Initiation, persistence, and progression of hepatocellular carcinoma

肝细胞癌的发生、持续和进展

• 批准号: 7963702
• 负责人: EDWARD E SCHMIDT
• 金额: $ 19.01万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-07 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963702
• 关键词: Adolescent; Affect; Age; Age-Months; Alcoholic Liver Cirrhosis; Alleles; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Applications Grants; Birth; Cancer Model; Cancerous; Cells; Cessation of life; Chimera organism; Chronic; Cirrhosis; Complex; Control Groups; DNA; Development; Diagnosis; Diethylnitrosamine; Disease; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Early Diagnosis; Excision; Fetal Liver; Fostering; Frequencies; Future; Genes; Genetic; Genomics; Genotype; Goals; Growth; Harvest; Health; Hepatitis B; Hepatocyte; Human; In Situ; Incidence; Individual; Inflammatory; Intention; Investigation; Lead; Liver; Liver diseases; Liver neoplasms; Longevity; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Metabolic; Metabolism; Metals; Minority; Modeling; Mus; National Cancer Institute; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Play; Primary carcinoma of the liver cells; Process; Prognostic Marker; Prophylactic treatment; Protein p53; RNA; Recurrence; Refractory; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Solutions; Staging; Survival Rate; System; TP53 gene; Time; Toxic effect; Transplantation; Tumor Markers; Virus Diseases; Waiting Lists; base; cancer cell; cancer initiation; cancer therapy; carcinogenesis; cell type; chemotherapy; combinatorial; cost; drug candidate; drug metabolism; efficacy testing; improved; in utero; juvenile animal; liver metabolism; liver transplantation; men; novel; novel therapeutics; outcome forecast; prevent; public health relevance; pup; research study; response; thioredoxin reductase; thioredoxin reductase 1; tumor; tumor progression

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the 3rd most lethal cancer worldwide. Liver transplant remains the only therapy with a favorable prognosis, and even in these cases, 5-year survival rates are low and recurrence is common 1. Moreover, donor livers are in short supply, and the cost and technical difficulty of transplantation puts therapy out of reach of all by a small minority of people stricken with the disease. Clearly there is a need for pharmaceutical-based therapies for this disease, even if just to extend longevity after transplant. However, the complexities of liver metabolism have kept this goal out of reach. Cytoplasmic thioredoxin reductase (Txnrd1) plays a major role in liver metabolism. Many anti-cancer drugs or drug-candidates, as well as some compounds thought to be active in prophylaxis against cancer initiation, either affect Txnrd1 activity or are substrates for metabolism by Txnrd1 5,6. This suggests that Txnrd1 plays crucial roles in cancer initiation, persistence, and progression. However, prior to now, no studies have been performed in systems having complete and specific genetic disruption of Txnrd1. Therefore, it is unclear what role Txnrd1 plays in responses to these compounds, and what roles undefined 'other targets' might play. We have developed the first animal model with Txnrd1-deficient hepatocytes 3. In the proposed study, we will develop the first animal model with Txnrd1-deficient HCC and to use this model to study initiation, persistence, and progression of HCC in cells that either have or lack Txnrd1. To do this, we have put forth two Specific Aims. First, we will determine whether Txnrd1-deficient hepatocytes are either more susceptible or more refractory than normal hepatocytes to initiation of HCC. Second, we will determine whether Txnrd1 activity is necessary, advantageous, or antagonistic for persistence and progression of HCC cells in situ. This two-year Developmental R21 project is proposed with the intention of establishing and publicly disseminating a novel and powerful animal model for studying HCC, and to provide important understanding of the roles of Txnrd1 in cancer initiation and persistence/progression. PUBLIC HEALTH RELEVANCE: Globally, hepatocellular carcinoma (HCC) is the 3rd most lethal cancer and the most prevalent liver cancer 7. Generally it is a sequelae of chronic inflammatory liver diseases, including hepatitis B and C virus infections, alcoholic cirrhosis, and hepatotoxic exposures 8. The National Cancer Institute (NCI) lists HCC as the most rapidly increasing cancer in the US. HCC causes 14,000 annual deaths in the US and ranks 8th in cancer- related deaths among men. Untreated, HCC is usually fatal within less than a year of primary diagnosis. Since it is often diagnosed at an advanced stage and associated with severe cirrhosis, treatments can be complicated, ineffective, and poorly tolerated, and the prognosis is generally poor (http://pathology2.jhu.edu/ liver/intro.cfm). The preferred treatment is surgical removal and replacement of the cancerous liver with a non- diseased donor-liver (http://www.mayoclinic.com/health/liver-cancer/DS00399/DSECTION=treatments). There are far more people on waiting lists for donor livers than there are livers available. Thus, there is a critical need for improved strategies for preventing, detecting, and treating HCC. HCC does not respond well to current modes of chemotherapy. Whole-liver replacement, the only therapy with a favorable prognosis, has a high incidence of recurrence. Prognostic markers are being refined in hopes of directing transplants to more likely successful patients and efforts are being made to promote earlier diagnosis. However, efforts toward pharmaceutical treatments, perhaps in combination with surgical procedures, should not be abandoned. The combinations of metabolic activities that could be potentially targeted in HCC are vast and relatively un-explored. Continued investigation will eventually lead to improved strategies. Thioredoxin reductase 1 (Txnrd1) has been viewed as a promising cancer drug-target for many years. There at least two dozen drugs or drug-candidates that have Txnrd1-inhibitory activities; another large group of compounds, including potent metal-based anti-cancer drugs, are bio-converted by Txnrd1 into compounds with different physiological activities and toxicities. In addition, we have shown that disruption of Txnrd1 activates drug metabolism pathways, which will likely alter drug activities in hepatocytes. Are there, somewhere in this richly complex metabolic-pharmacologic puzzle, solutions that could help increase the survivability of HCC? We believe there are; however a better understanding of the metabolic and response pathways in liver must be achieved to foster more productive combinatorial trials. To this end, we have developed the first viable animal models entirely lacking hepatocytic Txnrd1, and here we propose to develop the first cancer model, an HCC, lacking Txnrd1. These mice will allow us to far more accurately define the roles of Txnrd1 in cancerous processes and in anti-cancer therapies. In this R21 Grant Application, we propose to develop this HCC model and to use it to resolve the roles of Txnrd1 in initiation and progression of HCC. In the future, we foresee utility for this model in measuring metabolic/pharmacokinetic aspects of potential drug combinations, and in testing efficacy of novel therapeutic strategies on HCC.

