Modulation of retinoic acid action in renal cancer

描述：(申请人提供)肾细胞癌是成人中最常见的原发于肾脏的癌症，也是一种常见的 美国的癌症发病率和死亡率，每年有超过12000人死亡。 目前，还没有一致有效的化疗或生物治疗方法。 晚期疾病患者的治疗方式。最近的结果是 晚期肾癌(RC)患者的临床试验，以及 使用细胞培养和人类RC组织标本的临床前研究表明 维生素A的天然和合成衍生物(视黄醇)，一组 被称为维甲酸的化合物在RC的治疗中发挥着作用。我们有 初步数据显示，细胞内维甲酸(RA)水平 在人RC细胞中显著减少，视黄醇代谢 与正常人肾近端小管细胞相比，RC细胞发生了异常。 此外，我们的数据表明，将维甲酸与 增强类维甲酸的作用，如干扰素(干扰素)或组蛋白脱乙酰酶(HDAC) 抑制剂，可显著增强RA的抗肿瘤作用。在这笔赠款中 应用，我们建议研究调节维甲酸的抗肿瘤作用 通过将类风湿关节炎与其他疗法相结合来发挥作用。具体目标是：1) 进行一系列旨在评估安全性的I-II期临床试验 脂质体全反式维甲酸(ATRA)与维甲酸调节剂联合应用的疗效 如干扰素和HDAC抑制剂对转移性RC患者的治疗；2) 采集外周血样和肿瘤组织，以便进行实验室分析 为了监测特定疗法的存在和规模 维甲酸代谢产物和维甲酸相关基因；3)分析调节物 干扰素和HDAC抑制剂等RA在RC细胞中分子水平的表达 LINE和异种移植模型来描述作用机制，并使用这一 设计策略以结合RA测试特定药物的信息 为未来的临床试验做准备。这些目标将使我们能够实现 临床试验和实验室研究旨在更好地了解 视黄醇类物质参与肿瘤的发生、发展和治疗 RC.此外，本申请中提出的实验将有助于澄清 维甲酸作为一种治疗策略治疗慢性粒细胞白血病的可能性 RC，并可能导致识别新的治疗剂，从而导致 在治疗不同阶段肾脏疾病中增加视黄醇的作用 癌症。

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.