Assessment of hyperthermia-based multimodal approach for hepatic colorectal metastases

基于热疗的多模式治疗肝结直肠转移瘤的评估

基本信息

批准号：
10517858
负责人：
YONG J LEE
金额：
$ 44.36万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517858
关键词：
Apoptosis Applications Grants Biochemical Biological Products Blood Cancer Etiology Cardiovascular system Cause of Death Cell Death Cells Cessation of life Chemoembolization Colorectal Colorectal Cancer Combined Modality Therapy Diagnosis Disease Dose Limiting Drug Kinetics Effectiveness Excision Gene Expression Profile Glomerular Filtration Rate Goals Grant Half-Life Hepatic Hepatic Tissue Human Hyperthermia Induction of Apoptosis Injections Intravenous Bolus Isolated Hepatic Perfusion Kidney Life Ligands Liver Malignant - descriptor Malignant Neoplasms Maximum Tolerated Dose Metabolic Clearance Rate Metastatic Neoplasm to the Liver Mitochondria Modeling Molecular Neoplasm Metastasis Normal Cell Oncologist Operative Surgical Procedures Outcome Outcome Study Pathway interactions Patient-Focused Outcomes Patients Persons Play Proteins Radiation therapy Radioembolization Rattus Receptor Gene Regimen Research Project Grants Rest Role Serum Signal Pathway Sprague-Dawley Rats TNF gene TNFSF10 gene Techniques Testing Therapeutic Thermal Ablation Therapy Toxic effect Tumor Tissue United States Unresectable Woman Xenograft procedure anti-cancer artesunate biological adaptation to stress colon cancer patients combinatorial cytotoxicity endoplasmic reticulum stress genetic signature hyperthermia treatment improved in vivo insight interest men multimodality new therapeutic target novel novel strategies novel therapeutics patient derived xenograft model preclinical efficacy preclinical study receptor sensor subcutaneous systemic toxicity treatment strategy tumor tumor growth

项目摘要

ABSTRACT Worldwide, colorectal cancer is responsible for approximately 0.4 million deaths annually, which represent approximately 10% of all cancer deaths. The main cause of death in colorectal cancer patients is hepatic metastasis. Although regional treatment options, including hyperthermic isolated hepatic perfusion (IHP) and percutaneous IHP, offer the benefits of both aggressive local treatment and limited systemic toxicity, the management of unresectable hepatic colorectal metastases remains a major unsolved issue and more effective novel regimens are needed. During the grant period, we propose developing a novel treatment strategy for hepatic colorectal metastases. Considering our previous studies, the combined treatment of hyperthermia, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), and ferroptotic agent synergistically induces cytotoxicity and effectively enhances the tumoricidal efficacy of subcutaneous xenografts. In this grant application, we hypothesize that a combinatorial treatment of mild hyperthermia, the biologic agent TRAIL, and the ferroptotic agent artesunate (ART) is effective in treating unresectable hepatic colorectal metastases (HCM). The specific aims of this project are to (1) elucidate the mechanism of synergistic anti-tumor efficacy caused by hyperthermia in combination with TRAIL and ART treatment (HTA: hyperthermia + TRAIL + ART) in tumoroid models, and (2) investigate the preclinical efficacy of this HTA treatment in humanized rat isolated hepatic perfusion (IHP) models. The proposed studies for the first aim will establish tumoroid models with tumor tissues from patients with HCM and employ biochemical and molecular techniques to investigate the cell death mechanism induced by synergistic effects of the HTA treatment. For the second aim, we will develop humanized rat IHP models with tumor tissues from patients with HCM and then evaluate the therapeutic advantage of the HTA treatment. We believe that the successful outcome of this study will support the application of this multimodal approach to HCM.

抽象的在全世界范围内，结直肠癌每年导致约 40 万人死亡，这代表约占所有癌症死亡的 10%。结直肠癌患者死亡的主要原因是肝癌转移。尽管局部治疗方案包括高温离体肝灌注（IHP）和经皮 IHP 具有积极的局部治疗和有限的全身毒性的优点，不可切除的肝结直肠转移瘤的治疗仍然是一个未解决的主要问题需要有效的新疗法。在资助期间，我们建议开发一种新的治疗方法肝结直肠转移的策略。考虑到我们之前的研究，联合治疗热疗、TRAIL（肿瘤坏死因子相关凋亡诱导配体）和铁死亡剂协同诱导细胞毒性，有效增强皮下注射的杀瘤功效异种移植物。在本次拨款申请中，我们假设对轻度热疗、生物制剂 TRAIL 和铁死亡剂青蒿琥酯 (ART) 可有效治疗不可切除的肝结直肠转移瘤（HCM）。该项目的具体目标是（1）阐明热疗联合TRAIL协同抗肿瘤作用机制和 ART 治疗（HTA：热疗 + TRAIL + ART）在肿瘤模型中的应用，以及（2）研究临床前这种 HTA 治疗在人源化大鼠离体肝灌注 (IHP) 模型中的疗效。拟议的研究第一个目标是利用 HCM 患者的肿瘤组织建立肿瘤模型，并利用生化和分子技术研究协同效应诱导的细胞死亡机制 HTA 治疗。对于第二个目标，我们将开发人源化大鼠 IHP 模型，其肿瘤组织来自 HCM 患者，然后评估 HTA 治疗的治疗优势。我们相信这项研究的成功结果将支持这种多模式方法在 HCM 中的应用。