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
基本信息
- 批准号:10737695
- 负责人:
- 金额:$ 99.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2030-08-31
- 项目状态:未结题
- 来源:
- 关键词:BindingBiochemicalBiological AssayCDK4 geneCachexiaCancer EtiologyCell LineCellsChemicalsClear cell renal cell carcinomaClustered Regularly Interspaced Short Palindromic RepeatsCompensationCyclin D1DHODH geneDNADevelopmentDioxygenasesDrosophila genusDrug TargetingEndogenous RetrovirusesEventFailureGenetic ScreeningGenomicsGliomaHumanHydroxylationHypercalcemiaKRAS2 geneLinkMalignant NeoplasmsMultiple MyelomaMutationOncoproteinsOxygenPatientsPeptidesProcollagen-Proline DioxygenaseProtein SecretionProteinsRenal carcinomaResistanceRetinoblastoma ProteinSiteSourceThalidomideTranslatingVHL Gene InactivationVHL geneValidationVegf InhibitorVon Hippel-Lindau Tumor Suppressor ProteinWorkalpha ketoglutaratebeta cateninc-myc Genescancer therapyhistone demethylasehypoxia inducible factor 1immunogenicinhibitorinsightinterestknockout geneleukemiamouse modelmutantparalogous geneprogramsprototyperecruitsmall moleculesomatic cell gene editingtranscription factortumorubiquitin ligase
项目摘要
VHL tumor suppressor protein (pVHL) inactivation is the usual initiating (“truncal”) event in the most common
form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL forms a ubiquitin ligase that targets the
HIF transcription factor for degradation. HIF2, but not HIF1, promotes ccRCC. Binding to pVHL requires that
the HIFalpha subunit be prolyl hydroxylated by one of the 3 oxygen-sensitive EglN prolyl hydroxylases, which
are 2-oxoglutarate (2-OG)-dependent dioxygenases (as are the TET DNA demethylases and KDM histone
demethylases). IDH mutant cancers accumulate the 2-OG competitor 2-hydroxyglutarate (2-HG). Our work
contributed to the development of VEGF inhibitors/HIF2 inhibitors for ccRCC and 2-HG inhibitors for IDH
mutant leukemia. Our discovery that thalidomide reprograms cereblon to destroy the IKZF1/3 myeloma
oncoproteins has also galvanized interest in small molecule degraders.
Not all ccRCCs respond to VEGF inhibitors/HIF2 inhibitors and 2-HG inhibitors are fairly inactive against
IDH mutant gliomas. Synthetic lethality (SL) should be a source of alternative drug targets for such tumors, and
more generally, for cancers linked to “undruggable” mutations. We have identified new potential SL interactors
for VHL (CDK4/6 and ITGAV) and mutant IDH (DHODH and GSK3b) and now propose further validation and
mechanistic studies. Intriguingly, Cyclin D1, the partner for CDK4/6, is a HIF2 target in ccRCC, but the SL
between VHL and CDK4/6 is not HIF2-dependent. We also embarked on SL screens in Drosophila cells
because paralog compensation likely causes many false-negatives in genetic screens with human cells.
We created an “up” screen for chemicals and gene knockouts that can degrade a protein of interest. We
used it to discover that Spautin-1 is a cereblon-independent IKZF1 degrader and are pursuing the underlying
mechanism. We are also applying it to various undruggable oncoproteins (e.g., c-Myc, K-Ras, b-Catenin).
Failure to downregulate Cyclin D1 causes resistance of VHL-/- ccRCC to HIF2 inhibitors in a pRB-
independent manner. We are using biochemical approaches to identify the relevant Cyclin D1 substrate(s).
We unexpectedly found that HIF1 and HIF2 bind to approximately the same genomic sites, yet recruit
different proteins. We are validating these associated proteins in biochemical and functional assays. We are
also using substrate-trapping conditions to recover non-HIF EglN substrates and non-histone KDM substrates.
We are continuing our efforts to use somatic gene editing with CRISPR to make a murine model of HIF2-
dependent VHL-/- ccRCC. We have also identified new pVHL-dependent secreted proteins including PTH-LH,
which might cause the cachexia and hypercalcemia seen in some ccRCC patients.
ccRCC is highly immunogenic, but the reason is unknown. We found that HIF2 drives the expression of
many endogenous retroviruses, some of which can be translated and presented as HLA-bound peptides. We
are examining additional ccRCC cell lines and tumors for such peptides and whether they are immunogenic.
VHL肿瘤抑制蛋白(pVHL)失活是最常见的起始(“截尾”)事件
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The INDIGO trial: Precision medicine finally comes to glioma.
INDIGO 试验:精准医学终于来到了神经胶质瘤。
- DOI:10.1093/neuonc/noad162
- 发表时间:2023
- 期刊:
- 影响因子:15.9
- 作者:Shi,DianaD;Kaelin,WilliamG
- 通讯作者:Kaelin,WilliamG
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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:
$ 99.78万 - 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:
$ 99.78万 - 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:
$ 99.78万 - 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:
$ 99.78万 - 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:
$ 99.78万 - 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:
$ 99.78万 - 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:
$ 99.78万 - 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:
$ 99.78万 - 项目类别:
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 - 财政年份:2010
- 资助金额:
$ 99.78万 - 项目类别:
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