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

• 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
• 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

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.

摘要 在世界范围内，结直肠癌每年造成约40万人死亡，这代表了 大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 转移尽管局部治疗选择，包括高温隔离肝灌注（IHP）和 经皮IHP，提供了积极的局部治疗和有限的全身毒性的好处， 不能切除的肝结直肠转移瘤的治疗仍然是一个主要的未解决的问题， 需要有效的新方案。在拨款期间，我们建议开发一种新的治疗方法， 肝结直肠转移治疗策略考虑到我们以前的研究， 热疗、TRAIL（肿瘤坏死因子相关凋亡诱导配体）和铁毒性剂 协同诱导细胞毒性并有效增强皮下注射的杀肿瘤功效。 异种移植在这项拨款申请中，我们假设， 热疗，生物制剂TRAIL和铁中毒剂青蒿琥酯（ART）是有效的， 治疗不可切除的肝结直肠转移（HCM）。本项目的具体目标是：（1） 阐明热疗联合TRAIL协同抗肿瘤作用的机制 和ART治疗（HTA：热疗+ TRAIL + ART），以及（2）研究临床前 在人源化大鼠离体肝灌注（IHP）模型中，该HTA治疗的功效。拟议的研究 第一个目标是用HCM患者的肿瘤组织建立类瘤模型， 利用生物化学和分子生物学技术研究协同效应诱导的细胞死亡机制 的HTA治疗。对于第二个目标，我们将开发人源化大鼠IHP模型，肿瘤组织来自 HCM患者，然后评估HTA治疗的治疗优势。我们认为 本研究的成功结果将支持这种多模式方法在HCM中的应用。