Hyperthermic Intraperitoneal Chemotherapy Mechanisms in Epithelial Ovarian Cancer

上皮性卵巢癌腹腔热灌注化疗机制

• 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
• 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

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 上皮性卵巢癌（EOC）是女性妇科癌症死亡的主要原因，突出了关键的 临床需要新的治疗策略。2018年，约有22，000名女性被诊断患有EOC， 美国和他们中的大多数人最终会屈服于他们的疾病。这背后的原因 生存率低是由于诊断不佳，80%的EOC患者处于晚期（III-IV期） 预后差（5年癌症特异性生存率分别为42%和26%）。温热 腹腔内化疗（HIPEC）是最近出现的一种提高总生存率的临床方案 对于晚期EOC患者，与标准治疗相比，治疗时间延长12个月以上。尽管其临床证明 然而，HIPEC如何延长生存期仍然知之甚少。肿瘤控制的改善是由 细胞毒性作用增加或肿瘤微环境改变？免疫系统扮演什么角色 玩？为了克服这一局限性，我们分析了卵巢肿瘤在减瘤手术时， 遵循HIPEC方案。由于EOC经常转移到网膜脂肪，我们关注 这个网站询问细胞和分子的变化。我们利用单细胞RNA测序来鉴定 网膜肿瘤的主要人群以及伴随HIPEC的潜在细胞和分子变化。 我们的数据表明，HIPEC激活免疫细胞并调节上皮细胞和巨噬细胞的转录组。 基质细胞群与此同时，我们使用小鼠EOC线开发了一种创新的热 化疗模型我们确定热化疗导致免疫细胞浸润增加 免疫抑制细胞相应减少。基于这些观察，我们假设， HIPEC赋予的存活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HIPEC和单细胞的创新小鼠模型的互补组合的假设 分析人类患者样本研究。我们提出两个具体目标。在目标1中，我们将测试 假设HIPEC促进适应性免疫系统的转录激活。在目标2中，我们将测试 假设HIPEC通过减弱免疫抑制改善EOC。这项研究的目的是获得 有价值的信息进入HIPEC用来破坏EOC进展的细胞通路， 将这些发现用于辅助治疗，以进一步增强HIPEC对以下患者的临床获益： 先进的EOC