IL-1 Receptor-Associated Kinase as a Cancer Therapeutic Target

IL-1 受体相关激酶作为癌症治疗靶点

• 批准号: 9058865
• 负责人: Eduardo V Davila
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058865
• 关键词: Address; Age; Angiogenic Factor; Antibodies; Attenuated; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Clinical Trials; Cytoplasm; Cytosol; Data; Development; Endothelial Cells; Engineering; FDA approved; Fibroblasts; Gene Expression; General Population; Generations; Genes; Health; Human; IRAK1 gene; In Vitro; Incidence; Inflammatory; Interleukin-1; Interleukin-18; Kinetics; Life; Link; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Monitor; Mus; Mutate; Names; Neoplasm Metastasis; Nuclear; Nutrient; PDCD1LG1 gene; Pathway interactions; Patients; Phase; Phosphotransferases; Play; Population; Process; Production; Proteins; Reporting; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Site; Skin Cancer; Small Interfering RNA; Survival Rate; Tenascin; Testing; Therapeutic Agents; Time; Toll-like receptors; Treatment Efficacy; Variant; Veterans; Vinblastine; advanced disease; angiogenesis; cancer cell; cancer therapy; cellular engineering; chemokine; chemotherapy; cytokine; in vivo; in vivo Model; inhibitor/antagonist; insight; interest; killings; knock-down; melanoma; mouse model; neoplastic cell; neovascularization; new therapeutic target; novel; overexpression; prevent; receptor; research study; resistance gene; response; screening; small hairpin RNA; statistics; targeted delivery; therapeutic target; tissue culture; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): The incidence of melanoma has been on the rise over the last 30 years with the 5 year survival rate approaching 2% for patients with metastatic melanoma; veterans are up to 4.5 times more likely to develop melanoma than the general population. These dismal statistics are partly due to the fact that melanoma is notoriously resistant to cancer therapies. We reported that melanoma cell lines and patient samples express elevated levels of the IL-1 receptor-associated kinase-4 (IRAK-4) and IRAK-1. IRAK-4 plays a central role in Toll-like receptor, IL-1, IL-18 and IL-33 signaling. Attenuating IRAK-1,-4 signaling in melanoma cells with pharmacological inhibitors or siRNA diminished the production of various chemokines/cytokines known to promote angiogenesis and the induction of tumor-associated fibroblasts. IRAK inhibition also enhanced the effects of certain chemotherapies in vitro and in tumor-bearing mice. In contrast, the activation of IRAK-4 signaling in melanoma cells increased the production of these cytokines/chemokines and promoted chemotherapeutic resistance. Supernatant from tumor cells engineered to overexpress the IRAK-4 gene augmented endothelial cell proliferation and activated human fibroblasts, as demonstrated by increased expression of Tenascin-C and ¿-SMA. Interestingly, while IRAK-4 is known to localize in the cytosol, we observed that in melanoma IRAK-4 translocates to the nucleus and this is increased upon chemotherapy exposure. The overarching hypothesis is that IRAK-4 nuclear mobilization promotes chemoresistance and that IRAK signaling orchestrates changes in the tumor microenvironment that promotes tumor growth and metastases. The proposed studies are focused on gaining greater mechanistic insights (molecular and cellular) on how IRAK-4 signaling in tumor cells: (1) influences angiogenesis, chemoresistance and metastases, (2) changes the tumor microenvironment, and (3) can be used as a therapeutic target to enhance the efficacy of chemotherapies. Aim 1 is to gain a mechanistic understanding regarding the role that nuclear IRAK-4 plays in chemotherapy resistance and gene expression. Determining the function of nuclear IRAK-4 is novel and independent of known mechanisms of IRAK-4-mediated activation. This will be investigated using melanoma lines engineered to express IRAK-4 variants including wild type, shRNA-IRAKs, kinase dead IRAKs, and IRAK- 4 SUMO, in which SUMOylation sites have been mutated to increase cytosolic levels but prevent nuclear mobilization. Aim 2 is to determine the effect that inhibiting IRAK-4 in melanoma has on metastasis and angiogenesis. We will use an inducible model of melanoma in mice (BRAFV600PTEN mice) as well as human and mouse melanoma cells engineered to overexpress or knockdown IRAK-4 to monitor tumor neovascularization and metastases using in vivo and ex vivo models. Aim 3 is to discover the role that IRAK-4 signaling in melanoma plays in altering the tumor microenvironment to promote tumor growth. Building on preliminary data showing that IRAK-4 signaling in melanoma induces the expression of factors that support tumor associated fibroblasts, this aim will explore the cellular mechanism and investigate the previously unrecognized concept that IRAK signaling within tumor cells is critical for orchestrating the generation of a microenvironment favoring tumor growth and metastasis. Aim 4 seeks to determine the therapeutic efficacy of targeted delivery of IRAK inhibitor to tumors when combined with chemotherapies. We will use anti-PD-L1 antibodies to deliver FDA-approved chemotherapies plus IRAK-1,-4 inhibitor (currently in Phase II/III clinical trials). The results from these studies will provide a greater molecular and cellular understanding of how IRAK-4 signaling in melanoma enhances chemoresistance and metastasis and will identify new therapeutic targets to enhance chemotherapeutic responses.

