Brain Tumor Update Genomics and Targeted Therapy For Malignant Gliomas Hassan FathallahShaykh, M'D',

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Brain Tumor UpdateGenomics and Targeted Therapy
For Malignant GliomasHassan Fathallah-Shaykh,
M.D., Ph.D.The Brain Tumor and Research
Program,Mathematics and Cell BiologyThe
University of Alabama at Birmingham
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PLAN

• Introduction
• Updates on the treatment of low-grade gliomas
• The role of epigenetics in mediating
  tumor-responsiveness/resistance to Temodar.
• Pseudoprogression
• Bevacizumab results, new insights, and
  controversies
• Integrated genomics in GBM implications for
  targeted therapy
• Research interests

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Low Grade Astrocytoma
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Anaplastic Astrocytoma
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Glioblastoma Multiforme
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Astrocytoma Classifications
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Radionecrosis
Brandsma et al. Lancet Oncol 9 453-461, 2008
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FDG/FLT PET in GLIOMAS
Chen et al. J Nucl Med 46956-952, 2005
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FDG/FLT PET in GLIOMAS
Chen et al. J Nucl Med 46956-952, 2005
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PERFUSION MRI in GLIOMAS
Law et al. radiology 2005
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Pseudoprogression

• Pseudoprogression is a recently recognized
  phenomenon that appears to be caused by the
  combination of Temodar and Radiation therapy.

Brandsma et al. Lancet Oncol 9 453-461, 2008
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Pseudoprogression
Brandsma et al. Lancet Oncol 9 453-461, 2008
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LOW GRADE GLIOMA UPDATE

• RTOG study
• 111 patients, lt 40 years of age.
• WHO grade II astrocytoma, oligodendroglioma, or
  mixed.
• All patients has neurosurgeon-determined gross
  total resection.
• Overall survival at 2 and 5 years was 99 and
  93, respectively.

Shaw et al. J Neurosurg 109 835-841, 2008
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Treatment Options in Low-Grade Glioma
Shaw et al. J Neurosurg 109 835-841, 2008
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Treatment Options in Low-Grade Glioma
Shaw et al. J Neurosurg 109 835-841, 2008
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Treatment Options in Low-grade Glioma
Shaw et al. J Neurosurg 109 835-841, 2008
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MALIGNANT ASTROCYTOMA UPDATE
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BCNU And/or Radiotherapy in The Treatment of
Malignant Gliomas
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Radiotherapy Temozolomide in The Treatment of
GBM573 Patients
Stupp et al. NEJM 352987-996, 2005
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Radiotherapy Temozolomide Overall Survival
Stupp et al. NEJM 352987-996, 2005
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Radiotherapy Temozolomide Survival
Stupp et al. NEJM 352987-996, 2005
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Radiotherapy Temozolomide PFS at 6 months
Stupp et al. NEJM 352987-996, 2005
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Epigenetic Control of Sensitivity to Temodar

• In human cells MGMT (O6-methylguanine DNA methyl
  transferase) is a repair protein that removes
  O6-alkylguanine DNA adducts (such as methyl-,
  ethyl-, cloroethylgroups).

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Epigenetic Control of Sensitivity to Temodar
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Epigenetics Control of Drug Sensitivity 46 in
Each Group
Heigi et al. NEJM 352997-1003, 2005
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Epigenetics Control of Drug Sensitivity
Heigi et al. NEJM 352997-1003, 2005
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Epigenetics Control of Drug Sensitivity

• Determination of the MGMT promotor methylation
  status by methylation-specific PCR may allow the
  selection of patients most likely to benefit from
  Temozolomide treatment patients whose tumors are
  not methylated at the MGMT promotor appear to
  derive little or no benefit from the addition of
  Temozolomide to radiotherapy.

Heigi et al. NEJM 352997-1003, 2005
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BEVACIZUMB INITIAL HYPOTHESIS
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BEVACIZUMB CPT11 FOR RECURRENT MALIGNANT GLIOMA

• (1) Vredenburgh JJ, et al J Clin Oncol
  2007254722-9.
• (2) Vredenburgh JJ, et el. Clin Cancer Res
  2007131253-9.
• (3) Pope WB, et al. Neurology 2007661258-60.
• (4) Guiu S, et al. Rev Neurol 2008164588-94.
• (5) Bokstein F, et al . Cancer 20081122267-73.

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BEVACIZUMB CPT11 FOR RECURRENTMALIGNANT GLIOMA
Tim Cloughesy, Abstract, ASCO 2008
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Single-Agent Bevacizumab
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Single-Agent Bevacizumab
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Single-Agent Bevacizumab
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Single-Agent Bevacizumab
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Bevacizumab Radiological Response at 3 Months
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Bevacizumab Radiological Response at 12 Months
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BEVACIZUMB NEWS WAYS OF PROGRESSION AND
CONTROVERSIES

• Bev normalizes the BBB less enhancement does not
  always mean anti-tumor effects.
• Patients may show evidence of progression by
  increased FLAIR not by enlarging enhancement.
• Stopping Bev appears to be associated with rapid
  disease progression.

