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BioAssay: AID 624357

Summary assay for small molecule inhibitors of HIF-2a

Most solid tumors and their metastases experience regions of hypoxia, which promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1alpha and HIF-2alpha. HIF-1alpha and HIF-2alpha are non-redundant and regulate both overlapping and unique downstream target genes. HIF-1alpha has been associated with poor patient more ..
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AID: 624357
Data Source: Burnham Center for Chemical Genomics (SBCCG-A872-HIF-2a-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2012-07-05
Modify Date: 2012-07-09
Target
Depositor Specified Assays
AIDNameTypeComment
624352uHTS identification of HIF-2a Inhibitors in a luminesence assayscreening
651589Single concentration confirmation of HIF-2a Inhibitors in a HIF-1a counterscreen in human MiAPaCa-2 Cells luciferase reporter assayscreening
651580Single concentration confirmation of uHTS identification of HIF-2a Inhibitors in a luminesence assayscreening
651581Dose response confirmation of uHTS identification of HIF-2a Inhibitors in screening - selectivity counterscreen assaysconfirmatory
652011SAR Analysis small molecule inhibitors of HIF-1a in a panel assayconfirmatory
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, La Jolla, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: 1 R03 DA033980-01A1
Assay Provider: Mei Yee Koh, Ph.D., University of Texas M.D. Anderson Cancer Center

Most solid tumors and their metastases experience regions of hypoxia, which promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1alpha and HIF-2alpha. HIF-1alpha and HIF-2alpha are non-redundant and regulate both overlapping and unique downstream target genes. HIF-1alpha has been associated with poor patient survival in multiple tumor types and is currently being pursued as a target for inhibition for cancer therapy 1, 2. HIF-2alpha has also been associated with poor patient prognosis in specific tumor types such as renal cell carcinoma (RCC), neuroblastoma, glioblastoma (GBM) and non-small cell lung cancer (NSCLC) 3-6. The tumor type specific function of HIF-2alpha has been linked with the ability of HIF-2alpha (but not HIF-1alpha) to co-operate with a number of oncoproteins such as c-Myc, EGFR and K-Ras 5, 7, 8, and also to activate genes involved in proliferation, invasion and in the maintenance of cancer stem cells (CSCs) 9, 10. Hence, although the validity of HIF-1alpha as a target in multiple tumor types cannot be denied, emerging data suggest that in certain settings, the specific inhibition of HIF-2alpha versus HIF-1alpha would be warranted. Additionally, the newly established role of HIF-2alpha in the maintenance of neoplastic but not in normal stem cells, suggests that HIF-2alpha inhibition may provide a novel strategy for the targeting of CSCs 11, 12, 13. Thus our hypothesis is that the specific inhibition of HIF-2alpha will be a useful strategy for treating HIF-2alpha driven tumors and for targeting the CSC population. The overall goal of the study is to identify small molecule specific inhibitors of HIF-2alpha that will lead to the development of new anti-cancer therapies.

REFERENCES
1. Gordan J D, Bertout J A, Hu C J, Diehl J A,Simon M C. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 2007; 11: 335-47.
2. Scrideli C A, Carlotti C G, Jr., Mata J F, Neder L, Machado H R, Oba-Sinjo S M et al. Prognostic significance of co-overexpression of the EGFR/IGFBP-2/HIF-2A genes in astrocytomas. J Neurooncol 2007; 83: 233-9.
3. Kim W Y, Perera S, Zhou B, Carretero J, Yeh J J, Heathcote S A et al. HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest 2009; 119: 2160-70.
4. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 2006; 10: 413-23.
5. Franovic A, Holterman C E, Payette J,Lee S. Human cancers converge at the HIF-2alpha oncogenic axis. Proc Natl Acad Sci U S A 2009; 106: 21306-11.
6. Giatromanolaki A, Koukourakis M I, Sivridis E, Turley H, Talks K, Pezzella F et al. Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 2001; 85: 881-90.
7. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 2009; 15: 501-13.
8. Seidel S, Garvalov B K, Wirta V, von Stechow L, Schanzer A, Meletis K et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 2010; 133: 983-95.
9. Pietras A, Hansford L M, Johnsson A S, Bridges E, Sjolund J, Gisselsson D et al. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proc Natl Acad Sci U S A 2009; 106: 16805-10.
10. Qing G,Simon M C. Hypoxia inducible factor-2alpha: a critical mediator of aggressive tumor phenotypes. Curr Opin Genet Dev 2009; 19: 60-6.
11. Carroll V A,Ashcroft M. Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 2006; 66: 6264-70.
12. Dutta D, Ray S, Vivian J L,Paul S. Activation of the VEGFR1 chromatin domain: an angiogenic signal-ETS1/HIF-2alpha regulatory axis. J Biol Chem 2008; 283: 25404-13.
13. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S et al. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 16: 678-86.
Protocol
Please see pertinent AIDs: 624352
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.
Additional Information
Grant Number: 1 R03 DA033980-01A1

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