STATs as Key Targets in Tumor Angiogenesis

STATs 作为肿瘤血管生成的关键靶点

• 批准号: 8258194
• 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/8258194
• 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; public health relevance; 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)： 问题摘要：大多数(如果不是全部)癌症依赖于新血管的形成(血管生成)来生长和发展。针对血管生成的治疗干预策略开始显示出希望，但不幸的是，疾病最终会发展，因为肿瘤细胞找到了绕过被阻断的途径的方法(例如，通过增加另一种促血管生成因子的分泌)。同时针对多个促血管生成信号的治疗方法将提供巨大的优势。初步数据：STAT(信号转导和激活物)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，FGF2、FGF8和VEGF激活STAT5和STAT1，但不激活STAT3。利用结构性活性和显性阴性的STAT5突变体，我们确定STAT5特异性地介导成纤维细胞生长因子诱导的内皮细胞迁移、侵袭和管状形成，但不参与有丝分裂。假设：STATs在几个有效的介体下游调节关键的血管生成事件。STATs作为多条信号通路的结合点，代表着机会的抗血管生成靶点。研究设计：这一假说将通过追求以下特定目标来检验：目标1：将统计数据表征为促血管生成因子的介体。我们将确定微血管内皮细胞对FGF2和血管内皮生长因子的反应中STAT的激活模式。将分析STATS在血管生成反应中的具体参与。将详细剖析STATS在成纤维细胞生长因子受体下游信号转导中的作用。目的2：确定STATS在体内的作用并评价其作为治疗靶点的作用。STAT5在血管生成中的作用将通过遗传学方法在体内确定。在动物中，内皮细胞特异性的STAT的消融将使用CRE-LOX方法来完成。在体内用小分子抑制STAT将为新的治疗干预策略提供原则证明支持。STAT激活在人类疾病中的作用将通过分析人类肿瘤样本来确定。对退伍军人医疗保健的潜在影响：最近，每年死于癌症的人数已经超过了死于心血管疾病的人数。这一令人不安的统计事实突显了癌症威胁的严重性。退伍军人的平均年龄较高，这使这一群体容易患上多种恶性肿瘤。以多种肿瘤类型的肿瘤血管生成为靶点并绕过耐药发展机制的新的治疗策略将是非常理想的。这是一项重要的工作，旨在了解一个研究不足的分子，具有为退伍军人群体带来高回报的潜力。 公共卫生相关性： 相关声明最近，死于癌症的人数已经超过了心脏病和中风。癌症发病率随着年龄的增长而增加，因此，癌症是整个美国人口，特别是退伍军人的一个主要健康问题。这种对健康和生命的威胁在脑瘤和肺癌的情况下尤为明显，这是这项提案的重点。脑瘤并不常见，但它们被认为是人类最致命的癌症之一。肺癌既常见又致命。我们迫切需要对这些和其他类型的癌症进行更有效的治疗。肿瘤的生长和发展依赖于新血管的形成(血管生成)。癌细胞分泌因子，从周围组织中招募血管。因此，以血管生长为靶点似乎是一种有效的癌症治疗方法。最近的临床试验表明，设计用来抑制血管诱导因子的药物可以减缓肿瘤生长，延长生存期。不幸的是，肿瘤最终会恢复其无情的生长，并杀死患者。实验室证据表明，肿瘤在治疗过程中会适应，并分泌替代的血管刺激因子--有效地绕过了治疗障碍。如果能找到一种方法同时阻断几个血管刺激通路，可能会阻止耐药性的发展，并可能在癌症治疗方面取得突破。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蛋白可能是这样的靶标。我们发现STATS被几个关键的血管诱导因素激活。在实验室里，阻断统计数据会扰乱血管的形成。我们建议详细研究统计数据，以了解它们的功能，并探索它们作为治疗靶点的有效性。作为这个项目的一部分，我们将测试最近可用的STATS抑制剂。如果有效，STAT抑制剂不仅可以治疗脑瘤和肺癌，还可以治疗各种癌症，改善美国退伍军人的生活。