Targeting ovarian cancer spheroid formation and metabolic adaptation by APJ inhibition

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，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）， 它们能更好地独立存活，对化疗更有抵抗力，并能更好地定植到新的部位。 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）用于转移进展、存活和耐药性。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 用于急需的治疗干预。我们最近发现了一个新的靶点，爱帕琳受体（APJ）， 其配体apelin赋予HGSOC的这种适应性，导致治疗无效和转移性 进展我们以前报道过APJ在促进HGSOC中的临床和病理意义 转移和进展。我们的新数据显示，APJ地区促进MTS形成，导致耐药性， 通过抑制APJ来降低MTS显著增加药物功效。此外，脂肪细胞衍生的爱帕琳蛋白驱动 表达APJ的癌细胞迁移和侵入富含脂质的组织，并促进代谢重编程 用于高能源生产。证明了具有稳定的APJ敲低HGSOC的人异种移植物 显著降低转移性肿瘤负荷。本研究的主要目的是：（1）扩大 通过阐明MTS形成和代谢的潜在机制作用， APJ的作用以及APJ抑制剂在耐药和转移中的作用; 2）开发预测性的 计算模型，该模型考虑了肿瘤和解剖结构的独特生理细胞特征， 描述药物转运机制和产生的治疗效果的腹膜腔特性;以及 3)利用这些知识，对HGSOC中的APJ抑制进行概念验证临床前评价 并进一步指导APJ抑制剂的模型知情药物开发。因此，我们建议调查 APJ的代谢效应及其在已建立的和原代HGSCO和非HGSOC细胞系中的抑制作用（目的 1）。我们将在体外研究APJ抑制MTS形成对药物疗效和转移的影响 并建立一个基于生理学的腹膜肿瘤PK/PD模型（目的2）。我们将评估 在HGSOC的临床前转移模型中单独使用APJ抑制剂或与化疗联合使用（目的3）。到 为了实现这些目标，我们组建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）;和转化和临床卵巢 研究和免疫疗法（Kunle Odunsi）。成功完成本研究将建立apelin/APJ 轴作为HGSOC的重要治疗靶点，为APJ抑制剂在HGSOC中的应用提供科学依据。 在细胞减灭疗法中或作为维持疗法与标准护理细胞毒素组合。

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.