Hyperthermic Intraperitoneal Chemotherapy Mechanisms in Epithelial Ovarian Cancer

上皮性卵巢癌腹腔热灌注化疗机制

基本信息

批准号：
10285567
负责人：
Ofer Reizes
金额：
$ 22.58万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285567
关键词：
Abdomen Accounting Adaptive Immune System Adoptive Cell Transfers Aftercare Animal Model Animals B-Lymphocytes CD8-Positive T-Lymphocytes Cancer Etiology Cancer Patient Cancer cell line Cell Hypoxia Cells Cessation of life Cisplatin Clinical Combination immunotherapy Complement Complement Activation Data Diagnosis Disease Endothelial Cells Epithelial Epithelial Cells Epithelial ovarian cancer Fatty acid glycerol esters Fibroblasts Foundations Genetic Genetic Transcription Genomics Goals Heat-Shock Response Heterogeneity Human Immune Immune system Immunosuppression Immunosuppressive Agents In Vitro Infiltration Inflammatory Lead Link Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Maps Memory Metabolic Metabolic Activation Methods Modeling Molecular Mus Myeloid-derived suppressor cells Natural Killer Cells Neoadjuvant Therapy Neoplasm Metastasis Omentum Operative Surgical Procedures Outcome Ovarian Pathway interactions Patient-Focused Outcomes Patients Pilot Projects Platinum Play Population Prognosis Protocols documentation Randomized Controlled Trials Regimen Role Sampling Signal Transduction Site Specimen Stromal Cells Suppressor-Effector T-Lymphocytes Techniques Temperature Testing Therapeutic Time Transcriptional Activation Translating Transplantation Tumor Debulking Tumor-infiltrating immune cells United States Woman Work attenuation base cancer stem cell chemotherapy cytotoxic efficacious treatment genetic signature improved innovation insight intraperitoneal therapy macrophage mouse model mutant neoplastic cell novel novel therapeutic intervention ovarian neoplasm patient response peritoneal cancer randomized controlled design response sample collection single cell analysis single-cell RNA sequencing standard of care success taxane therapeutic development therapy resistant time interval transcriptome tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Project Summary Epithelial ovarian cancer (EOC) is a leading cause of gynecologic cancer death in women, highlighting the critical clinical need for new therapeutic strategies. In 2018 approximately 22,000 women were diagnosed with EOC in the United States and the majority of them will ultimately succumb to their disease. The reason underlying the poor survival is due to poor diagnosis with 80% of patients with EOC present in advanced stage (III-IV) accounting for the poor prognosis (5-year cancer-specific survival 42% and 26%, respectively). Hyperthermic intraperitoneal chemotherapy (HIPEC) has recently emerged as a clinical regimen that prolongs overall survival for patients with advanced EOC by over 12 months compared to standard of care. Despite its proven clinical benefit, how HIPEC extends survival remains poorly understood. Is the improvement in tumor control driven by increased cytotoxic effects or alterations in the tumor microenvironment? What role does the immune system play? To overcome this limitation, we analyzed ovarian tumors at the time of the debulking surgery and immediately following HIPEC protocol. As EOC is often found to metastasize to the omental fat, we focused on this site to interrogate cellular and molecular changes. We leveraged single cell RNA sequencing to identify the major populations in the omental tumors and underlying cellular and molecular changes accompanying HIPEC. Our data demonstrated that HIPEC activates immune cells and modulates the transcriptome of epithelial and stromal cell populations. In parallel, we used a mouse EOC lines to develop an innovative hyperthermic chemotherapy model. We determined that hyperthermic chemotherapy leads to increased immune cell infiltration with a corresponding decrease in immune suppressor cells. Based on these observations, we hypothesize that the survival benefit conferred by HIPEC is due to its ability to augment immune cell infiltration. We will test this hypothesis using a complementary combination with an innovative mouse model of HIPEC and single cell analysis of human patient specimen studies. We propose two Specific Aims. In Aim 1, we will test the hypothesis that HIPEC promotes transcriptional activation of adaptive immune system. In Aim 2, we will test hypothesis that HIPEC via attenuation of immune suppression improves EOC. The goal of the study is to gain valuable information into the cellular pathways that HIPEC uses to disrupt EOC progression in order to translate these findings into adjunct therapies to further enhance the clinical benefit of HIPEC for patients with advanced EOC.

项目摘要上皮卵巢癌（EOC）是女性妇科癌症死亡的主要原因，突出了关键对新的治疗策略的临床需求。 2018年，大约有22,000名妇女被诊断出患有EOC 美国和大多数人最终将屈服于他们的疾病。原因生存率差是由于80％的EOC患者诊断不良，因此在晚期（III-IV）中存在EOC患者预后不良（5年癌症特异性生存率分别为42％和26％）。高温腹膜内化疗（HIPEC）最近成为一种临床方案，可延长总体生存率与标准护理相比，对于晚期EOC的患者比例超过12个月。尽管临床证明了受益，HIPEC如何扩展生存仍然知之甚少。是由肿瘤控制的改善肿瘤微环境的细胞毒性作用增加或改变？免疫系统有什么作用玩？为了克服这一局限性，我们在延伸手术和立即遵循HIPEC协议。由于经常发现EOC转移到胶质脂肪，我们专注于该部位询问细胞和分子变化。我们利用单细胞RNA测序来识别 HIPEC伴随着肿瘤的主要种群以及潜在的细胞和分子变化。我们的数据表明，HIPEC激活免疫细胞并调节上皮和基质细胞种群。同时，我们使用鼠标EOC线发展创新的高温化学疗法模型。我们确定高温化疗导致免疫细胞浸润增加免疫抑制细胞的相应降低。基于这些观察，我们假设 HIPEC赋予的生存益处是由于其增强免疫细胞浸润的能力。我们将测试这个使用与HIPEC和单细胞的创新小鼠模型的互补组合假设人类患者标本研究的分析。我们提出了两个具体目标。在AIM 1中，我们将测试 HIPEC促进自适应免疫系统的转录激活的假设。在AIM 2中，我们将测试假设HIPEC通过衰减免疫抑制可改善EOC。研究的目的是获得 HIPEC用来破坏EOC进展以翻译的蜂窝路径的有价值信息这些发现进入辅助疗法，以进一步提高HIPEC的临床益处高级EOC。