Modulation of retinoic acid action in 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，也是导致以下疾病的常见原因： 美国癌症发病率和死亡率，每年有超过 12,000 人死亡。 目前，尚无持续有效的化疗或生物疗法 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 使用细胞培养物和人类 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 称为类视黄醇的化合物在 RC 的治疗中发挥作用。我们有 初步数据表明细胞内视黄酸（RA）水平 人类 RC 细胞中的视黄醇代谢显着减少 与正常人肾近端小管细胞相比，RC 细胞存在异常。 此外，我们的数据表明，将类维生素A与药物相结合 增强类视黄醇作用，例如干扰素 (IFN) 或组蛋白脱乙酰酶 (HDAC) 抑制剂，显着增加 RA 的抗肿瘤作用。在这笔补助金中 应用，我们建议研究调节类视黄醇抗肿瘤的效果 将 RA 与其他疗法结合起来发挥作用。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 RA (ATRA) 与 RA 调节剂组合的功效 例如转移性 RC 患者的干扰素和 HDAC 抑制剂； 2）到 收集外周血样本和肿瘤组织以进行实验室分析 为了监测特定疗法的存在和程度 类维生素A代谢物和类维生素A相关基因； 3) 分析调制器 干扰素和 HDAC 抑制剂等在 RC 细胞分子水平上对 RA 的影响 线和异种移植模型来描述作用机制，并使用它 设计与 RA 联合测试特定药物的策略的信息 为未来的临床试验做准备。这些目标将使我们能够执行 旨在更好地了解的临床试验和实验室研究 类视黄醇参与疾病的发生、进展和治疗 RC。此外，本申请中提出的实验将有助于阐明 类维生素A的潜在用途作为治疗患有以下疾病的患者的治疗策略 RC，并可能导致新治疗药物的鉴定，从而产生 增加视黄醇作用以治疗不同阶段的肾病 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.