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

摘要 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个新病例。肝转移，生命的主要特征- 限制性疾病，发生在大约20-50%的结肠直肠癌患者中。虽然区域 治疗选择，包括热隔离肝灌注（HIHP）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，不可切除的 结肠直肠肝转移仍然是一个主要的未解决的问题，需要更有效的新的治疗方案。 在资助期间，我们将开发一种新的靶向HIHP治疗策略。我们假设 靶向热疗的组合治疗，生物剂Fc-TRAIL（免疫球蛋白Fc 结构域融合的肿瘤坏死因子相关凋亡诱导配体），以及化疗药物 奥沙利铂将有效治疗不可切除的结直肠肝转移瘤。具体目标 本项目的主要目的是：（1）阐明基于Fc-TRAIL的肿瘤抑制剂对肿瘤细胞具有协同抗肿瘤作用的机制。 有针对性的多模式治疗，和（2）研究这种组合治疗在临床前的疗效， IHP大鼠模型。第一个目标的拟议研究将采用生物化学和分子技术， 研究多模式治疗。对于第二个目标，我们将使用同系肝转移大鼠 结直肠癌模型，以研究多模式治疗的功效。我们认为，我们提出的 方案将提供关于基于Fc-TRAIL的多模式治疗的潜在治疗优势的信息。 对患者的治疗。

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.