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

二十二碳六烯酸负载低密度脂蛋白：肝细胞癌的新型生物干预措施。

• 批准号: 10607845
• 负责人: Ian Ronald Corbin
• 金额: $ 43.7万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607845
• 关键词: Acute; Address; Aftercare; Antitumor Response; Biological; Biomedical Engineering; Cancer Etiology; Catheterization; Cessation of life; Chemoembolization; Cirrhosis; Clinic; Compensation; Consumption; Curative Surgery; Data; Deterioration; Development; Diagnosis; Disease; Docosahexaenoic Acids; Dose; Effectiveness; Engineering; Etiology; Extensive Necrosis; Fluoroscopy; Funding Opportunities; Goals; Growth; Hepatic; Hepatic artery; Hepatocyte; High Dose Chemotherapy; Histopathology; Human; Hypoxia; Incidence; Injury; Intervention; Ischemia; Light; Lipoprotein (a); Liver; Liver Cirrhosis; Liver diseases; Liver neoplasms; Low-Density Lipoproteins; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Medicine; Metabolism; Methods; Modeling; Molecular; Necrosis; Omega-3 Fatty Acids; Palliative Care; Parents; Patients; Perfusion; Population Heterogeneity; Primary carcinoma of the liver cells; Process; Property; Radiology Specialty; Rattus; Recurrent tumor; Research Proposals; Residual Neoplasm; Resolution; Risk Reduction; Rodent; Safety; Signal Transduction; Solid Neoplasm; Surveillance Program; Survival Rate; Technology; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Burden; United States; United States National Institutes of Health; Unresectable; Vascular Endothelial Growth Factors; Work; angiogenesis; anti-cancer; biomaterial compatibility; clinical practice; dietary; effective therapy; efficacy evaluation; epithelial to mesenchymal transition; feeding; hepatoprotective; high risk population; image guided; improved; in vivo; innovation; ischemic injury; liver cancer model; liver function; liver injury; liver preservation; nanoparticle; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; patient population; reconstitution; response; treatment strategy; tumor; tumor eradication; tumor growth; uptake

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.

项目概要/摘要 肝细胞癌（HCC）被列为全球癌症相关死亡的第二大常见原因。 经动脉化疗栓塞（TACE）仍然是不可切除的中间肿瘤的唯一一线治疗方法。 HCC 阶段，尽管事实上该阶段由具有广泛范围的异质性患者组成 肝功能、不同肿瘤数量和大小。在临床实践中，只有 50-60% 的患者患有中间型 HCC受益于TACE，因此进行重复轮次TACE治疗以达到最大肿瘤 经济衰退。影响TACE治疗效果的关键因素是肝功能恶化 和肿瘤复发。前者是由肝脏进行性脱靶栓塞缺血损伤引起的，而 后者是缺氧诱导的血管生成、上皮间质转化 (EMT) 和肿瘤的结果 TACE 引发的生长。这些过程不可避免地主导了这种疾病的进程，导致长期不良的结果。 长期生存率，5年生存率<12%。迫切需要针对 HCC 的新疗法 在美国，HCC 的发病率正在稳步上升。近年来天然Omega-3脂肪酸， 二十二碳六烯酸 (DHA) 已被证明具有良好的抗癌特性及其食用量 与降低 HCC 风险有关。膳食 DHA 对已形成的实体瘤的影响是 名义上的。为了解决这个问题，我们的实验室设计了一种新型低密度脂蛋白（LDL）生物制剂， 用未酯化的 DHA（本文称为 LDL-DHA）重构。在治疗上，我们已经展示了 同系 HCC 大鼠模型，经动脉输送 LDL-DHA 能够诱导广泛坏死 (>80%) HCC 肿瘤并阻止肿瘤生长（3 倍）而不损伤周围的正常肝脏。而且， 重复动脉内 LDL-DHA 治疗可实现 HCC 的持续消退。此外， 正常肝脏摄取 LDL-DHA 被证明不仅是安全的，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证明 LDL-DHA 能够下调 HIF-1α 和 HCC 细胞中的 EMT 信号传导，从而抑制肿瘤血管生成/再生活性。目前的目标 该提案旨在评估图像引导局部 LDL-DHA 疗法治疗中期 HCC 的实用性。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 肝硬化大鼠模型中的给药； 2) 比较 LDL-DHA 与传统疗法的治疗效果 TACE 方法可在患者来源的 HCC 异种移植大鼠模型中提供持续的肿瘤控制。我们期望 这些目标的结合将验证 LDL-DHA 治疗在保护肝功能方面的安全性 在肝硬化的情况下，并证明这种疗法在持续根除肿瘤方面的功效 TACE。 LDL-DHA 治疗策略将具有重要意义，因为它提供了一种有效治疗的新方法 肝癌同时保留肝功能。最终，我们努力将这项技术引入临床。 预计将为不可切除的 HCC 的治疗提供安全有效的方法。