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）： 抽象问题：大多数（如果不是全部）癌症取决于新血管（血管生成）的生长和进展。靶向血管生成的治疗干预策略开始显示出希望，但不幸的是，该疾病最终进展，因为肿瘤细胞找到了绕过阻塞途径的方法（例如，通过增加替代性亲血管生成因子的分泌而增加）。一种同时针对多个促血管生成信号的治疗方法将带来巨大的优势。 初步数据：血管生成中STAT（信号传感器和激活剂）蛋白的特定功能目前尚不清楚。我们实验室的初步数据表明，在脑内皮细胞中，FGF2，FGF8和VEGF激活了STAT5和STAT1，但不能激活STAT3。使用组成型活性和主导的负STAT5突变体，我们确定STAT5特异性介导FGF诱导的内皮细胞迁移，侵袭和管形成，而不是有丝分裂发生。 假设：统计数据介导了几个有效介体下游的关键血管生成事件。作为多个信号通路的集成点，统计数据代表了机会的抗血管生成目标。 研究设计：该假设将通过追求以下特定目的来检验：目标1：将统计数据描述为促血管生成因素的介体。我们将根据FGF2和VEGF响应微血管内皮细胞中的统计激活模式。将分析数据在血管生成反应中的特定参与。将详细阐述Stat在FGF受体下游信号传导中的作用。 目标2：确定统计在体内的作用，并评估其作为治疗靶标的效用。 STAT5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方法来完成动物统计数据的内皮细胞特异性消融。用小分子在体内抑制的统计抑制作用将为新的治疗干预策略提供原则上的支持。 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。 对退伍军人的医疗保健的潜在影响：癌症死亡的年数最近超过了心血管疾病的死亡人数。这个令人不安的统计事实强调了癌症威胁的大小。退伍军人的高级平均年龄使这个人口群体偏爱多种恶性肿瘤。在多种肿瘤类型中靶向肿瘤血管生成的新型治疗策略和抗抗性发展的机制是非常需要的。这是旨在理解研究不足的分子的重要工作，并有可能为退伍军人人口带来高收益。 公共卫生相关性： 癌症的相关性陈述死亡最近超过了心脏病和中风的死亡。癌症的发病率随着年龄的增长而增加，因此，癌症代表了整个美国人口，尤其是退伍军人的主要健康问题。在脑肿瘤和肺癌的情况下，这种对健康和生命的威胁尤其明显，这是该提案的重点。脑肿瘤不是很常见，但它们被计算为人类最致命的癌症。肺癌既常见又致死。我们迫切需要对这些和其他癌症类型的更有效的治疗方法。 癌性肿瘤取决于形成新血管（血管生成）以进行生长和进展。癌细胞分泌从周围组织募集血管的因素。因此，靶向血管生长可能是一种有效的癌症治疗方法，这似乎是合理的。最近的临床试验表明，旨在抑制诱导血管的因子减慢肿瘤生长并延长生存率的药物。不幸的是，肿瘤最终会恢复其不断的生长并杀死患者。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素 - 有效地绕过治疗块。如果可以找到一种同时阻止几种血管刺激途径的方法，则可以防止耐药性发展，并且可以实现癌症治疗的突破。不幸的是，目前尚不清楚肿瘤血管中的普遍药物靶标。 我们的研究表明，统计蛋白可能是这样的靶标。我们发现，统计数据是通过几个关键血管诱导因素激活的。在实验室中，阻止统计数据破坏了血管形成。我们建议详细研究统计数据，以了解其功能，并探索其作为治疗目标的实用性。作为该项目的一部分，我们将测试最近可用的统计数据抑制剂。如果有效，则可以使用Stat抑制剂来治疗大脑和肺部肿瘤，还可以治疗各种癌症，改善美国退伍军人的生活。