Modulation of retinoic acid action in renal cancer

视黄酸在肾癌中作用的调节

• 批准号: 6522891
• 负责人: David M. Nanus
• 金额: $ 35.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-03 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522891
• 关键词: amidohydrolases; clinical trial phase I; combination cancer therapy; complementary DNA; drug screening /evaluation; enzyme inhibitors; gene induction /repression; human subject; human therapy evaluation; interferon alpha; kidney neoplasms; laboratory mouse; liposomes; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; patient oriented research; retinoate; western blottings

DESCRIPTION: (Provided by applicant) Renal cell carcinoma is the most common primary cancer arising from the kidney in adults, and is a frequent cause of cancer morbidity and mortality in the U.S., with over 12,000 deaths per year. Currently, there are no consistently effective chemotherapeutic or biologic treatment modalities for patients with advanced disease. Recent results of clinical trials in patients with advanced renal cancer (RC), and of pre-clinical studies using cell culture and human RC tissue specimens, suggest that natural and synthetic derivatives of vitamin A (retinol), a group of compounds called retinoids, play a role in the therapy of RC. We have preliminary data that intracellular levels of retinoic acid (RA) are significantly diminished in human RC cells and that retinol metabolism is aberrant in RC cells as compared to normal human kidney proximal tubule cells. Furthermore, our data indicate that combining retinoids with agents which augment retinoid actions, such as IFN (IFN) or histone deacetylase (HDAC) inhibitors, significantly increases the anti-tumor effect of RA. In this grant application, we propose to study the effects of modulating retinoid anti-tumor action by combining RA with other therapies. The specific aims are: 1) to perform a series of Phase I-II clinical trials designed to evaluate the safety and efficacy of combining liposomal all trans RA (ATRA) with modulators of RA such as interferon and HDAC inhibitors in patients with metastatic RC; 2) to collect peripheral blood samples and tumor tissues to allow laboratory analysis in order to monitor the presence and magnitude of specific therapies on retinoid metabolites and retinoid related genes; and 3) to analyze modulators of RA such as interferon and HDAC inhibitors at a molecular level in RC cell lines and xenograft models to delineate mechanisms of action, and to use this information to design strategies to test specific drugs in combination with RA in preparation for future clinical trials. These aims will allow us to perform clinical trials and laboratory studies aimed at gaining a better understanding of the involvement of retinoids in the development, progression and therapy of RC. Moreover, the experiments proposed in this application will help to clarify the potential use of retinoids as a therapeutic strategy to treat patients with RC, and may lead to the identification of new therapeutic agents which result in increased retinol actions for the treatment of various stages of renal cancer.

描述：（由申请人提供）肾细胞癌是成人肾脏最常见的原发性癌症，并且是经常引起的原因 美国的癌症发病率和死亡率，每年有12,000多人死亡。 目前，没有一贯有效的化学治疗或生物学 患有晚期疾病患者的治疗方式。最新结果 晚期肾癌（RC）患者的临床试验和 使用细胞培养和人RC组织标本的临床前研究表明 维生素A（视黄醇）的天然和合成衍生物，一组 称为类维生素的化合物，在RC的治疗中起作用。我们有 初步数据，细胞内视黄酸（RA）是 在人RC细胞中显着减少，视黄醇代谢是 与正常的人肾近端小管细胞相比，RC细胞中异常。 此外，我们的数据表明，将类维生素类似与药剂相结合 增强类维生素性作用，例如IFN（IFN）或组蛋白脱乙酰基酶（HDAC） 抑制剂，显着增加了RA的抗肿瘤作用。在这笔赠款中 应用，我们建议研究调节性类维生素性抗肿瘤的影响 通过将RA与其他疗法结合起来的作用。具体目的是：1） 进行一系列I-II期临床试验，旨在评估安全性 将所有反式RA（ATRA）与RA调节剂相结合的脂质体的功效 例如转移性RC患者的干扰素和HDAC抑制剂； 2）到 收集外周血样品和肿瘤组织以允许实验室分析 为了监测特定疗法的存在和大小 维生素代谢产物和类维生素性相关的基因； 3）分析调节器 在RC细胞中分子水平的干扰素和HDAC抑制剂等RA的RA 线和异种移植模型描述了作用机制，并使用 信息以设计策略以结合RA结合测试特定药物 为将来的临床试验做准备。这些目标将使我们能够执行 临床试验和实验室研究旨在获得更好的了解 类视网膜类似参与的发展，进展和治疗 RC。此外，本申请中提出的实验将有助于澄清 类维生素类似作为治疗患者的治疗策略的潜在用途 RC，并可能导致对新的治疗剂的识别 在增加视黄醇动作以治疗肾脏的各个阶段 癌症。