STATs as Key Targets in Tumor Angiogenesis

STATs 作为肿瘤血管生成的关键靶点

• 批准号: 7682783
• 负责人: ANDREAS FRIEDL
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682783
• 关键词: Ablation; Activator Appliances; Age; Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiogenic Factor; Animals; Blood Vessels; Brain; Brain Neoplasms; Breeding; Budgets; Bypass; Cancerous; Cardiovascular Diseases; Cell Proliferation; Cell Survival; Cessation of life; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Databases; Development; Dimerization; Disease; Dominant-Negative Mutation; Drug Delivery Systems; Drug Design; Endothelial Cells; Event; Extracellular Matrix; FGF2 gene; FGF8 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genetic; Grant; Growth; Health; Healthcare; Heart Diseases; Human; Immunofluorescence Microscopy; In Vitro; Incidence; Intervention; Knock-out; Knowledge; Laboratories; Life; Lung Neoplasms; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mediator of activation protein; Pathway interactions; Patients; Pattern; Physiologic Neovascularization; Population; Population Group; Proteins; Recruitment Activity; Regulation; Reliance; Research; Resistance; Resistance development; Role; STAT protein; STAT1 gene; STAT3 gene; STAT5A gene; Sampling; Series; Signal Pathway; Signal Transduction; Stimulation of Cell Proliferation; Stroke; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transducers; Tube; Tumor Angiogenesis; Validation; Vascular Endothelial Growth Factors; Veterans; Work; abstracting; angiogenesis; cancer cell; cancer therapy; cancer type; cell motility; cell type; effective therapy; expectation; experience; human disease; improved; in vivo; inhibitor/antagonist; killings; mouse model; mutant; neoplastic cell; novel therapeutic intervention; novel therapeutics; paracrine; pre-clinical; prevent; programs; protein function; response; small molecule; success; therapeutic target; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Abstract PROBLEM: Most, if not all, cancers depend on the formation of new blood vessels (angiogenesis) for growth and progression. Therapeutic intervention strategies targeting angiogenesis are beginning to show promise, but unfortunately, the disease eventually progresses because the tumor cells find a way to bypass the blocked pathway (e.g., by increased secretion of an alternative pro-angiogenic factor). A therapeutic approach that targets multiple pro-angiogenic signals simultaneously would offer a tremendous advantage. PRELIMINARY DATA: The specific functions of STAT (signal transducers and activators) proteins in angiogenesis are currently unknown. Preliminary data from our laboratory indicate that in brain endothelial cells, FGF2, FGF8, and VEGF activate STAT5 and STAT1 but not STAT3. Using constitutively active and dominant negative STAT5 mutants, we determined that STAT5 specifically mediates FGF-induced endothelial cell migration, invasion, and tube formation but not mitogenesis. HYPOTHESIS: STATs mediate critical angiogenic events downstream of several potent mediators. As integration points of multiple signaling pathways, STATs represent anti-angiogenic targets of opportunity. STUDY DESIGN: This hypothesis will be tested by pursuing the following specific aims: Aim 1: Characterize STATs as mediators of pro-angiogenic factors. We will determine the pattern of STAT activation in microvascular endothelial cells in response to FGF2 and VEGF. The specific involvement of STATs in angiogenic responses will be analyzed. The role of STATs in downstream signaling of FGF receptors will be dissected in detail. Aim 2: Determine the role of STATs in vivo and evaluate their utility as therapeutic targets. The role of STAT5 in angiogenesis will be determined in vivo using a genetic approach. The endothelial cell-specific ablation of STATs in animals will be accomplished using the Cre-lox approach. STAT inhibition with small molecules in vivo will provide proof-of-principle support for novel therapeutic intervention strategies. The role of STAT activation in human disease will be determined by analyzing human tumor samples. POTENTIAL IMPACT ON VETERANS' HEALTH CARE: The number of annual deaths from cancer has recently surpassed the number of deaths from cardiovascular disease. This disturbing statistical fact underscores the magnitude of the cancer threat. The advanced average age of veterans predisposes this population group to a multitude of malignancies. Novel therapeutic strategies that target tumor angiogenesis in a variety of tumor types and circumvent mechanisms of resistance development would be highly desirable. This is important work aimed at understanding an understudied molecule with the potential for high payoff for the veteran population. PUBLIC HEALTH RELEVANCE: Relevance Statement Deaths from cancer have recently surpassed deaths from heart disease and stroke. Cancer incidence increases with age, and therefore, cancer represents a major health problem for the US population as a whole and especially veterans. This threat to health and life is particularly evident in the case of brain tumors and lung cancer, the focus points of this proposal. Brain tumors are not very common, but they are counted among the deadliest cancers in humans. Lung cancer is both common and lethal. We urgently need more effective treatments for these and other cancer types. Cancerous tumors depend on the formation of new blood vessels (angiogenesis) for growth and progression. Cancer cells secrete factors that recruit blood vessels from the surrounding tissue. Therefore, it appears plausible that targeting blood vessel growth could be an effective cancer treatment approach. Recent clinical trials show that drugs designed to inhibit a vessel-inducing factor slow down tumor growth and prolong survival. Unfortunately, the tumor eventually resumes its relentless growth and kills the patient. Laboratory evidence indicates that tumors adapt during treatment and secrete alternative vessel stimulating factors - effectively bypassing the therapeutic block. If one could find a way of blocking several vessel-stimulating pathways simultaneously, resistance development might be prevented, and a breakthrough in cancer therapy might be achieved. Unfortunately, universal drug targets in tumor vessels are currently unknown. Our research indicates that the STAT proteins might be such targets. We found that STATs are activated by several critical vessel-inducing factors. In the lab, blocking STATs disrupts vessel formation. We propose to study STATs in detail to understand their function and to explore their usefulness as a treatment target. As part of this project, we will test inhibitors of STATs that have recently become available. If effective, STAT inhibitors could be used to treat not only brain and lung tumors, but a variety of cancers, improving the lives of US veterans.

