Targeted hyperthermia in combination with chimeric TRAIL and chemotherapeutic agent treatment for colorectal liver metastasis

靶向热疗联合嵌合TRAIL及化疗药物治疗结直肠肝转移

基本信息

批准号：
9360701
负责人：
YONG J LEE
金额：
$ 7.82万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360701
关键词：
ABL1 gene Adjuvant Apoptosis Applications Grants BCL2 gene Biochemical Cancer Etiology Cause of Death Cessation of life Chimeric Proteins Colorectal Colorectal Cancer Combined Modality Therapy Diagnosis Disease Drug Kinetics Excision Fc Immunoglobulins Fc domain Goals Grant Half-Life Hepatotoxicity Hyperthermia Immunocompetent Induction of Apoptosis Injectable Intravenous Bolus Isolated Hepatic Perfusion Large Intestine Carcinoma Life Ligands MAPK8 gene Malignant Neoplasms Metastatic Neoplasm to the Liver Modeling Molecular Neoadjuvant Therapy Operative Surgical Procedures Outcome Pathway interactions Patients Plasma Rattus Regimen Research Project Grants Serum Signal Transduction Signal Transduction Pathway TNF gene TNF-related apoptosis-inducing ligand TNFSF10 gene TRAF2 gene Techniques Testing Therapeutic Tumor Volume United States Unresectable Woman base c-abl Proto-Oncogenes cancer cell chemotherapeutic agent chemotherapy colon cancer patients combinatorial efficacy study hyperthermia treatment in vitro activity in vivo insight men multimodality new therapeutic target novel novel strategies oxaliplatin preclinical efficacy preclinical study systemic toxicity tumor tumor growth

项目摘要

Abstract Colorectal cancer is one of the most common cancers in both men and women in the United States and accounts for approximately 140,000 new cases annually. Hepatic metastasis, the dominant feature of life- limiting disease, occurs in approximately 20–50% of patients with colorectal cancer. Although regional treatment options, including hyperthermic isolated hepatic perfusion (HIHP) and percutaneous IHP, offer the benefits of both aggressive local treatment and limited systemic toxicity, the management of unresectable colorectal liver metastases remains a major unsolved issue and more effective novel regimens are needed. During the grant period, we will develop a novel strategy for targeted HIHP therapy. We hypothesize that a combinatorial treatment of targeted hyperthermia, the biologic agent Fc-TRAIL (immunoglobulin Fc domain fused tumor necrosis factor-related apoptosis-inducing ligand), and the chemotherapeutic agent oxaliplatin will be effective in treating unresectable colorectal liver metastases. The specific aims of this project are to (1) elucidate the mechanism of synergistic anti-tumor efficacy caused by Fc-TRAIL-based targeted multimodal treatment, and (2) investigate the preclinical efficacy of this combinatorial treatment in an IHP rat model. The proposed studies for the first aim will employ biochemical and molecular techniques to investigate multimodal treatment. For the second aim, we will employ a syngeneic hepatic metastasis rat model of colorectal carcinoma to study the efficacy of the multimodal treatment. We believe that our proposed regimen will provide information on the potential therapeutic advantage of an Fc-TRAIL-based multimodal treatment on patients.

抽象的结直肠癌是美国男性和女性最常见的癌症之一每年约为140,000个新案件。肝转移，生命的主要特征 - 限制疾病，大约20-50％的结直肠癌患者发生。虽然区域性治疗选择，包括高温孤立的肝灌注（HIHP）和经皮IHP 积极的局部治疗和有限的全身毒性的好处，无法切除的管理结直肠肝转移仍然是一个主要的未解决问题，需要更有效的新型方案。在赠款期间，我们将制定针对HIHP治疗的新型策略。我们假设一个靶向高温的组合治疗生物剂FC-TRAID（免疫球蛋白FC）结构域融合肿瘤坏死因子相关的凋亡诱导的配体）和化学治疗性奥沙利铂将有效治疗不可切除的结直肠肝转移。具体目标该项目的内容是（1）阐明基于FC-TRAIL引起的协同抗肿瘤效率的机制有针对性的多模式处理，（2）研究该组合治疗的临床前效率 IHP大鼠模型。提出的第一个目标研究将采用生化和分子技术研究多模式处理。为了第二个目标，我们将采用同步肝转移大鼠结直肠癌的模型研究多模式治疗的效率。我们相信我们的建议方案将提供有关基于FC的多模式的潜在治疗优势的信息对患者的治疗。