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有 140,000 例新发病例，这是生命的主要特征。约 20-50% 的结直肠癌患者发生限制性疾病。治疗方案包括高温离体肝灌注 (HIHP) 和经皮 IHP 积极的局部治疗和有限的全身毒性的好处，不可切除的治疗结直肠肝转移仍然是一个未解决的主要问题，需要更有效的新疗法。在资助期间，我们将开发一种针对 HIHP 靶向治疗的新策略。靶向热疗的组合治疗，生物制剂Fc-TRAIL（免疫球蛋白Fc 域融合肿瘤坏死因子相关凋亡诱导配体），以及化疗药物奥沙利铂制剂将有效治疗不可切除的结直肠肝转移瘤。该项目的目的是（1）阐明基于Fc-TRAIL的协同抗肿瘤功效的机制靶向多模式治疗，以及（2）研究这种组合治疗的临床前疗效 IHP 大鼠模型的第一个目标将采用生化和分子技术来研究。为了研究多模式治疗，我们将采用同基因肝转移大鼠。我们相信我们提出的结直肠癌模型来研究多模式治疗的功效。方案将提供有关基于 Fc-TRAIL 的多模式潜在治疗优势的信息对患者进行治疗。