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，肿瘤细胞从多细胞球体(MTS)中脱落， 它们独立生存得更好，对化疗更耐受，在新的地方定居得更好。 它们主要转移到富含脂肪的区域，如大网膜，癌细胞从那里依赖脂肪酸 氧化(粮农组织)对转移进展、生存和耐药性的作用。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利基 用于急需的治疗干预。我们最近发现了一个新的靶点，apelin受体(APJ)和 其配体apelin使HGSOC具有这种适应性，导致治疗无效和转移 进步。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。我们的新数据显示APJ促进MTS的形成，导致化疗耐药， 通过抑制APJ降低MTS可显著提高药物疗效。此外，脂肪细胞衍生的apelin驱动 表达APJ的癌细胞向富脂组织迁移和侵袭并促进代谢重编程 向粮农组织提供高产量的能源。证实APJ基因敲除HGSOC稳定的人移植瘤 显著减轻转移性肿瘤负担。拟议研究的主要目标是：1)扩大 关于我们的初步发现，通过阐明MTS形成和代谢的潜在机制作用 通过APJ和APJ抑制剂在耐药和转移中的作用；2)建立预测 解释肿瘤独特的生理细胞特征和解剖的计算模型 描述药物转运机制和由此产生的治疗效果的腹膜腔特性；以及 3)利用这些知识在HGSOC中执行APJ抑制的概念验证临床前评估 进一步指导APJ抑制剂的模型信息化药物开发。在此，我们建议调查 APJ在已建立和原代HGSCO和非HGSOC细胞系中的代谢作用及其抑制(AIM 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。 建立基于生理的腹膜肿瘤PK/PD模型(目标2)。我们将评估这些措施的效果 APJ抑制剂单独或联合化疗在HGSOC临床前转移模型中的应用(目标3)。至 实现这些目标我们组建了一支具有抗癌药理学专业知识的多学科团队 和计算模型(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 研究和免疫疗法(昆勒·奥敦西)。这项研究的成功完成将确立APELIN/APJ Axis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 在细胞减数治疗或维持治疗中与标准护理细胞毒性药物相结合。

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.