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

• 批准号: 8079678
• 负责人: WILLIAM G. KAELIN
• 金额: $ 27.34万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079678
• 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; 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; pre-clinical; prognostic; receptor expression; response; therapeutic target; tissue resource; transcription factor; tumor; ubiquitin ligase

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（VHL疾病）中的常见事件。 遗传性肾透明细胞癌，是最常见的肾癌。VHL基因 产物pVHL具有许多功能，包括作为泛素的底物识别组分 靶向异二聚体转录因子HIF的α亚基进行破坏的连接酶复合物。 基因型-表型相关性和临床前模型表明，HIF 2a的下调是两者兼而有之 pVHL抑制肾癌生长的必要性和充分性，从而验证HIF 2a作为一种潜在的 治疗的目标。不幸的是，转录因子如HIF 2a在历史上很难被发现。 用药物样有机小分子抑制。作为替代方案，我们建议使用siRNA抑制HIF 2a。 最近的研究表明，siRNA可以有效地在体内递送时，掺入 靶向转铁蛋白受体的纳米颗粒。在具体目标1和2中，我们将测试这是否 技术可用于下调在裸原位生长的VHL-/-肾癌细胞系中的HIF 2a 小鼠，我们将尝试开发适用于临床前和临床研究的药效学标志物。 在目标3中，我们将测量人类肾癌样本中的HIF 2a和转铁蛋白受体水平，以评估 它们彼此之间的关系和VHL损失，获得性耐药对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疗法益处的能力。 最后，在目标4中，我们提出了一个研究者发起的后续Ib期试验，以I期行业 赞助的“首次人体”含HIF 2a siRNA纳米颗粒的I期试验。该Ib期试验将是 在基于肿瘤HIF 2a选择的晚期透明细胞RCC患者人群中进行 表达和目标2和3中确定的其他因素，并将包括相关药效学 在目标2中开发的终点之后建模。总的来说，这项工作，显然从 从实验室到床边，应该建立针对这种关键病因的安全性和治疗潜力。 使用转铁蛋白靶向的、含siRNA的纳米颗粒技术， 这一潜在的令人兴奋的方法在患有这种疾病的患者中的未来临床开发的基础 疾病如果成功，这项试验也将对其他形式的癌症产生影响， “非药物性”癌蛋白。