描述（由申请人提供）： 在过去的30年中，黑色素瘤的事件一直在增加，转移性黑色素瘤患者的5年生存率接近2％。退伍军人发展黑色素瘤的可能性是普通人群的4.5倍。这些令人沮丧的统计数据部分是由于黑色素瘤对癌症疗法具有抵抗力。我们报告说，黑色素瘤细胞系和患者样品表达了IL-1受体相关激酶-4（IRAK-4）和IRAK-1的水平升高。 IRAK-4在Toll样受体，IL-1，IL-18和IL-33信号传导中起着核心作用。用药物抑制剂或siRNA衰减黑色素瘤细胞中的IRAK-1，-4信号传导减少了已知促进血管生成并诱导与肿瘤相关的成纤维细胞的各种趋化因子/细胞因子的产生。 IRAK抑制作用还增强了某些化学疗法在体外和肿瘤小鼠中的作用。相反，黑色素瘤细胞中IRAK-4信号的激活增加了这些细胞因子/趋化因子的产生，并促进了化学治疗抗性。从肿瘤细胞中的上清液过表达IRAK-4基因增强内皮细胞增殖并激活人成纤维细胞，如Tenascin-C和SMA的表达增加所证明的那样。有趣的是，尽管已知IRAK-4局部在细胞质中定位，但我们观察到，在黑色素瘤中，irak-4易位到核，并且在化学疗法暴露时会增加。总体假设是，IRAK-4核动员促进了化学抗性，而IRAK信号传导策划了促进肿瘤生长和转移酶的肿瘤微环境的变化。提出的研究集中在获得更大的机械见解（分子和细胞）上，以如何在肿瘤细胞中IRAK-4信号传导：（1）影响血管生成，化学抗性和转移酶，（2）可以改变肿瘤微环境，（3）用作提高化学疗法效率的治疗靶标。目的1是关于核IRAK-4在化学疗法抗性和基因表达中发挥作用的作用的机械理解。确定核IRAK-4的功能是新颖的，并且与IRAK-4介导的激活的已知机制无关。这将使用设计为表达IRAK-4变体的黑色素瘤品系进行研究，包括野生型，shrna-iraks，激酶死亡的iraks和Irak-4 Sumo，其中Sumoylation位点已突变以增加胞质水平，但可以预防核动弹。目的2是确定抑制黑色素瘤对转移和血管生成的作用。我们将使用小鼠（BRAFV600PTEN小鼠）以及设计过过表达或敲除IRAK-4的人和小鼠黑色素瘤细胞中的黑色素瘤模型，以使用体内和体内模型监测肿瘤新血管和转移。 AIM 3是发现IRAK-4信号在黑色素瘤中的作用在改变肿瘤微环境以促进肿瘤生长中的作用。在初步数据的基础上，黑色素瘤中的IRAK-4信号传导诱导了支持肿瘤相关的成纤维细胞的因素的表达，该目标将探索细胞机制，并调查先前未识别的肿瘤细胞中IRAK信号传导的概念，即在策划微观环境的产生偏爱肿瘤生长和转移的基础上至关重要。 AIM 4旨在确定与化学疗法结合使用靶向irak抑制剂到肿瘤的治疗效率。我们将使用抗PD-L1抗体进行FDA批准的化学疗法加上IRAK-1，-4抑制剂（目前正在II/III期临床试验中）。这些研究的结果将为您对黑色素瘤中的IRAK-4信号如何增强化学耐药性和转移的方式提供更大的分子和细胞理解，并将确定新的治疗靶标以增强化学疗法反应。