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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:.

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slide1

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

rogue metabolism in cancer
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

gliomas are a major health challenge
Gliomas are a Major Health Challenge

~15,000 cases/year in the US, affects all ages

Urgent need for new therapies

anaplastic oligodendroglioma

slide4

A Challenge

WHO is HuaHua?

slide5

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
isocitrate dehydrogenase 1 idh1 and 2 idh2 are frequently mutated in gliomas
Isocitrate Dehydrogenase 1 (IDH1) and 2 (IDH2) are Frequently Mutated in Gliomas

Parsons et al. Science 2008

Yan et al. NEJM 2009

slide7

Patients with IDH Mutations

are Younger

  • GBM without IDH mutations
  • Median age ~55
  • GBM with IDH mutation
  • Median age ~30
slide8

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.

slide9

IDH1 Mutant GBM from

Distinct Cell of Origin

Lai et al JCO 2011

slide11

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

idh1 and idh2 mutations
IDH1 and IDH2 Mutations

Yan et al. NEJM 2009

slide13

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.

slide14

IDH Mutations and 2-HG Production Cause Epigenetic Dysregulation

nature medicine volume 17 | number 3 | MARCH 2011

slide15

Tricarboxylic Acid (TCA) Cycle Metabolites

Affected by IDH Mutant Expression or 2-HG

Reitman, Jin et al., 2011, PNAS

rogue metabolism in cancer revisiting an old hypothesis and revolutionizing clinical genomics
Rogue Metabolism in Cancer: Revisiting an old hypothesis and revolutionizing clinical genomics

Diagnostic clarity

Quick diagnostic access

Improved prognosis

Targeted therapy

lab members and collaborators
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