Tumor-targeted anti-CK2 RNAi for treatment of HCC

肿瘤靶向抗 CK2 RNAi 治疗 HCC

基本信息

批准号：
8303919
负责人：
BETSY T KREN
金额：
$ 13.5万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303919
关键词：
Affect Animal Model Animals Antineoplastic Agents Apoptosis Biodistribution Blood Circulation Cancer Etiology Carcinoma in Situ Catalytic Domain Cell Death Cell Line Cessation of life Clinic Clinical Clinical Trials Coupling Dextrans Diagnosis Disease Dose Down-Regulation Dysprosium Effectiveness Encapsulated Environment Excision Failure Family Goals Head and Neck Cancer Hepatocyte Human Image Immunocompetent In Vitro Lanthanoid Series Elements Ligands Liver Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Methods Microscopy Modeling Mus Neutron Activation Analysis Normal Cell Nucleic Acids Oligonucleotides Oncogenic Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Phenotype Phosphotransferases Plasmids Primary carcinoma of the liver cells Procedures Production Proteins Proteolysis RNA RNA Interference RNA-Induced Silencing Complex Rattus Research Resistance Signal Pathway Site Specificity Staging Survival Rate System Techniques Testing Therapeutic Therapeutic Effect Tissues Transcript Transgenes United States Untranslated RNA Work Xenograft Model asialoorosomucoid cancer cell capsule casein kinase I casein kinase II cell growth cell killing cell type chemotherapy design dextran genetic regulatory protein hepatoma cell in vivo inhibitor/antagonist innovation killings member mortality nanocapsule nanometer neoplastic cell novel small molecule targeted delivery therapeutic target trafficking treatment strategy tumor tumor-specific gene delivery tumorigenesis tumorigenic uptake

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a rapidly increasing form of cancer in the United States, with ~ 14,000 deaths annually, ranking it as the 8th cause of cancer mortality. HCC is a highly malignant tumor type with the overall 1-year survival rate below 50% and the 5-year survival below 10%. Although progress has been made in interventional procedures for treating HCC in situ, the most successful recent chemotherapeutic developed, soranfenib only increased the median survival rate of patients from 7.9 to 10.7 months. Thus, alternate strategies are needed for HCC not amenable to surgery. The long-range goal of this project is to develop an effective RNA inhibition (RNAi) strategy targeting only the cancer cells for treatment of HCC. To accomplish this objective, this R21 is a proof-of-concept that will determine the utility of this approach using tumor-targeted delivery of a sub 50 nanometer (s50) encapsulated nucleic acid RNAi therapeutic targeting the key regulatory protein, casein kinase II (CK2) in treating HCC. The two Specific Aims proposed are designed to test the hypothesis that coupling the novel nonviral s50 nanocapsule that provides cell-type specific delivery to the liver in vivo, by use of an alternate ligand, tenfibgen (TBG), can effectively direct RNAi targeting CK2 specifically to the HCC tumors; and disabling CK2 activity via RNAi will effectively reduce or potentially clear the HCC in the animals as observed in mouse xenograft models of head neck and prostate cancer. Specific Aim 1, is designed to characterize and compare in vitro the uptake and specificity of TBG s50 nanocapsules containing RNAi targeting CK2? and ?' catalytic subunits to effectively silence CK2 activity in human and rat HCC cell lines and WB-F344 a "normal" rat hepatocyte cell line. The rationale for disabling CK2 activity is it has been identified as a key target involved in cancer signaling pathways, promoting tumorigenesis, is implicated directly in HCC proliferation and resistance to cell death. In contrast, inhibition of CK2 activity promotes HCC cell death as well as restoring their sensitivity to currently employed small molecule chemotherapeutic drugs making it an attractive target for treatment of HCC. Specific Aim 2 will examine the specificity of the delivery system in vivo via neutron activation analysis for the biodistribution of the TBG nanocapsules and the effectiveness of the anti-CK2 RNAi therapeutic strategy in treating HCC in a syngeneic heterotopic rat model. If successful, this will represent a major advance of this therapeutic strategy towards our ultimate goal, human clinical use having successfully transitioned from mouse xenograft models to an immunocompetent heterotopic rat model, a failure point enroute to the clinic for many promising therapies. Moreover, many potential anticancer agents too toxic to administer systemically may be possible to use with the TBG s50 tumor-cell specific delivery in vivo, reviving effective but systemically toxic anti-HCC therapeutics for clinical use. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma (HCC) is a rapidly increasing form of cancer in the United States, with ~ 14,000 deaths annually, ranking it as the 8th cause of cancer mortality. The most successful HCC chemotherapy drug recently approved only increased the median survival rate of patients from 8 to 11 months. We have devised an effective delivery system that can efficiently send a cell killing RNAi to only the tumor cells in vivo, sparing normal cells, with the goal of this research to develop this innovative tumor-targeted therapy for clinical use in HCC.

