Renalase inhibition for treatment of unresectable melanoma

肾酶抑制治疗不可切除的黑色素瘤

• 批准号: 9902357
• 负责人: Gary V. Desir
• 金额: $ 48.19万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/9902357
• 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-Lymphocytes; Death Rate; Disease; Drug Targeting; Drug resistance; Exposure to; Flavoproteins; Future; Genetic; Growth; Human; Immune checkpoint inhibitor; Immunocompetent; Immunooncology; Immunotherapy; In Vitro; Incidence; Injury; Innate Immune Response; Ischemia; Knockout Mice; Lead; MAP Kinase Gene; MEKs; 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; Testing; Translating; Tumor Burden; Tumor-associated macrophages; Unresectable; Vertebral column; Work; Xenograft procedure; adaptive immune response; anti-CTLA4; anti-PD-1; cancer therapy; cell killing; clinically relevant; cohort; cytokine; cytotoxic; effector T cell; functional status; improved; in vivo; inhibitor/antagonist; knock-down; macrophage; melanoma; mortality; mouse model; neoplastic cell; novel; novel therapeutics; programmed cell death protein 1; translational scientist; tumor; tumor growth; tumor progression

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，尤其是免疫切除剂抑制剂，导致总体生存率提高。尽管如此，由于事件的增加以及对免疫疗法的抗药性增加，黑色素瘤的死亡率继续增加。在先前的研究中，我们表明，分泌的黄素肾酶（RNL）在黑色素瘤细胞中进行了更新，人类肿瘤中的高表达与肿瘤进展和改善的生存有关。在鼠模型中，RNLS抗体和抑制性肽对RNL的敲除抑制肿瘤的生长，通过MAPK和PI3K途径抑制了肿瘤细胞中的信号传导，并导致CD163+肿瘤相关的巨噬细胞（TAMS）显着降低。此外，我们表明，CD163+ TAMS的RNLS产生增加通过激活STAT3促进了黑色素瘤的生长，这表明抑制RNL可能是通过直接肿瘤细胞靶向和抑制CD163+ TAMS治疗黑色素瘤的有用方法。后一种机制特别有趣，因为已知CD163+ TAM促进了效应T细胞对肿瘤细胞杀死的抗性。我们建议测试黑色素瘤中RNLS表达和信号传导失调的假设调节肿瘤的生长并扩散，并将进一步研究其机制。此外，我们在肿瘤细胞和TAM中进行RNL进行冲浪，可以调节先天和适应性免疫响应以促进癌症的生长和扩散。因此，与单独的两种方法相比，CD8+ T细胞中RNL和PD-1或CTLA4的共抑制可能会增强抗肿瘤活性。我们将利用包括新型动物模型，新颖的RNL抑制剂的可用性以及从接受免疫切除点抑制剂治疗的患者获得黑色素瘤标本的独特资源，并获得了一项研究，由基本，临床，临床和翻译研究人员组成的跨学科团队。我们提出了三个相互关联但不是相互依赖的目标。在AIM 1中，我们将确定RNL抑制作用影响黑色素瘤细胞内的信号通路的机制以及RNL在体外和体内调节对黑色素瘤的先天和适应性免疫的机制。在AIM 2中，我们将充分表征针对BRAF和NRAS突变，TAM（CD163+或CD86+），CD4和CD8+细胞在大量转移性黑色素瘤TUM中的肿瘤细胞中RNL的表达，包括来自免疫障碍抑制剂的患者的大量转移性黑色素瘤TUM。在AIM 3中，我们将检验以下假设：与人类肿瘤相关的免疫胜任鼠类黑色素瘤模型（BRAF或NRAS中的突变），与抗RNLS抗体和抗CTLA4或抗PD-1的联合疗法在免疫胜任的鼠类黑色素瘤模型中是协同作用。这些研究的潜在影响很高 - 我们正在为临床使用开发RNL抑制剂。如果成功，这些研究将导致对抗RNL和免疫切除剂抑制剂组合抗RNL的未来临床试验。这种方法也可以在其他疾病中进行研究，因此对癌症治疗具有深远的影响。