Targeting PPT1 in the Tumor Microenvironment

靶向肿瘤微环境中的 PPT1

基本信息

批准号：
10705658
负责人：
RAVI K AMARAVADI
金额：
$ 48.17万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705658
关键词：
3-Dimensional Acidity Acids Address Affect Animals Antimalarials Antineoplastic Agents Autologous Autophagocytosis BRAF gene Binding Proteins Biological Assay Cell Communication Cell Death Cell-Mediated Cytolysis Cells Cellular Assay Chemicals Chloroquine Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Critiques Data Enzymes Family Fibroblasts Future Genetic study Goals Hydroxychloroquine Immunocompetent Immunotherapy In Vitro Knock-out Knowledge Length Lipids Literature Lysosomes MEKs Macrophage Malignant Neoplasms Mediating Melanoma Cell Metabolic Modeling Molecular Target Neoplasm Metastasis Normal Cell Nude Mice Nutrient Pathway interactions Patient-Focused Outcomes Patients Penetration Pharmaceutical Preparations Phenotype Post-Translational Protein Processing Primary Neoplasm Protein Inhibition Proteins Quinacrine Refractory Reporting Resistance Role Signal Transduction Solubility Stress T-Cell Activation T-Lymphocyte Testing The Cancer Genome Atlas Tumor Immunity Tumor Promotion Tumor-associated macrophages Water Xenograft procedure aged analog anti-cancer aqueous cancer cell cancer therapy cell type clinical development conditional knockout cytotoxicity dimer immunosuppressive macrophages improved in vivo in vivo evaluation inhibition of autophagy inhibitor innovation lipid transport melanoma mouse model neoplastic cell new therapeutic target next generation novel novel therapeutics overexpression palmitoylation prevent programmed cell death protein 1 resistance mechanism response targeted treatment therapy resistant thioesterase PPT1 gene product three dimensional cell culture tool translational potential tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenic

项目摘要

Project Summary – Project 2 Therapy resistance in melanoma is a major hurdle to improved survival. This project will determine if therapy resistance can be reversed by targeting the lysosomal enzyme protein palmitoyl thioesterase 1 (PPT1). Autophagy is a lysosome-dependent pathway that promotes tumor growth and resistance to therapy in melanoma. Autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but has limited activity as a single agent. Clinical trials involving HCQ in melanoma show promising activity but concerns have been raised about the potency of HCQ, and its poorly understood mechanism of action. We have prepared dimeric antimalarial compounds that are 10-1000 fold more potent in vitro and in vivo than CQ or HCQ. Dimeric quinacrines (DQs) (Rebecca Cancer Discovery 2017) and dimeric chloroquines (DCs) (Rebecca Cancer Discovery in revision) look especially promising as both tool compounds and potential clinical drugs. In the current cycle, we have found that extending the linker length of these dimeric compounds increases lysosomal localization and anti-melanoma activity. These DQs and DCs with longer linkers as well as CQ were used to pull a new lysosomal target, PPT1, which is overexpressed in cancer, especially in metastatic lesions. Efforts to target the lysosome and autophagy in cancer cells have focused on the effects within cancer cells but recent literature suggests targeting this pathway in immunosuppressive cells within the TME also contributes to antitumor activity. We will leverage innovative collaborations with Projects 1, 3 and 4 and heavy support from the P01 cores to understand the effects of PPT1 inhibition in both tumor cells, the interaction between tumor cells and fibroblasts, tumor associated macrophages and T cells. The proposal is based on extensive new preliminary data in response to the reviewers’ critiques from the September 2017 submission. We will test the hypothesis that targeting PPT1 in tumor cells and macrophages overcomes therapy resistance in melanoma through completion of 3 aims: Aim 1 will develop innovative new compounds by introducing heteroatom substitutions into the linker, and developing the first ever dimeric ferroquine derivatives that could have better penetration in the acidic TME. We will also develop a novel assay for PPT1 that is compatible with live cells and animal studies. Aim 2 will leverage collaborations within the P01 to study the role of PPT1 in blocking lipid trafficking from aged fibroblasts to melanoma cells and reversing resistance to targeted therapy. Aim 3 will study the effects of PPT1 inhibition on tumor cell interactions with T cells and macrophages in 3D culture, immunocompetent mouse models, and a new conditional KO model of Ppt1, with the goal of reversing resistance to immunotherapy. The impact of these studies will be to unravel a deeper mechanistic understanding of the consequences of lysosomal inhibition within the TME, which will support clinical development of these agents in the future. Knowledge gained will ultimately lead to improved patient outcomes.

项目摘要 - 项目2 黑色素瘤的耐药性是提高生存率的主要障碍。该项目将确定是否治疗可以通过靶向溶酶体酶蛋白棕榈酰硫酯酶1（PPT1）来逆转抗性。自噬是一种溶酶体依赖性途径，可促进肿瘤的生长和对治疗的抵抗黑色素瘤。用氯喹（CQ）衍生物增强了许多抗癌效率的自噬抑制疗法，但作为单一代理的活动有限。黑色素瘤中涉及HCQ的临床试验显示有希望的活动，但对HCQ的效力引起了人们的关注，其理解不足作用机理。我们已经制备了二聚体抗性化合物，其潜力更高10-1000倍体外和体内比CQ或HCQ。二聚体喹ac（DQS）（Rebecca Cancer Discovery 2017）和二聚体氯喹（DCS）（修订中的丽贝卡癌发现）看起来特别有前途化合物和潜在的临床药物。在当前周期中，我们发现延长接头长度这些二聚体化合物增加了溶酶体定位和抗黑色素瘤活性。这些DQ和具有更长链接器以及CQ的DC用于拉出新的溶酶体靶过表达癌症，尤其是在转移性病变中。靶向溶酶体和自噬的努力癌细胞专注于癌细胞内的影响，但最近的文献表明针对这一点 TME中免疫抑制细胞中的途径也有助于抗肿瘤活性。我们将利用与项目1、3和4的创新合作以及P01核心的大力支持，以了解 PPT1抑制在两个肿瘤细胞中的影响，肿瘤细胞与成纤维细胞之间的相互作用，肿瘤相关的巨噬细胞和T细胞。该提案基于广泛的新初步数据从2017年9月提交的审稿人的Criverques。我们将检验以下假设肿瘤细胞和巨噬细胞中的PPT1通过完成3 目的：AIM 1将通过将杂原子替代引入接头，开发创新的新化合物，并开发有史以来第一个二聚体铁喹衍生物，可以更好地渗透到酸性中 TME。我们还将为PPT1开发一种与活细胞和动物研究兼容的新型测定法。目的 2将利用P01内的合作来研究PPT1在阻止脂质贩运中的作用成纤维细胞对黑色素瘤细胞，并反向靶向治疗。 AIM 3将研究 PPT1抑制3D培养中与T细胞和巨噬细胞相互作用的肿瘤细胞相互作用，免疫能力鼠标模型和PPT1的新有条件的KO模型，目的是逆转抵抗力免疫疗法。这些研究的影响将是揭示对 TME内溶酶体抑制的后果，这将支持这些药物的临床发展将来。获得的知识最终将导致改善患者的结果。