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BEVACIZUMB EFFECTS ON BLOOD BRAIN BARRIER
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Glioblastoma Multiforme
Angiogenesis
What drives this devastating phenotype?
Proliferation
Invasion
What role(s) do molecular alterations play in
improving treatment?
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Genome-Scale Expression Disovery in Malignant
Gliomas

• Expression levels of 19200 cDNA by microarrays
• 16 GBM and 16 lower-grade gliomas.

Fathallah-Shaykh et al, Oncogene 217164-7177,
2002
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Genome-Scale Expression Disovery in Malignant
Gliomas
Fathallah-Shaykh et al, Oncogene 217164-7177,
2002
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Molecular Subclasses of High-Grade Gliomas

• 76 high-grade Astrocytomas.
• Genome-scale expression discovery of microarrays.
• CGH Arrays.

H . Phillips, et al. Cancer Cell 9 157-173, 2006
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Molecular Subclasses of High-Grade Gliomas
H . Phillips, et al. Cancer Cell 9 157-173, 2006
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Molecular Subclasses of High-Grade Gliomas
H . Phillips, et al. Cancer Cell 9 157-173, 2006
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Integrated Genomic Analysis

• 22 GBM.
• Next generation sequencing.
• CGH arrays.

Parsons et al. Science 321 1807- 1812, 2008
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Integrated genomic Analysis of 22 GBM
Parsons et al. Science 321 1807- 1812, 2008
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Isocitrate Dehydrogenase 1 Mutations in 12 of GBM
Parsons et al. Science 321 1807- 1812, 2008
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Integrated Genomic Analysis of 22 GBM

• Affected pathways include the Akt, PI3K, and RB1.

Parsons et al. Science 321 1807- 1812, 2008
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Cancer Genome Atlas Research Network

• 206 newly diagnosed GBM tumors
• Full cDNA sequence analysis
• DNA copy number
• mRNA expression profile analysis
• Methylation at CpG dinucleotide analysis

Nature 455/23 October 2008/doi.10.1038/nature0738
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Cancer Genome Atlas Research Network
Nature 455/23 October 2008/doi.10.1038/nature0738
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Ligands/ growth factors
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Ligands/ growth factors
extracellular compartment

cytoplasmic membrane
EGFR, PDGFR, IGFR1
K
intracellular compartment
K
RasGTP
PTEN
mTOR
FKHR, GSK-3, Bad
VEGF
Proliferation
Transcription
Protein-synthesis
Cell cycle regulation Cell survival
Angiogenesis
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Targeted Therapy 1st Generation Trials Malignant
Glioma
Agent
Target
Activity
Citation
Phase
No.
Eligibility
Iressa
EGFR
II
Rec GBM
Rich JCO 2004
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9 SD gt 6 mths
Tarceva
EGFR
II
Rec MG
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1 PR/6SD PFS 8-12 wks
Raizer ASCO 2004,1502
Tarceva
EGFR
II
Rec GBM
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5 PR/5SD gt 6 mths
Vogelbaum ASCO 2004,1558
Tarceva
EGFR
II
Rec GBM
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6 PR/5 SD
Prados ASCO 2003,
Tarceva
EGFR
II
Rec GBM
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1 CR/1 PR/11 SD
Yung ASCO 2004, 1555
II
Rec GBM
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3 PR/5 SD gt 6 mths
Gleevec
PDGF
Van den Bent ASCO 2004, 1501
Gleevec
PDGF
I/II
Rec GBM
95
2 PR/14 SD
Wen SNO 2004, TA 63
CCI 779
mTOR
I
Rec MG
12
4 SD
Chang J Inv Drugs
CCI 779
mTOR
II
Rec GBM
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No rad response
Galanis ASCO 2004, 1503
PTK787
VEGF
I
Rec GBM
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2 PR/31 SD PFS12.1 wks
Conrad ASCO 2004, 1512
I
Rec GBM
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5 PR
LY317615
PKC-?2
Fine ASCO 2004, 1511
I
Rec MG
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2 CR/3 PR/13 SD
?V?3
Cilengitide
Nabors SNO 2004, TA 39
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Targeted Therapy Plus Cytotoxic Therapy

• Bev pathway blocker cytotoxic therapy
• Rationale
• Targeted therapeutics enhance apoptosis/diminish
  survival and may increase efficacy of cytotoxins
• Homology to HIV therapy

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Research Interests
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SUMMARY

• New results about surgical management of
  low-grade gliomas.
• Epigenetic effects on Temodar sensitivity.
• Controversies and new progression patterns in
  Bev-treated patients.
• Pseudoprogression
• Genomic analysis data reveal a complex network of
  aberrant molecular pathways in malignant gliomas.