P2 - Treament of VHL-/- clear cell renal carcinoma with HIF2a siRNA

P2 - 使用 HIF2a siRNA 治疗 VHL-/- 透明细胞肾癌

基本信息

批准号：
8517016
负责人：
WILLIAM G. KAELIN
金额：
$ 25.48万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2015-09-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517016
关键词：
Animal Model Biopsy Specimen Cell Line Clear Cell Clinical Clinical Data Clinical Research Clinical Trials Complex Conventional (Clear Cell) Renal Cell Carcinoma Dana-Farber Cancer Institute Development Disease Down-Regulation Encapsulated Evaluation Event Failure Future Genotype Growth Human Industry Inherited Investigation Malignant Neoplasms Measures Modeling Nude Mice Oncogene Proteins Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase I Clinical Trials Phenotype Population Pre-Clinical Model Renal Cell Carcinoma Renal carcinoma Research Personnel Resistance Safety Sampling Small Interfering RNA Specificity Technology Testing Therapeutic Transferrin Transferrin Receptor Treatment Efficacy Tumor Tissue VHL Gene Inactivation VHL protein Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Work Xenograft Model base bench to bedside efficacy testing fluorodeoxyglucose positron emission tomography in vivo inhibitor/antagonist man nanoparticle outcome forecast overexpression patient population preclinical study prognostic receptor expression response therapeutic target tissue resource transcription factor tumor ubiquitin ligase

项目摘要

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.

VHL肿瘤抑制基因的失活是遗传性（VHL疾病）和非 - 遗传性透明细胞肾癌，这是肾癌最常见的形式。 VHL基因产品PVHL具有许多功能，包括充当泛素的底物识别成分靶向异二聚体转录因子HIF的α亚基的连接酶复合物用于破坏。基因型 - 表型相关性和临床前模型表明HIF2A的下调都是需要PVHL抑制肾癌生长的必要和足够该疾病的治疗靶标。不幸的是，诸如HIF2A之类的转录因素在历史上很难用类似药物的小有机分子抑制。作为替代方案，我们建议使用siRNA抑制HIF2A。最近的研究表明，将siRNA纳入在体内可以有效地传递针对转铁蛋白受体的纳米颗粒。在特定目标1和2中，我们将测试是否技术可用于在VHL - / - 肾脏癌线中下调HIF2A，以裸色生长小鼠和我们将尝试开发适合临床前和临床研究的药效标记。在AIM 3中，我们将测量人类肾癌样品中的HIF2A和转铁蛋白受体水平以评估他们彼此之间的关系和VHL的损失，对VEGFR封锁的抵抗力的影响它们的表达以及预后的意义和预测标准疗法益处的能力。最后，在AIM 4中，我们提出了一名研究人员对I期行业进行后续LB试验的启动赞助了含HIF2A的含siRNA的纳米颗粒的“第一阶段” I期试验。该阶段LB试验将是在基于肿瘤HIF2A的晚期透明细胞RCC患者的群体中进行 AIM 2和3中确定的表达和其他因素，并将包括相关药效学以AIM 2中开发的端点为模型。总的来说，这项工作显然来自板凳至卧式，应确定针对这种关键病因的安全性和治疗潜力使用含siRNA的纳米粒子技术和LAY的VHL - / - 清除细胞RCC中的清除细胞RCC 这种潜在令人兴奋的方法的未来临床发展的基础疾病。如果成功，该试验也将对其他形式的癌症产生影响 “不良”癌蛋白。