Modulation of retinoic acid action in renal cancer

描述：（由申请人提供）肾细胞癌是最常见的 成人肾脏原发性癌症，是导致 癌症发病率和死亡率在美国，每年有超过一万两千人死亡 目前，没有持续有效的化疗或生物制剂， 晚期疾病患者的治疗方式。最近的结果 晚期肾癌（RC）患者的临床试验， 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， 称为类维生素A的化合物在RC的治疗中起作用。我们有 初步数据表明，细胞内维甲酸（RA）水平是 在人RC细胞中显著减少， 与正常人肾近端小管细胞相比，RC细胞中的细胞凋亡异常。 此外，我们的数据表明，将类维生素A与 增强类维生素A作用，如IFN（IFN）或组蛋白脱乙酰酶（HDAC） 抑制剂，显著增加RA的抗肿瘤作用。在这份赠款中， 应用，我们建议研究调节类维生素A抗肿瘤的作用 将RA与其他疗法结合。具体目标是：1） 进行一系列I-II期临床试验，旨在评估 以及脂质体全反式RA（ATRA）与RA调节剂组合的功效 例如干扰素和HDAC抑制剂; 2） 采集外周血样本和肿瘤组织，以便进行实验室分析 为了监测特定治疗的存在和程度， 类维生素A代谢物和类维生素A相关基因;和3）分析调节剂 RA如干扰素和HDAC抑制剂在RC细胞中的分子水平 线和异种移植模型来描绘作用机制，并使用这种 信息设计策略，以测试特定药物与RA的组合 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更好地了解 类维生素A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A作为治疗策略的潜在用途， RC，并可能导致新治疗药物的鉴定，从而 在增加视黄醇的作用，用于治疗各种阶段的肾 癌

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.