Docosahexaenoic Acid Loaded Low-density Lipoproteins: A Novel Biologic Intervention for Hepatocellular Carcinoma.

项目总结/摘要 肝细胞癌（HCC）是全球癌症相关死亡的第二大常见原因。 经动脉化疗栓塞术（TACE）仍然是不可切除的中间型肝癌的唯一一线治疗方法。 阶段HCC，尽管事实上，这个阶段是由一组异质性的患者组成， 肝功能，不同的肿瘤数量和大小。在临床实践中，只有50-60%的患者 HCC受益于TACE，因此进行重复的TACE治疗以实现最大肿瘤 衰退影响TACE治疗效果的关键因素是肝功能恶化 和肿瘤复发。前者由肝脏进行性脱靶栓塞性缺血损伤引起，而 后者是由缺氧诱导的血管生成、上皮细胞向间质细胞转化（EMT）和肿瘤 TACE引发的增长。这些过程不可避免地主导了这种疾病的过程，导致长期不良的结果。 5年生存率<12%。迫切需要针对HCC的新疗法， 在美国，HCC的发病率稳步上升。近年来，天然omega-3脂肪酸， 二十二碳六烯酸（DHA）已被证明具有有希望的抗癌特性， 与降低HCC风险有关。膳食DHA对已建立的实体瘤的影响是 名义上的为了解决这个问题，我们的实验室已经设计了一种新的低密度脂蛋白（LDL）生物， 用未酯化的DHA（本文称为LDL-DHA）重构。从治疗学上讲，我们已经证明， 在HCC同系大鼠模型中，LDL-DHA的经动脉递送能够诱导广泛的坏死（>80%） 并且阻止肿瘤生长（3倍）而不损伤周围正常肝脏。此外，委员会认为， 重复动脉内LDL-DHA治疗显示出提供HCC的持续消退。此外，委员会认为， 在正常肝脏中摄取LDL-DHA显示出不仅是安全的，而且具有潜在的保肝作用。在 此外，我们小组最近的初步数据表明，LDL-DHA能够下调HIF-1α， 和EMT信号传导，从而抑制肿瘤血管生成/再生长活性。目前的目标是 建议是评估实用的图像引导局部LDL-DHA治疗中期肝癌。到 为了实现这一目标，我们将研究以下具体目标：1）评估动脉内LDL-DHA的安全性 在肝硬化大鼠模型中的递送;和2）比较LDL-DHA与常规的LDL-DHA的治疗功效。 TACE方法在HCC的患者来源的异种移植大鼠模型中提供持续的肿瘤控制。我们预计 这些目标的结合工作将验证LDL-DHA治疗在保护肝功能方面的安全性 在肝硬化的情况下，并证明这种疗法的疗效，以提供持续的肿瘤根除超过 TACE。LDL-DHA治疗策略将是重要的，因为它提供了一种有效治疗LDL-DHA的新方法。 HCC同时保留肝功能。最终，我们奋进将这项技术带到诊所， 预计将提供安全有效的方法来管理不可切除的HCC。

PROJECT SUMMARY/ ABSTRACT Hepatocellular carcinoma (HCC) is ranked as the second most common cause of cancer-related death globally. Transarterial chemoembolization (TACE) remains the only first-line treatment for unresectable intermediate- stage HCC, despite the fact that this stage is comprised of a heterogeneous group of patients with a wide range of liver function, variable tumor number and size. In clinical practice only 50-60% of patients with intermediated HCC benefit from TACE, thus repeated rounds of TACE therapy are performed to achieve maximum tumor recession. The critical factors that impact the effectiveness of TACE therapy are the worsening of liver function and tumor recurrence. The former arises from progressive off-target embolic ischemic injury to the liver, while the latter results from hypoxia-induced angiogenesis, epithelial-to-mesenchymal transition (EMT) and tumor growth triggered by TACE. These processes inevitably dominate the course of this disease resulting in poor long term survival, with a 5-year survival rates <12%. Novel therapies against HCC are urgently needed as the incidence of HCC is steadily increasing in the United States. In recent years the natural omega-3 fatty acid, docosahexaenoic acid (DHA) has been shown to possess promising anticancer properties and its consumption has been implicated in reducing the risk of HCC. The effects of dietary DHA on established solid tumors is nominal. To address this issue, our lab has engineered a novel low-density lipoprotein (LDL) based biologic that is reconstituted with unesterified DHA (herein referred to as LDL-DHA). Therapeutically, we have shown in a syngeneic rat model of HCC, that transarterial delivery of LDL-DHA is able to induce extensive necrosis (>80%) of HCC tumors and impede the tumor growth (3 fold) without injury to surrounding normal liver. Moreover, repeated intra-arterial LDL-DHA treatments was shown to provide sustained regression of HCCs. Furthermore, the uptake of LDL-DHA in the normal liver was shown to be not only safe but potentially hepatoprotective. In addition, recent preliminary data from our group has documented that LDL-DHA is able to downregulate HIF-1α and EMT signaling in HCC cells, thus inhibiting tumor angiogenic/regrowth activity. The goal of the present proposal is to evaluate the utility image-guided locoregional LDL-DHA therapy for intermediate-stage HCC. To address this goal we will examine the following specific aims: 1) evaluate the safety of intra-arterial LDL-DHA delivery in rat models of cirrhosis; and 2) compare the therapeutic efficacy of LDL-DHA versus conventional TACE methods to provide sustained tumor control in a patient derived-xenograft rat model of HCC. We expect that the combined work of these Aims will validate the safety of LDL-DHA treatment in preserving liver function in settings of cirrhosis and demonstrate the efficacy of this therapy to provide sustained tumor eradication over TACE. The LDL-DHA treatment strategy will be significant because it offers a new method of effectively treating HCC while preserving liver function. Ultimately it is our endeavor to bring this technology to the clinic, where it is anticipated to provide safe and efficacious approach to managing of unresectable HCC.