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Isocitrate Dehydrogenase 1 (IDH1) R132 Mutation Human Melanoma Metastasis Cell Line

Posted Nov 25 2010 7:00pm

Description of Invention:
Isocitrate dehydrogenase 1 (IDH1) plays an important role in glucose metabolism in the cytoplasm, converting isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+ to NADPH). However, when IDH1 harbors a R132 mutation it results in the accumulation of 2-hydroxyglutarate and has a corresponding association with cancer. This mutation in IDH1 has previously been identified in approximately 80% of progressive gliomas and 10% acute myeloid leukemias (AML). In contrast, this mutation is very rare in other cancers. Therefore, additional research on the IDH1 R132 mutation could be useful for diagnostic, prognostic, and therapeutic purposes.

The researchers at the NIH have developed a human melanoma cell line designated 2633, which harbors the IDH1 R132C mutation. The inventors used low passage cell lines derived from a panel of confirmed metastatic melanoma tumor resections, paired with apheresis-collected peripheral blood mononuclear cells to identify IDH1 mutations. Sequencing of IDH1 in this panel allowed them to discover a melanoma cell line with the IDH1 R132C mutation. Until now no such cell line has been found and this has hindered the understanding of the effects mutated IDH1 has on cancer progression as well as the development of drugs that would be specific for cells that harbor this mutation. Use of this cell line will allow researchers decipher the biology of this gene as well as aid in the development of specific inhibitors of its mutated form.

Applications:
  • In vitro and in vivo cell model for the IDH1 R132C mutation in melanoma. This would be an extremely useful research tool for investigating the underlying biology of IDH1 phenotypes, including effects on growth, motility, invasion, and metabolite production.
  • Research tool for testing the activity of inhibitors to IDH1, where such inhibitors could be used as a therapeutic drug to treat particular cancers including potentially glioma, AML and melanoma.
  • Research tool to generate cell lines where the R132C mutation is knocked out or the wild type gene is knocked in using an adeno-associated virus. These resulting cells can be used understand the underlying biology of IDH1 phenotypes or to identify candidate small molecule and other therapeutic drugs.


Advantages:
  • Cell line is derived from a melanoma patient: This cell line likely retains many features of primary melanoma samples. For example novel melanoma antigens identified from this cell would be expected to correlate with antigens expressed on human melanoma tumors. Studies performed using this cell line could be used to elucidate to the biological basis of the initiation and progression of melanoma in humans as well as aid in the identification and/or testing of IDH1 R132-targeted inhibitors.
  • Expresses the R132 IDH1 mutation in melanoma: IDH1 R132 mutations frequently occur in advanced gliomas, however this is the first identification of an IDH1 mutation in melanoma. Therefore, the 2633 cell line represents a tool that can be utilized to study the impact of this IDH1 gene and the R132C mutation on melanoma and other cancers.


Inventors:
No Inventor Information Available.

Patent Status:
Research Tool. Patent protection is not being pursued for this technology.

Licensing Status:
Available for licensing

Collaborative Research Opportunity:
The National Human Genome Research Institute’s Cancer Genetics Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate and/or commercialize this newly identified melanoma-associated gene as a diagnostic marker as well as utilize the IDH1 R132 cell line to identify and test IDH1 inhibitors as possible therapeutic drug candidates to treat melanoma and other cancers. Please contact Dr. Yardena Samuels at samuelsy@mail.nih.gov for more information.


For Licensing Information Please Contact:
Whitney Hastings
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: hastingw@mail.nih.gov
Phone: 301-451-7337
Fax: 301-402-0220


Ref No: 2193

Updated: 11/2010

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