Renalase inhibition for treatment of unresectable melanoma

肾酶抑制治疗不可切除的黑色素瘤

基本信息

批准号：
9319928
负责人：
Gary V. Desir
金额：
$ 49.03万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319928
关键词：
Affect Animal Model Antibodies Automobile Driving BRAF gene CD4/CD8 ratio procedure CD8-Positive T-Lymphocytes CD86 gene CD8B1 gene CTLA4 gene Cell Death Cell Survival Cells Cessation of life Clinic Clinical Clinical Trials Combined Modality Therapy Congenic Mice Coupled Cytotoxic T-Lymphocyte-Associated Protein 4 Cytotoxic T-Lymphocytes Death Rate Disease Drug Targeting Drug resistance Flavoproteins Future Genetic Growth Human Immune Immune checkpoint inhibitor Immunooncology Immunotherapy In Vitro Incidence Injury Innate Immune Response Ischemia Knockout Mice Lead MAP Kinase Gene Malignant Neoplasms Measures Melanoma Cell Metastatic Melanoma Methods Modeling Monoclonal Antibodies Mus Mutation Myeloid Cells Nature PI3K/AKT Pathway interactions Patients Peptides Pharmaceutical Preparations Play Primary Neoplasm Production Publishing Regulatory T-Lymphocyte Resistance Resources Role STAT3 gene Signal Pathway Signal Transduction Small Interfering RNA Specimen Systemic Therapy T-Lymphocyte Testing Translating Tumor Burden Unresectable Vertebral column Work Xenograft procedure adaptive immune response cancer therapy cell killing clinically relevant cohort cytokine cytotoxic functional status improved in vivo inhibitor/antagonist knock-down macrophage melanoma mortality mouse model neoplastic cell novel novel therapeutics translational scientist tumor tumor growth tumor progression

项目摘要

Recent advances in treating metastatic melanoma, particularly with immune checkpoint inhibitors, have resulted in improved overall survival. Despite this, the mortality from melanoma continues to rise due to the increased incidence and to primary and acquired resistance to immunotherapy. In previous studies we showed that the secreted flavoprotein Renalase (RNLS) is upregulated in melanoma cells and high expression in human tumors is associated with tumor progression and decreased survival. Knock-down of RNLS by RNLS antibodies and an inhibitory peptide in murine models inhibited tumor growth, decreased signaling through the MAPK and PI3K pathways in tumor cells, and caused a marked reduction in CD163+ Tumor Associated Macrophages (TAMs). Furthermore, we showed that increased RNLS production by CD163+ TAMs facilitates melanoma growth by activating STAT3, suggesting that inhibition of RNLS might be a useful approach for treating melanoma by direct tumor cell targeting and by inhibition of CD163+ TAMs. The latter mechanism is particularly interesting as CD163+ TAMs are known to facilitate resistance to tumor cell kill by effector T cells. We propose to test the hypothesis that dysregulated RNLS expression and signaling in melanomas modulates tumor growth and spread and will further study the mechanism thereof. Furthermore, we surmise that RNLS in tumor cells and TAMs modulates both the innate and adaptive immune response to promote cancer growth and spread. Therefore, co-inhibition of RNLS and PD-1 or CTLA4 in CD8+ T cells could result in enhanced anti-tumor activity compared to either approach alone. We will capitalize on unique resources available to our team that include novel animal models, availability of a novel RNLS inhibitor, and access to melanoma specimens from patients treated with immune checkpoint inhibitors, and the studies will be conducted by an interdisciplinary team of basic, clinical and translational researchers. We propose three inter-related but not inter-dependent aims. In Aim 1 we will determine the mechanism by which RNLS inhibition affects signaling pathways within melanoma cells and the mechanism by which RNLS modulates the innate and adaptive immune response to melanoma in vitro and in vivo. In Aim 2 we will fully characterize expression of RNLS in tumor cells characterized for BRAF and NRAS mutations, TAMs (CD163+ or CD86+), CD4 and CD8+ cells in large cohorts of metastatic melanoma tumors, including tumors from patients treated with immune checkpoint inhibitors. In Aim 3 we will test the hypothesis that combination therapy with anti-RNLS antibodies and anti-CTLA4 or anti-PD-1 are synergistic in immune competent murine melanoma models with genetic aberrations relevant to human tumors (mutations in BRaf or NRas). The potential impact of these studies is high – we are developing a RNLS inhibitor for clinical use. If successful, these studies will lead to future clinical trials of the combination anti-RNLS with an immune checkpoint inhibitor. This approach can be studied in other diseases as well and can thus have far-reaching implications for cancer therapy.

治疗转移性黑色素瘤的最新进展，特别是使用免疫检查点抑制剂，已改善了总体生存率，但由于发病率增加以及对免疫治疗的原发性和获得性耐药性，黑色素瘤的死亡率持续上升。分泌性黄素蛋白肾酶 (RNLS) 在黑色素瘤细胞中上调，在人类肿瘤中高表达与肿瘤进展和小鼠中 RNLS 抗体和抑制肽的敲低 RNLS 相关。模型抑制肿瘤生长，减少肿瘤细胞中 MAPK 和 PI3K 通路的信号传导，并导致 CD163+ 肿瘤相关巨噬细胞 (TAM) 显着减少。此外，我们发现 CD163+ TAM 产生的 RNLS 增加通过激活 STAT3 促进黑色素瘤生长。 RNLS 的抑制可能是通过直接肿瘤细胞靶向和 CD163+ TAM 的抑制来治疗黑色素瘤的有用方法。后者的机制是。特别有趣的是，已知 CD163+ TAM 可以促进效应 T 细胞对肿瘤细胞杀伤的抵抗力，我们建议测试黑色素瘤中 RNLS 表达和信号传导失调调节肿瘤生长和扩散的假设，并将进一步研究其机制。肿瘤细胞和 TAM 中的 RNLS 调节先天性和适应性免疫反应，以促进癌症生长和扩散，因此，RNLS 和 PD-1 或 CTLA4 共同抑制。与单独使用任何一种方法相比，CD8+ T 细胞可以增强抗肿瘤活性，我们将利用我们团队可用的独特资源，包括新型动物模型、新型 RNLS 抑制剂的可用性以及获得免疫治疗患者的黑色素瘤标本。检查点抑制剂，研究将由基础、临床和转化研究人员组成的跨学科团队进行。在目标 1 中，我们将确定 RNLS 影响抑制信号通路的机制。黑色素瘤细胞以及 RNLS 在体外和体内调节对黑色素瘤的先天性和适应性免疫反应的机制在目标 2 中，我们将全面表征 RNLS 在以 BRAF 和 NRAS 突变、TAM（CD163+ 或 CD86+）为特征的肿瘤细胞中的表达。大量转移性黑色素瘤中的 CD4 和 CD8+ 细胞，包括接受免疫检查点抑制剂治疗的患者的肿瘤。在目标 3 中，我们将检验以下假设：抗 RNLS 抗体和抗 CTLA4 或抗 PD-1 的联合治疗在具有与人类肿瘤相关的遗传畸变（BRaf 或 NRas 突变）的免疫活性小鼠黑色素瘤模型中具有协同作用。这些研究的潜在影响很大——我们。正在开发一种用于临床的 RNLS 抑制剂，如果成功，这些研究将导致未来抗 RNLS 与免疫检查点抑制剂联合的临床试验，这种方法也可以在其他疾病中进行研究，因此可以用于其他疾病。对癌症治疗具有深远影响。