描述（由申请人提供）： 摘要问题：大多数，如果不是全部，癌症依赖于新血管的形成（血管生成）的生长和进展。靶向血管生成的治疗性干预策略开始显示出希望，但不幸的是，疾病最终进展，因为肿瘤细胞找到了绕过被阻断的途径的方法（例如，通过增加替代促血管生成因子的分泌）。同时靶向多个促血管生成信号的治疗方法将提供巨大的优势。 初步资料：STAT（信号转导和激活）蛋白在血管生成中的具体功能目前尚不清楚。我们实验室的初步数据表明，在脑内皮细胞中，FGF 2、FGF 8和VEGF激活STAT 5和STAT 1，但不激活STAT 3。使用组成型活性和显性负性STAT 5突变体，我们确定STAT 5特异性介导FGF诱导的内皮细胞迁移、侵袭和管形成，但不介导有丝分裂。 假设：STAT介导几种有效介质下游的关键血管生成事件。作为多种信号通路的整合点，STAT代表了抗血管生成的机会靶点。 研究设计：这一假设将通过追求以下具体目标进行测试：目标1：表征STAT作为促血管生成因子的介质。我们将确定微血管内皮细胞对FGF 2和VEGF的STAT激活模式。将分析STAT在血管生成反应中的具体参与。STAT在FGF受体下游信号传导中的作用将被详细分析。 目的2：确定STAT在体内的作用，并评估其作为治疗靶点的效用。STAT 5在血管生成中的作用将使用遗传方法在体内确定。将使用Cre-lox方法完成动物中STAT的内皮细胞特异性消融。小分子在体内的STAT抑制作用将为新的治疗干预策略提供原理验证支持。STAT激活在人类疾病中的作用将通过分析人类肿瘤样品来确定。 对兽医医疗保健的潜在影响：每年死于癌症的人数最近超过了死于心血管疾病的人数。这一令人不安的统计事实强调了癌症威胁的严重性。退伍军人的平均年龄偏高，使这一人群容易患多种恶性肿瘤。靶向多种肿瘤类型中的肿瘤血管生成并规避耐药性发展机制的新治疗策略将是非常需要的。这是一项重要的工作，旨在了解一种未充分研究的分子，这种分子具有为退伍军人提供高回报的潜力。 公共卫生相关性： 最近，癌症死亡人数超过了心脏病和中风死亡人数。癌症发病率随着年龄的增长而增加，因此，癌症是美国人口尤其是退伍军人的主要健康问题。这种对健康和生命的威胁在脑瘤和肺癌的情况下尤其明显，这是本提案的重点。脑肿瘤并不常见，但它们被认为是人类最致命的癌症之一。肺癌是一种常见且致命的疾病。我们迫切需要更有效的治疗这些和其他类型的癌症。 癌性肿瘤的生长和进展依赖于新血管的形成（血管生成）。癌细胞分泌因子，从周围组织募集血管。因此，靶向血管生长似乎是一种有效的癌症治疗方法。最近的临床试验表明，旨在抑制血管诱导因子的药物可以减缓肿瘤生长并延长生存期。不幸的是，肿瘤最终恢复其无情的增长，并杀死病人。实验室证据表明，肿瘤在治疗过程中适应并分泌替代血管刺激因子-有效地绕过治疗阻断。如果人们能找到一种方法，同时阻断几个血管刺激途径，耐药性的发展可能会被阻止，癌症治疗可能会取得突破。不幸的是，肿瘤血管中的通用药物靶点目前尚不清楚。 我们的研究表明，STAT蛋白可能是这样的目标。我们发现STAT被几个关键的血管诱导因子激活。在实验室中，阻断STAT会破坏血管形成。我们建议详细研究STAT，以了解它们的功能，并探索它们作为治疗靶点的有用性。作为该项目的一部分，我们将测试最近可用的STAT抑制剂。如果有效，STAT抑制剂不仅可以用于治疗脑肿瘤和肺癌，还可以用于治疗各种癌症，改善美国退伍军人的生活。