SCC 靶向治疗方法。最近，癌症基因组图谱对 178 个人类鳞状细胞癌进行了测序，并确定了许多可能作为有价值的治疗靶点的基因改变。由于鳞状细胞癌与吸烟高度相关，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“驱动者”和“乘客”突变。显然，鳞状细胞癌治疗的一个主要未满足需求是确定新的治疗靶点和治疗策略。转录因子 Sox2 是 SCC 中最常见改变的基因之一，在人类 SCC 中扩增率为 23%，并且在 60-90% 中过度表达。然而，Sox2在肺鳞状细胞癌中的功能和关键靶基因尚不清楚。此外，目前还没有抑制该转录因子的靶向疗法。我们最近开发了一种由 Sox2 表达驱动的新型鳞状细胞癌小鼠模型，该模型在组织病理学、生物标志物表达和通路激活水平上与人类疾病高度相似。该模型将成为识别新治疗靶点和生物标志物、阐明肿瘤进展机制、识别起源细胞以及测试鳞状细胞癌新疗法和药物组合的有用工具。本研究的目的是利用这种新型小鼠模型和人类肺癌细胞来识别 Sox2 驱动的鳞状细胞癌的关键途径，并阐明体内鳞状细胞癌的起源细胞。我们假设小鼠肿瘤（因为未接触致癌物）的基因改变比人类疾病少，因此可以作为生物过滤器来识别由 Sox2 驱动或与 Sox2 合作的重要途径。根据初步的体外和体内数据，我们预测 Sox2 驱动对肿瘤发生和/或维持至关重要的靶向途径。鉴于 Sox2 驱动的 SCC 表达基底细胞标记，我们预测 Sox2 要么出现在基底细胞中，要么将其他肺细胞类型转化为基底细胞身份。为了检验这些假设，我们将：1）使用下一代测序来识别小鼠和人类鳞状细胞癌之间保守的遗传变化，2）测试抑制表达 Sox2 的人类肺癌细胞中关键通路的影响，以及 3）使用我们的双顺反子具有细胞类型特异性启动子的慢病毒系统，用于确定哪种肺细胞类型作为体内 Sox2 驱动的 SCC 的起源细胞。这种方法具有创新性，因为我们将采用一种新型的鳞状细胞癌小鼠模型，该模型高度再现了人类疾病。这项研究意义重大，因为肺癌是美国癌症死亡的主要原因，而且目前还没有批准用于鳞状细胞癌的靶向疗法。更好地了解鳞状细胞癌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。