Targeting ovarian cancer spheroid formation and metabolic adaptation by APJ inhibition

通过 APJ 抑制靶向卵巢癌球体形成和代谢适应

基本信息

批准号：
10528490
负责人：
Sukyung Woo
金额：
$ 39.28万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528490
关键词：
3-Dimensional APLN gene Accounting Adhesions Adipocytes Anatomy Anoikis Area Ascites Automobile Driving Basic Science Biodistribution Cancer cell line Cell model Cells Cellular Spheroids Cessation of life Characteristics Chemoresistance Cisplatin Clinical Coculture Techniques Computer Models Data Diagnosis Disease Dose Drug Kinetics Drug Transport Drug resistance Extracellular Matrix G-Protein-Coupled Receptors Goals Greater sac of peritoneum Growth Health Histology Human Immunocompetent Immunotherapy Implant In Vitro Invaded Knowledge Ligands Link Lipids Maintenance Therapy Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Mesothelium Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Neoplasm Metastasis Normal tissue morphology Omentum Operative Surgical Procedures Organ Outcome Ovarian Ovarian Carcinoma Ovarian Serous Adenocarcinoma Paclitaxel Pathologic Pathway interactions Patient-Focused Outcomes Patients Peritoneal Phenotype Physiological Pre-Clinical Model Primary Neoplasm Production Property Receptor Inhibition Reporting Research Resistance Role Serous Site Surface TP53 gene Testing Therapeutic Intervention Tissues Toxic effect Treatment Effectiveness Treatment Efficacy Tumor Burden Tumor Weights Woman Xenograft procedure adipokines advanced disease antagonist barrier to care cancer cell cancer pharmacology chemotherapy clinically significant cytotoxic density drug development drug distribution drug efficacy efficacious treatment established cell line experimental study fatty acid oxidation genetic approach immune cell infiltrate immune function improved improved outcome in vivo ineffective therapies inhibitor intraperitoneal knock-down metabolomics migration mortality mouse model multidisciplinary neoplastic cell novel novel strategies overexpression patient derived xenograft model pharmacodynamic model pharmacologic pre-clinical preclinical evaluation prevent receptor spatiotemporal standard of care therapeutic effectiveness therapeutic target trait treatment effect treatment group tumor tumor microenvironment tumor progression uptake

3-Dimensional APLN gene Accounting Adhesions Adipocytes Anatomy Anoikis Area Ascites Automobile Driving Basic Science Biodistribution Cancer cell line Cell model Cells Cellular Spheroids Cessation of life Characteristics Chemoresistance Cisplatin Clinical Coculture Techniques Computer Models Data Diagnosis Disease Dose Drug Kinetics Drug Transport Drug resistance Extracellular Matrix G-Protein-Coupled Receptors Goals Greater sac of peritoneum Growth Health Histology Human Immunocompetent Immunotherapy Implant In Vitro Invaded Knowledge Ligands Link Lipids Maintenance Therapy Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Mesothelium Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Neoplasm Metastasis Normal tissue morphology Omentum Operative Surgical Procedures Organ Outcome Ovarian Ovarian Carcinoma Ovarian Serous Adenocarcinoma Paclitaxel Pathologic Pathway interactions Patient-Focused Outcomes Patients Peritoneal Phenotype Physiological Pre-Clinical Model Primary Neoplasm Production Property Receptor Inhibition Reporting Research Resistance Role Serous Site Surface TP53 gene Testing Therapeutic Intervention Tissues Toxic effect Treatment Effectiveness Treatment Efficacy Tumor Burden Tumor Weights Woman Xenograft procedure adipokines advanced disease antagonist barrier to care cancer cell cancer pharmacology chemotherapy clinically significant cytotoxic density drug development drug distribution drug efficacy efficacious treatment established cell line experimental study fatty acid oxidation genetic approach immune cell infiltrate immune function improved improved outcome in vivo ineffective therapies inhibitor intraperitoneal knock-down metabolomics migration mortality mouse model multidisciplinary neoplastic cell novel novel strategies overexpression patient derived xenograft model pharmacodynamic model pharmacologic pre-clinical preclinical evaluation prevent receptor spatiotemporal standard of care therapeutic effectiveness therapeutic target trait treatment effect treatment group tumor tumor microenvironment tumor progression uptake

