Treament of VHL-/- clear cell renal carcinoma with HIF2a siRNA

VHL抑癌基因失活是遗传性(VHL病)和非遗传性白血病的常见事件 遗传性透明细胞肾癌，这是肾癌最常见的形式。VHL基因 产物pVHL具有多种功能，包括作为泛素的底物识别成分 以异二聚体转录因子HIF的α亚基为靶点的连接酶复合体。 基因型-表型相关性和临床前模型表明，HIF2A的下调既是 PVHL抑制肾癌生长的充要条件，从而验证了HIF2A作为一种潜在的 这种疾病的治疗靶点。不幸的是，像HIF2A这样的转录因子在历史上很难 用类药物的有机小分子抑制。作为替代方案，我们建议使用siRNA来抑制HIF2A。 最近的研究表明，当siRNA被掺入体内时，可以有效地在体内传递 靶向转铁蛋白受体的纳米颗粒。在具体目标1和2中，我们将测试这一点 技术可用于下调裸鼠原位生长的VHL-/肾癌细胞中HIF2A的表达 我们将尝试开发适合临床前和临床研究的药效学标记物。 在目标3中，我们将检测人类肾癌样本中hif2a和转铁蛋白受体的水平，以评估 它们之间的相互关系与VHL的丢失，获得性抵抗对VEGFR阻断的影响 它们的表达，以及它们的预后意义和预测标准治疗的益处的能力。 最后，在目标4中，我们建议由研究人员启动第一阶段行业的后续lb阶段试验。 赞助“人类首例”含HIF2AsiRNA纳米粒子的第一阶段试验。这一阶段Lb试验将是 在一组根据肿瘤HIF2A选择的晚期透明细胞肾癌患者中进行 目标2和3中确定的表达和其他因素，并将包括相关的药效学 以在Aim 2中开发的端点为模型。综合来看，这项工作显然来自 从病床到床边，应该确定针对这一关键病因的安全性和治疗潜力 利用转铁蛋白靶向、含有siRNA的纳米颗粒技术和LAY技术在VHL-/-Clear细胞RCC中的因子 这一潜在的令人兴奋的方法对患有这种疾病的患者未来的临床开发奠定了基础 疾病。如果成功，这项试验还将对其他形式的癌症产生影响，这些癌症由 “无法下药的”癌蛋白。

Inactivation of the VHL tumor suppressor gene is a common event in hereditary (VHL Disease) and non- hereditary clear cell renal carcinoma, which is the most common form of kidney cancer. The VHL gene product, pVHL, has many functions including acting as the substrate recognition component of an ubiquitin ligase complex that targets the alpha subunit of the heterodimeric transcription factor HIF for destruction. Genotype-phenotype correlations and preclinical models suggest that downregulation of HIF2a is both necessary and sufficient for pVHL to suppress renal carcinoma growth, thus validating HIF2a as a potential therapeutic target in this disease. Unfortunately, transcription factors such as HIF2a are historically difficult to inhibit with drug-like small organic molecules. As an alternative, we propose to inhibit HIF2a using siRNA. Recent studies suggest that siRNA can be effectively delivered in vivo when incorporated within nanoparticles targeted to the transferrin receptor. In specific aims 1 and 2 we will test whether this technology can be used to downregulate HIF2a in VHL-/- renal carcinoma lines grown orthotopically in nude mice and we will attempt to develop pharmacodynamic markers suitable for preclinical and clinical studies. In Aim 3 we will measure HIF2a and transferrin receptor levels in human kidney cancer samples to assess their relationship to each other and VHL loss, the influence of acquired resistance to VEGFR blockade on their expression, as well as their prognostic significance and ability to predict benefit to standard therapies. Finally, in Aim 4 we proposed an investigator initiated follow-on Phase lb trial to a Phase I industry sponsored "first in man" Phase I trial of HIF2a siRNA-containing nanoparticles. This Phase lb trial will be performed in a population of patients with advanced clear cell RCC selected based on tumor HIF2a expression and other factors identified in Aims 2 and 3 and will include correlative pharmacodynamic endpoints modeled after those developed in Aim 2. Taken together, this work, which clearly goes from bench-to-bedside, should establish the safety and therapeutic potential for targeting this critical etiologic factor in VHL -/- clear cell RCC using transferrin-targeted, siRNA-containing nanoparticle technology and lay the groundwork for future clinical development of this potentially exciting approach in patients with this disease. If successful, this trial would also have implications for other forms of cancer that are driven by "undruggable" oncoproteins.