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.

抽象的全球大肠癌每年约有40万人死亡，代表所有癌症死亡中约有10％。结直肠癌患者死亡的主要原因是肝转移。尽管区域治疗方案，包括高温孤立的肝灌注（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，管理不可切除的肝大肠转移仍然是一个主要的未解决的问题，还有更多需要有效的新型方案。在赠款期间，我们建议开发一种新颖的治疗方法肝结直肠转移的策略。考虑到我们以前的研究，高温（肿瘤坏死因子相关凋亡诱导配体）和铁毒剂协同诱导细胞毒性，并有效增强皮下的肿瘤功效异种移植物。在此赠款应用中，我们假设对轻度的组合治疗高温，生物剂径径和铁毒剂敏捷（ART）有效治疗不可切除的肝结肠直肠转移（HCM）。该项目的具体目的是（1）阐明由热疗与TRAIL相结合引起的协同抗肿瘤功效的机制和艺术治疗（HTA：高温 + TRAIL + ART）在瘤模型中，（2）研究临床前这种HTA处理在人源性大鼠分离的肝灌注（IHP）模型中的功效。提出的研究第一个目标将建立来自HCM患者的肿瘤组织的瘤模型，并采用生化和分子技术研究了由协同作用引起的细胞死亡机制 HTA处理。为了第二个目标，我们将开发具有肿瘤组织的人源性大鼠IHP模型 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上的应用。