METABOLIC DRIVERS OF LUNG CANCER INITIATION, PROGRESSION AND THERAPY RESPONSE

肺癌发生、进展和治疗反应的代谢驱动因素

• 批准号: 9121521
• 负责人: Narendra Wajapeyee
• 金额: $ 21.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-06 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121521
• 关键词: Accounting; Adenocarcinoma Cell; Angiogenesis Inhibitors; Avastin; Biochemical; Biochemical Genetics; Cancer Etiology; Cell Culture Techniques; Cell Line; Cessation of life; Clinical; Drug Combinations; Drug Targeting; Epithelial Cells; Genes; Genomic approach; Growth; Health; Heparitin Sulfate; Human; KRAS2 gene; Lung; Lung Adenocarcinoma; Malignant neoplasm of lung; Mediating; Metabolic; Metabolic Pathway; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; PTEN gene; Pathway interactions; Patients; Phenotype; RNA Interference; RNA interference screen; Regulation; Role; Signal Transduction; Staging; Testing; Transforming Growth Factor beta; Tumor Suppressor Genes; United States; United States Food and Drug Administration; Up-Regulation; Woman; base; bevacizumab; cancer cell; cancer initiation; cancer therapy; cancer type; effective therapy; functional genomics; improved; in vivo; inhibitor/antagonist; knock-down; men; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; research study; response; small hairpin RNA; sulfotransferase; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Lung cancer account for ~150,000 deaths annually in the United States alone and lung adenocarcinoma (LUAD), which is a subtype of non-small cell lung cancer accounts for half of all lung cancers. Current therapies for advanced-stage lung cancer do not provide durable clinical benefit and only 1% of the stage IV LUAD patients survive more than 5 years. Therefore, improved molecular understanding of LUAD initiation and progression is essential for developing effective therapies. Metabolic deregulation due to the alterations in metabolic pathways is one of the key hallmarks of cancer cells. However, the role of metabolic alterations in LUAD has neither been comprehensively analyzed nor fully understood. Therefore, to identify metabolic drivers of LUAD, we performed a large-scale in vivo RNAi screening and identified heparan sulfate 2-O- sulfotransferase 1 (HS2ST1) as a gene necessary for LUAD growth and metastasis. The central hypothesis is that metabolic alterations are crucial regulators of LUAD initiation, progression and therapy response. The overall objective is to determine the role of HS2ST1 in LUAD initiation and progression, ascertain its mechanisms-of-action and determine its clinical utility as a drug target for LUAD therapy. Specifically, in Aim 1, we will determine the role of HS2ST1 in lung adenocarcinoma initiation and progression. Specifically, we will determine if HS2ST1 is sufficient to transform immortalized lung epithelial cells and if it is necessary for oncogenic KRAS-induced transformation. Additionally, because HS2ST1 confers invasive phenotype to LUAD cells, we will investigate if HS2ST1 is necessary for LUAD progression. To do so, we will use cell culture-based models of immortalized human lung epithelial cells, established LUAD cell lines and orthotopic mouse models of LUAD tumor growth and progression. In Aim 2, we will determine the mechanism(s) of HS2ST1 action. First, based on our results that HS2ST1 inhibition leads to increased expression of PTEN tumor suppressor gene, we will test the role of PTEN in HS2ST1 mediated LUAD initiation and progression. Additionally, because HS2ST1 can potentially regulate WNT and TGF-ß pathways, the role of these pathways in mediating the driver function of HS2ST1 will also be determined. The experiments will include biochemical, genetic, cell culture and in vivo orthotopic mouse model of LUAD-based approaches. In Aim 3, we will evaluate HS2ST1 as a drug target for lung adenocarcinoma therapy. Towards this end, we will test the effect of HS2ST1 inhibitor surfen alone or in combination with US Food and Drug Administration (FDA) approved angiogenesis inhibitor bevacizumab for its ability to inhibit LUAD tumor growth in the orthotopic mouse model of LUAD tumorigenesis. Collectively, the results of our experiments will uncover novel driver genes and pathways in LUAD initiation and progression, significantly improve the molecular understanding of LUAD and reveal new drug targets and drug combinations for effective LUAD therapies.

 描述（由申请人提供）：仅在美国，肺癌每年造成约150，000例死亡，肺腺癌（LUAD）是非小细胞肺癌的一种亚型，占所有肺癌的一半。目前晚期肺癌的治疗不能提供持久的临床获益，只有1%的IV期LUAD患者存活超过5年。因此，改善LUAD的启动和进展的分子理解是开发有效的治疗方法所必需的。由于代谢途径的改变而导致的代谢失调是癌细胞的关键标志之一。然而，代谢改变在LUAD中的作用既没有得到全面分析，也没有得到充分理解。因此，为了鉴定LUAD的代谢驱动因子，我们进行了大规模的体内RNAi筛选，并鉴定硫酸乙酰肝素2-O-磺基转移酶1（HS 2ST 1）为LUAD生长和转移所必需的基因。核心假设是代谢改变是LUAD启动、进展和治疗反应的关键调节因子。总体目标是确定HS 2ST 1在LUAD起始和进展中的作用，确定其作用机制，并确定其作为LUAD治疗药物靶点的临床效用。具体而言，在目标1中，我们将确定HS 2ST 1在肺腺癌发生和进展中的作用。具体来说，我们将确定HS 2ST 1是否足以转化永生化肺上皮细胞，以及是否是致癌KRAS诱导转化所必需的。此外，由于HS 2ST 1赋予LUAD细胞侵袭性表型，我们将研究HS 2ST 1是否是LUAD进展所必需的。为此，我们将使用基于细胞培养的永生化人肺上皮细胞模型、建立的LUAD细胞系和LUAD肿瘤生长和进展的原位小鼠模型。在目标2中，我们将确定HS 2ST 1作用的机制。首先，基于我们的结果，即HS 2ST 1抑制导致PTEN肿瘤抑制基因的表达增加，我们将测试PTEN在HS 2ST 1介导的LUAD起始和进展中的作用。此外，由于HS 2ST 1可以潜在地调节WNT和TGF-β通路，因此这些通路在介导HS 2ST 1的驱动功能中的作用也将被确定。实验将包括生化，遗传，细胞培养和体内原位小鼠模型的LUAD为基础的方法。在目标3中，我们将评估HS 2ST 1作为肺腺癌治疗的药物靶点。为此，我们将测试HS 2ST 1抑制剂surfen单独或与美国食品和药物管理局（FDA）批准的血管生成抑制剂贝伐单抗组合在LUAD肿瘤发生的原位小鼠模型中抑制LUAD肿瘤生长的能力的效果。总的来说，我们的实验结果将揭示LUAD启动和进展中的新驱动基因和途径，显着提高LUAD的分子理解，并揭示有效LUAD治疗的新药物靶点和药物组合。