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.

项目摘要/摘要 肝细胞癌是全球第二大癌症相关死亡原因。 肝动脉化疗栓塞术(TACE)仍然是不能切除的中间体的唯一一线治疗方法。 尽管这一阶段是由一组范围广泛的不同类型的患者组成的，但这一阶段的肝癌 肝功能，不同的肿瘤数量和大小。在临床实践中，只有50%-60%的患者处于中间状态 肝癌从TACE中受益，因此反复进行TACE治疗以获得最大的肿瘤 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。前者源于进行性非靶点栓塞性肝缺血损伤，而后者 后者是由低氧诱导的血管生成、上皮向间充质转化(EMT)和肿瘤所致 由TACE引发的增长。这些过程不可避免地主导了这种疾病的病程，导致了不良的长期 长期生存，5年生存率为12%。迫切需要抗肝癌的新疗法，因为 在美国，肝癌的发病率正在稳步上升。近年来天然的omega-3脂肪酸， 二十二碳六烯酸(DHA)已被证明具有良好的抗癌性能及其消费 与降低肝细胞癌的风险有关。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，我们的实验室设计了一种基于低密度脂蛋白(LDL)的新型生物 与未酯化的DHA(这里称为低密度脂蛋白-DHA)重组。在治疗方面，我们已经在一个 同基因大鼠肝细胞癌模型，经动脉注射低密度脂蛋白-DHA可引起广泛的坏死(80%) 抑制肿瘤生长(3倍)，对周围正常肝脏无损伤。此外， 反复动脉内注射低密度脂蛋白-DHA治疗可使肝细胞癌持续消退。此外， 在正常肝脏中摄取低密度脂蛋白-DHA不仅是安全的，而且具有潜在的肝脏保护作用。在……里面 此外，我们小组最近的初步数据证明，低密度脂蛋白-脱氧核糖核酸能够下调缺氧诱导因子-1的α 和肝癌细胞中的EMT信号，从而抑制肿瘤血管生成/再生长活性。当前的目标是 建议评估影像引导的局部低密度脂蛋白-DHA治疗中期肝细胞癌的实用性。至 为了实现这一目标，我们将检查以下具体目标：1)评估动脉内注射低密度脂蛋白-DHA的安全性 2)比较低密度脂蛋白-DHA与常规药物的治疗效果。 TACE方法在患者来源的异种肝细胞癌大鼠模型中提供持续的肿瘤控制。我们预计 这些目标的联合工作将验证低密度脂蛋白-DHA治疗在保护肝功能方面的安全性 在肝硬变的情况下，并展示了这种疗法的有效性，以提供持续的肿瘤根除 TACE。低密度脂蛋白-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 肝细胞癌，同时保留肝功能。归根结底，将这项技术带到临床是我们的努力 有望为不能切除的肝细胞癌提供安全有效的治疗方法。