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（HCC）被评为全球与癌症相关死亡的第二大最常见原因。 跨性化学栓塞（TACE）仍然是唯一的一线治疗 阶段HCC，使命，这个阶段已经完成了一群范围广泛的异质患者 肝功能，可变肿瘤数和大小。在临床实践中，只有50-60％的中间患者 HCC受益于TACE，因此进行了重复的TACE治疗以实现最大的肿瘤 经济衰退。影响TACE治疗有效性的关键因素是肝功能的担心 和肿瘤复发。前者是由肝脏脱靶栓塞性缺血性损伤引起的，而 后者是由于缺氧引起的血管生成，上皮到间质转变（EMT）和肿瘤引起的 由TACE触发的增长。这些过程不可避免地主导着这种疾病的进程，导致长期很差 期限生存期，5年生存率<12％。迫切需要针对HCC的新型疗法作为 在美国，HCC的发病率正在稳步增加。近年来，天然omega-3脂肪酸， 已显示二十六六烯酸（DHA）具有有希望的抗癌特性及其消耗量 已经暗示降低HCC的风险。饮食DHA对既定实体瘤的影响是 名义。为了解决这个问题，我们的实验室已经设计了一种新型的基于低密度脂蛋白（LDL）的生物学的生物学 用未固定的DHA（以下称为LDL-DHA）重组。从治疗上，我们已经显示了 HCC的合成大鼠模型，LDL-DHA的跨细胞膜递送能够诱导广泛的坏死（> 80％） HCC肿瘤并阻碍肿瘤的生长（3倍），而没有损伤正常肝脏。而且， 反复的动脉内LDL-DHA治疗可提供HCC的持续回归。此外， 正常肝脏中LDL-DHA的摄取不仅是安全的，而且可能具有肝保护性。在 此外，我们小组的最新初步数据已证明LDL-DHA能够下调HIF-1α HCC细胞中的EMT信号传导，从而抑制肿瘤血管生成/再生活性。现在的目标 提案是评估用于中级HCC的效用图像引导的局部LDL-DHA疗法。到 解决这个目标，我们将研究以下特定目的：1）评估动脉内LDL-DHA的安全性 在大鼠肝硬化模型中递送； 2）比较LDL-DHA与常规的治疗效率 TACE方法可在HCC的患者衍生 - Xenograpt大鼠模型中提供持续的肿瘤控制。我们期望 这些目标的合并工作将验证LDL-DHA治疗在保存肝功能方面的安全性 在肝硬化的环境中，并证明了这种疗法的效率 Tace。 LDL-DHA治疗策略将非常重要，因为它提供了一种有效治疗的新方法 HCC保留肝功能。最终，我们将这项技术带到诊所是我们的努力 预计将提供安全有效的方法来管理无法切除的HCC。