描述（由申请人提供）：肝细胞癌（HCC）是世界上第三大致死性癌症。肝移植仍然是唯一预后良好的治疗方法，即使在这些情况下，5年生存率也很低，而且复发很常见1。此外，供体肝脏供应短缺，移植的成本和技术难度使少数患者无法接受治疗。显然，这种疾病需要基于药物的疗法，即使只是为了延长移植后的寿命。然而，肝脏代谢的复杂性使这一目标无法实现。 细胞质硫氧还蛋白还原酶（Txnrd1）在肝脏代谢中发挥着重要作用。许多抗癌药物或候选药物，以及一些被认为具有预防癌症发生作用的化合物，要么影响 Txnrd1 活性，要么是 Txnrd1 代谢的底物 5,6。这表明 Txnrd1 在癌症的发生、持续和进展中发挥着至关重要的作用。然而，在此之前，尚未对具有完全且特异性的 Txnrd1 基因破坏的系统进行研究。因此，尚不清楚 Txnrd1 在对这些化合物的反应中起什么作用，以及未定义的“其他靶标”可能起什么作用。我们开发了第一个 Txnrd1 缺陷肝细胞动物模型 3。在拟议的研究中，我们将开发第一个 Txnrd1 缺陷 HCC 动物模型，并使用该模型来研究具有或缺乏 Txnrd1 的细胞中 HCC 的起始、持续和进展。为此，我们提出了两个具体目标。首先，我们将确定 Txnrd1 缺陷的肝细胞是否比正常肝细胞更容易或更难发生 HCC。其次，我们将确定 Txnrd1 活性对于原位 HCC 细胞的持续存在和进展是否是必要的、有利的还是拮抗的。提出这个为期两年的开发 R21 项目的目的是建立并公开传播一种新颖且强大的动物模型来研究 HCC，并提供对 Txnrd1 在癌症发生和持续/进展中的作用的重要理解。 公共卫生相关性：在全球范围内，肝细胞癌 (HCC) 是第三大致死性癌症，也是最常见的肝癌 7. 一般来说，它是慢性炎症性肝病的后遗症，包括乙型和丙型肝炎病毒感染、酒精性肝硬化和肝毒性暴露 8. 美国国家癌症研究所 (NCI) 将 HCC 列为增长最快的癌症 在美国。 HCC 在美国每年导致 14,000 人死亡，在男性癌症相关死亡中排名第八。如果不进行治疗，HCC 通常在初次诊断后不到一年内就会致命。由于它通常在晚期被诊断出来并伴有严重的肝硬化，因此治疗可能很复杂、无效且耐受性差，而且预后通常较差(http://pathology2.jhu.edu/liver/intro.cfm)。优选的治疗是手术切除癌性肝脏并用未患病的供体肝脏替换(http://www.mayoclinic.com/health/liver-cancer/DS00399/DSECTION=treatments)。等待捐献肝脏的人数远远多于可用肝脏的数量。因此，迫切需要改进预防、检测和治疗 HCC 的策略。 HCC 对当前的化疗模式反应不佳。全肝置换是唯一预后良好的治疗方法，但复发率很高。预后标志物正在不断完善，希望能够将移植手术引导至更有可能成功的患者，并且正在努力促进早期诊断。然而，不应放弃药物治疗（也许与外科手术相结合）的努力。 HCC 中可能针对的代谢活动组合非常广泛且相对未经探索。持续的调查最终将导致改进策略。 硫氧还蛋白还原酶 1 (Txnrd1) 多年来一直被视为有前途的癌症药物靶点。至少有两打药物或候选药物具有 Txnrd1 抑制活性；另一大类化合物，包括有效的金属抗癌药物，被 Txnrd1 生物转化为具有不同生理活性和毒性的化合物。此外，我们还发现 Txnrd1 的破坏会激活药物代谢途径，这可能会改变肝细胞中的药物活性。在这个极其复杂的代谢药理学难题中，是否存在有助于提高 HCC 生存率的解决方案？我们相信有；然而，必须更好地了解肝脏的代谢和反应途径，以促进更有成效的组合试验。为此，我们开发了第一个完全缺乏肝细胞 Txnrd1 的可行动物模型，在这里我们建议开发第一个缺乏 Txnrd1 的癌症模型，即 HCC。这些小鼠将使我们能够更准确地定义 Txnrd1 在癌症过程和抗癌治疗中的作用。在此 R21 资助申请中，我们建议开发此 HCC 模型并用它来解决 Txnrd1 在 HCC 发生和进展中的作用。将来，我们预计该模型可用于测量潜在药物组合的代谢/药代动力学方面，以及测试 HCC 新型治疗策略的功效。