描述（由申请人提供）：肝细胞癌 (HCC) 是美国一种快速增长的癌症形式，每年约有 14,000 人死亡，被列为癌症死亡原因的第八大原因。 HCC是一种高度恶性的肿瘤类型，总体1年生存率低于50%，5年生存率低于10%。尽管在原位治疗 HCC 的介入手术方面取得了进展，但最近开发的最成功的化疗药物索兰非尼仅将患者的中位生存率从 7.9 个月提高到 10.7 个月。因此，对于不适合手术的 HCC 需要替代策略。该项目的长期目标是开发一种有效的 RNA 抑制 (RNAi) 策略，仅针对癌细胞来治疗 HCC。为了实现这一目标，R21 是一个概念验证，它将确定该方法的实用性，即使用亚 50 纳米 (s50) 封装的核酸 RNAi 治疗剂进行肿瘤靶向递送，靶向关键的调节蛋白酪蛋白激酶 II。 CK2) 治疗 HCC。提出的两个具体目标旨在测试以下假设：通过使用替代配体 tenfibgen，将新型非病毒 s50 纳米胶囊耦合到体内肝脏，从而提供细胞类型特异性递送 (TBG)，可以有效地将靶向CK2的RNAi特异性靶向HCC肿瘤；通过 RNAi 禁用 CK2 活性将有效减少或可能清除动物体内的 HCC，正如在小鼠头颈癌和前列腺癌异种移植模型中观察到的那样。具体目标 1，旨在体外表征和比较含有针对 CK2? 的 RNAi 的 TBG s50 纳米胶囊的摄取和特异性。和？'催化亚基可有效沉默人和大鼠 HCC 细胞系以及“正常”大鼠肝细胞系 WB-F344 中的 CK2 活性。禁用 CK2 活性的基本原理是，它已被确定为参与癌症信号传导途径、促进肿瘤发生的关键靶标，直接涉及 HCC 增殖和细胞死亡抵抗。相反，抑制 CK2 活性会促进 HCC 细胞死亡，并恢复其对目前使用的小分子化疗药物的敏感性，使其成为 HCC 治疗的有吸引力的靶点。具体目标 2 将检查以下方面的特殊性：通过中子活化分析体内递送系统，分析 TBG 纳米胶囊的生物分布以及抗 CK2 RNAi 治疗策略在同基因异位大鼠模型中治疗 HCC 的有效性。如果成功，这将代表这种治疗策略朝着我们的最终目标迈出的重大进步，人类临床应用已成功从小鼠异种移植模型转变为具有免疫功能的异位大鼠模型，这是许多有希望的疗法走向临床的失败点。此外，许多潜在的抗癌药物由于毒性太大而无法全身给药，因此可以与 TBG s50 肿瘤细胞特异性体内递送一起使用，从而使有效但具有全身毒性的抗 HCC 疗法重新投入临床使用。公共健康相关性：肝细胞癌 (HCC) 是美国一种快速增长的癌症形式，每年约有 14,000 人死亡，被列为癌症死亡原因的第八大原因。最近批准的最成功的HCC化疗药物仅将患者的中位生存率从8个月提高到11个月。我们设计了一种有效的递送系统，可以有效地将细胞杀伤性 RNAi 只发送到体内的肿瘤细胞，而不会伤害正常细胞，本研究的目标是开发这种创新的肿瘤靶向疗法，用于 HCC 的临床应用。