1 / 18

Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res.

C ancer Genomics and Metabolomics and Their Implications in Pathology and Oncology. isocitrate. Hai Yan Department of Pathology. R100. Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res. R110. R132. Rogue Metabolism in Cancer:.

questa
Download Presentation

Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Cancer Genomics and Metabolomics and Their Implications in Pathology and Oncology isocitrate Hai Yan Department of Pathology R100 Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res. R110 R132

  2. Rogue Metabolism in Cancer: “The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by aerobic glycolysis.”-Warburg

  3. Gliomas are a Major Health Challenge ~15,000 cases/year in the US, affects all ages Urgent need for new therapies anaplastic oligodendroglioma

  4. A Challenge WHO is HuaHua?

  5. Glioma Diagnosis is a Major Challenge • Secondary GBM • Median age ~45 • Arise from low- grade • Two different diseases! But… • They look the same! • And are treated the same! • Urgent need for new diagnosis Primary GBM • Median age ~60 • Arise de novo

  6. Isocitrate Dehydrogenase 1 (IDH1) and 2 (IDH2) are Frequently Mutated in Gliomas Parsons et al. Science 2008 Yan et al. NEJM 2009

  7. Patients with IDH Mutations are Younger • GBM without IDH mutations • Median age ~55 • GBM with IDH mutation • Median age ~30

  8. Patients with IDH Mutations Have a Better Survival Anaplastic astrocytoma GBM Patient Median Survival Mutated IDH: 65 months Wildtype IDH: 20 months Patient Median Survival Mutated IDH: 31 months Wildtype IDH: 14 months Yan et al. NEJM, 2009.

  9. IDH1 Mutant GBM from Distinct Cell of Origin Lai et al JCO 2011

  10. Glioma Pathogenesis CIC & FUBP

  11. IDH1 and IDH2 are Isocitrate Dehydrogenases Mitochondria Citrate Citrate Tricarboxylic acid cycle (TCA) Isocitrate Isocitrate NADP+ NAD+ NADP+ IDH2 IDH1 Cytosol IDH3 NADPH NADH NADPH α-ketoglutarate α-ketoglutarate Succinate Reitman and Yan (2010) J Natl Cancer Inst

  12. IDH1 and IDH2 Mutations Yan et al. NEJM 2009

  13. IDH1/2 Mutants Gain a Novel Enzyme Activity IDH1 WILD-TYPE Arg132Isocitrate β-carboxyl IDH1 MUTANT His132 α-ketoglutarate Dang et al. (2009) Nature Structures: Xu et al. (2004) J Biol Chem and Dang et al. (2009) Nature.

  14. IDH Mutations and 2-HG Production Cause Epigenetic Dysregulation nature medicine volume 17 | number 3 | MARCH 2011

  15. Tricarboxylic Acid (TCA) Cycle Metabolites Affected by IDH Mutant Expression or 2-HG Reitman, Jin et al., 2011, PNAS

  16. Rogue Metabolism in Cancer: Revisiting an old hypothesis and revolutionizing clinical genomics Diagnostic clarity Quick diagnostic access Improved prognosis Targeted therapy

  17. Lab Members and Collaborators • Yan Lab: Genglin Jin, Zach Reitman, Chris Duncan, Giselle Lopez, Pat Killela, Matt Wortham, Chris Pirozzi, Rui Yang, Lee Chen, Joey Webb, Jie Feng, Yu Wang • The Preston Robert Tisch Brain Tumor Center: Yiping He, Darell Bigner, Henry Friedman, Alan Friedman, Ivan Kos, Roger McLendon, Eric Lipp, Rasheed Ahmed, David Lister, Lisa Ehinger, Diane Satterfield • Johns Hopkins: Donald W. Parsons, Yuchen Jiao, Chetan Bettegowda, Victor Velculescu, Ken Kinzler, Nick Papadopolous, Luis Diaz, Bert Vogelstein

  18. Grant Support

More Related