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项目摘要

Project Abstract High-grade serous ovarian cancer (HGSOC) is the most common and lethal histology, accounting for 80% of ovarian cancer death. During peritoneal spread, tumor cells detached form multicellular spheroids (MTS), which survive better unattached and are more resistant to chemotherapy and colonizes better to new sites. They primarily metastasize into lipid-rich areas such as omentum from which cancer cells rely on fatty acid oxidation (FAO) for metastatic progression, survival, and drug resistance. Thus, MTS formation and metabolic adaptation capabilities enable HGSOC cells to adapt in tumor microenvironment and represent critical niches for urgently needed therapeutic interventions. We recently identified a novel target, apelin receptor (APJ) and its ligand apelin that confers such adaptabilities of HGSOC, contributing to treatment inefficacy and metastatic progression. We previously reported the clinical and pathological significance of APJ in promoting HGSOC metastasis and progression. Our new data show that APJ promotes MTS formation, leading to chemoresistant, and reducing MTS by APJ inhibition remarkably increased drug efficacy. Also, adipocyte-derived apelin drives APJ-expressing cancer cells to migrate and invade into lipid-rich tissues, and promote metabolic reprograming to FAO for high energy production. Human xenografts with stable APJ-knockdown HGSOC demonstrated significant reduction in metastatic tumor burden. The primary goals of the proposed research are 1) to expand on our preliminary findings by elucidating the underlying mechanistic roles of MTS formation and metabolism by APJ and the effects of APJ inhibitors in drug resistance and metastasis; 2) to develop a predictive computational model that accounts for the unique physio-cellular characteristics of tumors and anatomical properties in the peritoneal cavity to describe drug transport mechanisms and resulting treatment effects; and 3) leveraging this knowledge to perform the proof-of-concept preclinical evaluation of APJ inhibition in HGSOC and further guide model-informed drug development of APJ inhibitors. Herein, we propose to investigate metabolic effects of APJ and its inhibition in established and primary HGSCO and non-HGSOC cell lines (Aim 1). We will investigate the effects of APJ inhibition of MTS formation on drug efficacy and metastasis in vitro and develop a physiologically-based PK/PD model for peritoneal tumors (Aim 2). We will evaluate the effects of APJ inhibitors alone or combining with chemotherapy in preclinical metastasis models of HGSOC (Aim 3). To accomplish thes goals we have assembled a multi-disciplinary team with expertise in cancer pharmacology and computation modeling (Sukyung Woo); basic research and metabolic pathways of ovarian cancer (Resham Bhattacharya); ovarian cell and mouse model (Raya Huang); and translational and clinical ovarian research and immunotherapy (Kunle Odunsi). Successful completion of this study will establish the apelin/APJ axis as an important therapeutic target in HGSOC and provide scientific basis for APJ inhibitors used in combination with standard-of-care cytotoxics in cytoreductive therapy or as maintenance therapy.

项目摘要高级浆液卵巢癌（HGSOC）是最常见和致命的组织学，占80％卵巢癌死亡。在腹膜扩散期间，肿瘤细胞脱离形成多细胞球体（MTS），它可以保持更好的无关，并且对化学疗法更具抵抗力，并在新地点殖民。它们主要转移到富含脂质的区域，例如癌细胞依赖脂肪酸的区域用于转移性进展，生存和耐药性的氧化（FAO）。因此，MTS形成和代谢适应能力使HGSOC细胞能够适应肿瘤微环境并代表关键壁ni 迫切需要治疗干预措施。我们最近确定了一个新的靶标，Apelin受体（APJ）和它赋予HGSOC适应性的配体apelin，导致治疗效率低下和转移性进展。我们先前报道了APJ在促进HGSOC中的临床和病理意义转移和进展。我们的新数据表明，APJ促进MTS组，导致化学抗性，并通过APJ抑制作用降低MTS明显提高了药物疗效。此外，脂肪细胞衍生的Apelin驱动器表达APJ的癌细胞以迁移并侵入富含脂质的组织，并促进代谢重编程向粮农组织进行高能源生产。具有稳定APJ-KNOCKDOWN HGSOC的人异种移植物已证明转移性肿瘤负担的显着减轻。拟议研究的主要目标是1）扩展在我们的初步发现中，通过阐明MTS形成和代谢的潜在机制作用由APJ和APJ抑制剂在耐药性和转移中的影响； 2）发展预测计算模型，该模型是肿瘤和解剖学的独特生理细胞特征腹膜腔中的特性描述了药物传输机制和产生的治疗效果；和 3）利用此知识来执行HGSOC中APJ抑制的概念验证临床前评估并进一步指导模型的APJ抑制剂的药物开发。在此，我们建议调查 APJ的代谢作用及其在已建立的HGSCO和非HGSOC细胞系中的抑制作用（AIM 1）。我们将研究APJ抑制MTS形成对药物疗效和体外转移的影响并为腹膜肿瘤开发基于生理的PK/PD模型（AIM 2）。我们将评估单独使用APJ抑制剂或与HGSOC临床前转移模型中的化学疗法结合（AIM 3）。到实现这一目标，我们组装了一个具有癌症药理学专业知识的多学科团队和计算建模（Sukyung Woo）；卵巢癌的基础研究和代谢途径（Resham Bhattacharya）；卵巢细胞和小鼠模型（Raya Huang）；以及翻译和临床卵巢研究与免疫疗法（Kunle Odunsi）。这项研究的成功完成将建立APELIN/APJ 轴作为HGSOC中重要的治疗靶标，并为使用的APJ抑制剂提供科学基础结合细胞减少疗法或维持疗法的护理标准细胞毒素。