The von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer: Insights into Oxygen Sensing and Treating Cancers Caused by Undruggable Mutations
The von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer: Insights into Oxygen Sensing and Treating Cancers Caused by Undruggable Mutations
批准号:
10737695
负责人:
WILLIAM G. KAELIN
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
项目状态:
未结题
起止时间:
2016-09-01 至 2030-08-31
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
中文摘要
VHL肿瘤抑制蛋白(pVHL)失活是最常见的起始(“截尾”)事件
英文摘要
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.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
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:
Neuro-oncology
影响因子:
15.9
作者:
[Shi,DianaD, Kaelin,WilliamG]
通讯作者:
Kaelin,WilliamG
New Paradigms for Targeting Truncal Driver Mutations
-
批准号:10471191
-
项目类别:
-
资助金额:$96.29万
-
财政年份:2016
-
负责人:WILLIAM G. KAELIN
-
依托单位:
New Paradigms for Targeting Truncal Driver Mutations
-
批准号:10228726
-
项目类别:
-
资助金额:$98.25万
-
财政年份:2016
-
负责人:WILLIAM G. KAELIN
-
依托单位:
New Paradigms for Targeting Truncal Driver Mutations
-
批准号:9186766
-
项目类别:
-
资助金额:$98.25万
-
财政年份:2016
-
负责人:WILLIAM G. KAELIN
-
依托单位:
New Paradigms for Targeting Truncal Driver Mutations
-
批准号:9978002
-
项目类别:
-
资助金额:$98.25万
-
财政年份:2016
-
负责人:WILLIAM G. KAELIN
-
依托单位:
New Paradigms for Targeting Truncal Driver Mutations
-
批准号:9337392
-
项目类别:
-
资助金额:$98.25万
-
财政年份:2016
-
负责人:WILLIAM G. KAELIN
-
依托单位:
New Paradigms for Targeting Truncal Driver Mutations
-
批准号:9764295
-
项目类别:
-
资助金额:$95.3万
-
财政年份:2016
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)
-
批准号:10019488
-
项目类别:
-
资助金额:$34.64万
-
财政年份:2013
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Targeting the IDH Pathway
-
批准号:8588493
-
项目类别:
-
资助金额:$32.62万
-
财政年份:2013
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)
-
批准号:10245086
-
项目类别:
-
资助金额:$34.13万
-
财政年份:2013
-
负责人:WILLIAM G. KAELIN
-
依托单位:
P2 - Treament of VHL-/- clear cell renal carcinoma with HIF2a siRNA
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批准号:8079678
-
项目类别:
-
资助金额:$27.34万
-
财政年份:2010
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Functional Analysis of the Von Hippel-Lindau Protein
-
批准号:7909444
-
项目类别:
-
资助金额:$31.1万
-
财政年份:2009
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Treament of VHL-/- clear cell renal carcinoma with HIF2a siRNA
-
批准号:7742540
-
项目类别:
-
资助金额:$27.2万
-
财政年份:2009
-
负责人:WILLIAM G. KAELIN
-
依托单位:
A Luciferase Fusion Protein Library to Identify & Monitor Ubiquitylation Targets
-
批准号:7504000
-
项目类别:
-
资助金额:$20.52万
-
财政年份:2006
-
负责人:WILLIAM G. KAELIN
-
依托单位:
A Luciferase Fusion Protein Library to Identify & Monitor Ubiquitylation Targets
-
批准号:7187670
-
项目类别:
-
资助金额:$17.1万
-
财政年份:2006
-
负责人:WILLIAM G. KAELIN
-
依托单位:
2006 Cancer Model Mechanisms
-
批准号:7161054
-
项目类别:
-
资助金额:$0.7万
-
财政年份:2006
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Using Synthetic Lethality to Select Cancer Drug Targets
-
批准号:6718039
-
项目类别:
-
资助金额:$15.39万
-
财政年份:2004
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Real-Time Imaging of Hypoxia based on VHL Activity
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批准号:7078339
-
项目类别:
-
资助金额:$23.87万
-
财政年份:2004
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Real-Time Imaging of Hypoxia based on VHL Activity
-
批准号:6783847
-
项目类别:
-
资助金额:$18.68万
-
财政年份:2004
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Real-Time Imaging of Hypoxia based on VHL Activity
-
批准号:7089967
-
项目类别:
-
资助金额:$24.01万
-
财政年份:2004
-
负责人:WILLIAM G. KAELIN
-
依托单位:
Using Synthetic Lethality to Select Cancer Drug Targets
-
批准号:6869552
-
项目类别:
-
资助金额:$15.39万
-
财政年份:2004
-
负责人:WILLIAM G. KAELIN
-
依托单位:
海外基金