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:8079678
- 负责人:
- 金额:$ 27.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Animal ModelBiopsy SpecimenCell LineClear CellClinicalClinical DataClinical ResearchClinical TrialsComplexConventional (Clear Cell) Renal Cell CarcinomaDevelopmentDiseaseDown-RegulationEncapsulatedEvaluationEventFailureFutureGenotypeGrowthHumanIndustryInheritedInvestigationMalignant NeoplasmsMeasuresModelingNude MiceOncogene ProteinsPathologyPathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePhasePhase I Clinical TrialsPhenotypePopulationPre-Clinical ModelRenal Cell CarcinomaRenal carcinomaResearch PersonnelResistanceSafetySamplingSmall Interfering RNASpecificityTechnologyTestingTherapeuticTransferrinTransferrin ReceptorTreatment EfficacyTumor TissueVHL Gene InactivationVHL proteinVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth FactorsWorkXenograft Modelbasebench to bedsideefficacy testingfluorodeoxyglucose positron emission tomographyin vivoinhibitor/antagonistmannanoparticleoutcome forecastoverexpressionpatient populationpre-clinicalprognosticreceptor expressionresponsetherapeutic targettissue resourcetranscription factortumorubiquitin 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肿瘤抑制基因失活是遗传性和非遗传性VHL疾病的常见事件
项目成果
期刊论文数量(0)
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WILLIAM G. KAELIN其他文献
WILLIAM G. KAELIN的其他文献
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{{ truncateString('WILLIAM G. KAELIN', 18)}}的其他基金
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
- 批准号:
10471191 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
- 批准号:
10228726 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
- 批准号:
9186766 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
- 批准号:
9978002 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
The von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer: Insights into Oxygen Sensing and Treating Cancers Caused by Undruggable Mutations
von Hippel-Lindau 肿瘤抑制基因和肾癌:深入了解氧感应和治疗由不可药物突变引起的癌症
- 批准号:
10737695 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
- 批准号:
9337392 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
- 批准号:
9764295 - 财政年份:2016
- 资助金额:
$ 27.34万 - 项目类别:
Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)
项目 2 - 针对 IDH 突变神经胶质瘤 (Cahill/Kaelin)
- 批准号:
10019488 - 财政年份:2013
- 资助金额:
$ 27.34万 - 项目类别:
Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)
项目 2 - 针对 IDH 突变神经胶质瘤 (Cahill/Kaelin)
- 批准号:
10245086 - 财政年份:2013
- 资助金额:
$ 27.34万 - 项目类别:
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