Targeting Tankyrases to Mitigate Immunosuppression and Enhance Cancer Immunotherapy

靶向端锚聚合酶可减轻免疫抑制并增强癌症免疫治疗

基本信息

批准号：
9808268
负责人：
Steven Hsesheng Lin
金额：
$ 20.88万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808268
关键词：
Ablation Adenocarcinoma Cell Adenosine Diphosphate Ribose Antibody Therapy Attenuated Binding Sites Cancer cell line Catalytic Domain Cell Proliferation Cell physiology Cells Cervix carcinoma Down-Regulation Drug Design Drug Screening Effectiveness Family Genetic Genetically Engineered Mouse Germ-Line Mutation Homeostasis Human Immune Immune checkpoint inhibitor Immune response Immunofluorescence Immunologic Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Infiltration Link Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Metabolic Mitosis Modeling Monoclonal Antibodies Mus Mutate Mutation Neoplasm Metastasis PTEN gene Pathogenesis Pathway interactions Patients Peutz-Jeghers Syndrome Phenotype Play Poly(ADP-ribose) Polymerases Post-Translational Protein Processing Process Proteins Regulation Regulatory T-Lymphocyte Research Resistance Role STK11 gene Sampling Squamous cell carcinoma System TNKS gene Tankyrase Telomerase Telomere Maintenance Testing Tumor Immunity Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-infiltrating immune cells Ubiquitination WNT Signaling Pathway anti-PD-L1 beta catenin cancer immunotherapy cancer therapy cancer type clinical translation cytokine immune checkpoint blockade immunoregulation improved in vivo inhibitor/antagonist insight lung Carcinoma member multicatalytic endopeptidase complex mutant neutrophil novel novel therapeutic intervention novel therapeutics outcome forecast overexpression preclinical study prognostic response tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Liver kinase B1 (LKB1) is a key regulator of cellular energy homeostasis and well known tumor suppressor gene in many cancers, particularly lung cancer, where it is deleted in ~30 percent of tumors. LKB1 suppression or depletion leads to enhanced tumorigenesis, increased immunosuppression, and reduced response to immune checkpoint inhibitors. Despite the importance of LKB1 negative regulation on tumor growth and aggressiveness, there is no known upstream regulator of LKB1. Through a rationally designed drug screen, we identified tankyrases (TNKS; TNKS1, or PARP5A, and TNKS2, or PARP5B), as upstream negative regulators of LKB1. TNKS belong to the closely related members of the poly (ADP-ribose) polymerase (PARP) family that adds ADP-ribose moieties to target proteins using β-NAD+ as substrate, termed PARsylation. PARsylation of target proteins by TNKS typically leads to ubiquination and proteasome degradation, such as AXIN (which sequesters APC/β-catenin in Wnt signaling), PTEN, and telomerase. However, PARsylation of LKB1 does not lead to LKB1 degradation, but inhibit LKB1 activity. Overexpression of TNKS stimulates tumor cellular proliferation in vitro and enhances tumorigenesis in vivo that is LKB1-dependent. Lung tumors (both adenocarcinoma and squamous cell carcinoma) that overexpress TNKS1 in LKB1 expressing tumors portended to poorer prognosis. Given the fact that LKB1 mutant lung tumors are immune suppressed and respond poorly to immune checkpoint inhibitors, we hypothesize that TNKS potentially could be the negative regulator of LKB1 that induce immune suppression in LKB1 wild type tumors. We will test our hypothesis by: (1) determining the role of TNKS on conferring immunosuppression in the tumor microenvironment through the use of syngeneic orthotopic models and Genetically-Engineered Mouse Models (GEMMs) to better understand if TNKS levels confers immunosuppressive state in tumors; and (2) utilizing syngeneic orthotopic tumor models to evaluate the ability of TNKS expression to generate resistance to immunotherapy and determine the effectiveness of TNKS inhibition on enhancing immunotherapy response. Upon completion of this project, we will have a clearer understanding of the immunosuppressive state that is conferred by TNKS through the negative regulation of LKB1. This research will implicate TNKS as a target for clinical translation to improve current therapies in lung cancer.

项目概要肝激酶 B1 (LKB1) 是细胞能量稳态的关键调节因子，也是众所周知的肿瘤抑制因子该基因在许多癌症中存在，尤其是肺癌，约 30% 的 LKB1 抑制肿瘤中该基因被删除。或耗尽会导致肿瘤发生增强、免疫抑制增加以及对药物的反应降低尽管 LKB1 负调节对肿瘤生长和免疫检查点抑制剂很重要。攻击性，LKB1尚无已知的上游调节因子，通过合理设计的药物筛选，我们确定端锚聚合酶（TNKS；TNKS1 或 PARP5A，以及 TNKS2 或 PARP5B）为上游阴性 LKB1 的调节因子属于聚 (ADP-核糖) 聚合酶 (PARP) 的密切相关成员。使用 β-NAD+ 作为底物将 ADP-核糖部分添加到靶蛋白上的家族，称为 PARsylation。 TNKS 对靶蛋白进行 PARsylation 通常会导致泛素化和蛋白酶体降解，例如 AXIN（在 Wnt 信号传导中隔离 APC/β-连环蛋白）、PTEN 和端粒酶，但是，PARsylation。 LKB1不会导致LKB1降解，但抑制LKB1活性，TNKS的过度表达会刺激肿瘤。体外细胞增殖并增强体内 LKB1 依赖性的肿瘤发生（两者都是）。在表达 LKB1 的肿瘤中过度表达 TNKS1 的腺癌和鳞状细胞癌鉴于 LKB1 突变型肺肿瘤受到免疫抑制并且预后较差。对免疫检查点抑制剂反应不佳，我们勇敢地说 TNKS 可能是负面的在 LKB1 野生型肿瘤中诱导免疫抑制的 LKB1 调节因子我们将通过以下方式检验我们的假设： (1)通过以下方法确定TNKS在肿瘤微环境中赋予免疫抑制的作用使用同源原位模型和基因工程小鼠模型 (GEMM) 更好地理解如果 TNKS 水平赋予肿瘤免疫抑制状态；以及 (2) 利用同基因原位肿瘤模型评估 TNKS 表达产生免疫治疗耐药性的能力并确定 TNKS 抑制对增强免疫治疗反应的有效性。将更清楚地了解 TNKS 通过 LKB1 的负调控将意味着 TNKS 作为临床转化的目标来改善。目前肺癌的治疗方法。