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：
10366717
负责人：
Sukyung Woo
金额：
$ 41.7万
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/10366717
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 Computer Models Data Diagnosis Disease Dose Drug Kinetics Drug Transport Drug resistance Effectiveness Extracellular Matrix G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Greater sac of peritoneum Growth Health Histology Human Immune Immunocompetent Immunotherapy Implant In Vitro Infiltration Invaded Knowledge Lead Ligands Link Lipids Maintenance Therapy Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary 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 Pharmacology 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 base 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 function improved improved outcome in vivo ineffective therapies inhibitor intraperitoneal knock-down metabolomics mortality mouse model multidisciplinary neoplastic cell novel novel strategies overexpression patient derived xenograft model pharmacodynamic model pre-clinical preclinical evaluation prevent receptor spatiotemporal standard of care therapeutic target trait treatment effect treatment group tumor tumor microenvironment tumor progression uptake

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.

项目摘要高级别浆液性卵巢癌 (HGSOC) 是最常见和致命的组织学类型，占 80% 卵巢癌死亡。在腹膜扩散过程中，肿瘤细胞脱离形成多细胞球体（MTS），它们在未附着的情况下生存得更好，对化疗具有更强的抵抗力，并且能更好地殖民到新的位点。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网膜氧化（FAO）对转移进展、生存和耐药性的影响。因此，MTS 的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的生态位紧急需要的治疗干预措施。我们最近发现了一个新的靶标，apelin 受体 (APJ) 和其配体 apelin 赋予 HGSOC 如此的适应性，导致治疗无效和转移进展。我们之前报道了 APJ 在促进 HGSOC 方面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 形成，导致化疗耐药、通过抑制 APJ 来降低 MTS 显着提高药物疗效。此外，脂肪细胞衍生的 apelin 驱动表达 APJ 的癌细胞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提供高能源产量。人类异种移植物具有稳定的 APJ 敲低 HGSOC 显着减少转移性肿瘤负荷。拟议研究的主要目标是 1) 扩展基于我们的初步发现，阐明了 MTS 形成和代谢的潜在机制作用 APJ 以及 APJ 抑制剂对耐药和转移的影响； 2）制定预测解释肿瘤和解剖学独特的生理细胞特征的计算模型腹膜腔的特性来描述药物转运机制和由此产生的治疗效果；和 3) 利用这些知识对 HGSOC 中的 APJ 抑制进行概念验证临床前评估并进一步指导APJ抑制剂的模型知情药物开发。在此，我们建议调查 APJ 的代谢效应及其对已建立和原代 HGSCO 和非 HGSOC 细胞系的抑制（目的 1).我们将研究APJ抑制MTS形成对体外药效和转移的影响并开发基于生理学的腹膜肿瘤 PK/PD 模型（目标 2）。我们将评估以下效果在 HGSOC 临床前转移模型中单独使用 APJ 抑制剂或联合化疗（目标 3）。到为了实现这些目标，我们组建了一支具有癌症药理学专业知识的多学科团队和计算建模（Sukyung Woo）；卵巢癌基础研究及代谢途径（雷沙姆·巴塔查亚）；卵巢细胞和小鼠模型（Raya Huang）；以及转化和临床卵巢研究和免疫疗法（Kunle Odunsi）。成功完成这项研究将建立apelin/APJ 轴作为 HGSOC 的重要治疗靶点，为 APJ 抑制剂的应用提供科学依据在细胞减灭疗法或维持疗法中与标准护理细胞毒素组合。