Title: Brain Tumor Update Genomics and Targeted Therapy For Malignant Gliomas Hassan FathallahShaykh, M'D',
1Brain 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
2PLAN
- 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
3Low Grade Astrocytoma
4Anaplastic Astrocytoma
5Glioblastoma Multiforme
6Astrocytoma Classifications
7Radionecrosis
Brandsma et al. Lancet Oncol 9 453-461, 2008
8FDG/FLT PET in GLIOMAS
Chen et al. J Nucl Med 46956-952, 2005
9FDG/FLT PET in GLIOMAS
Chen et al. J Nucl Med 46956-952, 2005
10PERFUSION MRI in GLIOMAS
Law et al. radiology 2005
11Pseudoprogression
- 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
12Pseudoprogression
Brandsma et al. Lancet Oncol 9 453-461, 2008
13LOW 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
14Treatment Options in Low-Grade Glioma
Shaw et al. J Neurosurg 109 835-841, 2008
15Treatment Options in Low-Grade Glioma
Shaw et al. J Neurosurg 109 835-841, 2008
16Treatment Options in Low-grade Glioma
Shaw et al. J Neurosurg 109 835-841, 2008
17MALIGNANT ASTROCYTOMA UPDATE
18BCNU And/or Radiotherapy in The Treatment of
Malignant Gliomas
19Radiotherapy Temozolomide in The Treatment of
GBM573 Patients
Stupp et al. NEJM 352987-996, 2005
20Radiotherapy Temozolomide Overall Survival
Stupp et al. NEJM 352987-996, 2005
21Radiotherapy Temozolomide Survival
Stupp et al. NEJM 352987-996, 2005
22Radiotherapy Temozolomide PFS at 6 months
Stupp et al. NEJM 352987-996, 2005
23Epigenetic 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).
24Epigenetic Control of Sensitivity to Temodar
25Epigenetics Control of Drug Sensitivity 46 in
Each Group
Heigi et al. NEJM 352997-1003, 2005
26Epigenetics Control of Drug Sensitivity
Heigi et al. NEJM 352997-1003, 2005
27Epigenetics 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
28BEVACIZUMB INITIAL HYPOTHESIS
29BEVACIZUMB 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.
30BEVACIZUMB CPT11 FOR RECURRENTMALIGNANT GLIOMA
Tim Cloughesy, Abstract, ASCO 2008
31Single-Agent Bevacizumab
32Single-Agent Bevacizumab
33Single-Agent Bevacizumab
34Single-Agent Bevacizumab
35Bevacizumab Radiological Response at 3 Months
36Bevacizumab Radiological Response at 12 Months
37BEVACIZUMB 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.
38BEVACIZUMB EFFECTS ON BLOOD BRAIN BARRIER
39Glioblastoma Multiforme
Angiogenesis
What drives this devastating phenotype?
Proliferation
Invasion
What role(s) do molecular alterations play in
improving treatment?
40(No Transcript)
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42Genome-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
43Genome-Scale Expression Disovery in Malignant
Gliomas
Fathallah-Shaykh et al, Oncogene 217164-7177,
2002
44Molecular 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
45Molecular Subclasses of High-Grade Gliomas
H . Phillips, et al. Cancer Cell 9 157-173, 2006
46Molecular Subclasses of High-Grade Gliomas
H . Phillips, et al. Cancer Cell 9 157-173, 2006
47Integrated Genomic Analysis
- 22 GBM.
- Next generation sequencing.
- CGH arrays.
Parsons et al. Science 321 1807- 1812, 2008
48Integrated genomic Analysis of 22 GBM
Parsons et al. Science 321 1807- 1812, 2008
49Isocitrate Dehydrogenase 1 Mutations in 12 of GBM
Parsons et al. Science 321 1807- 1812, 2008
50Integrated Genomic Analysis of 22 GBM
- Affected pathways include the Akt, PI3K, and RB1.
Parsons et al. Science 321 1807- 1812, 2008
51Cancer 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
5
52Cancer Genome Atlas Research Network
Nature 455/23 October 2008/doi.10.1038/nature0738
5
53Ligands/ growth factors
54Ligands/ 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
55Targeted Therapy 1st Generation Trials Malignant
Glioma
Agent
Target
Activity
Citation
Phase
No.
Eligibility
Iressa
EGFR
II
Rec GBM
Rich JCO 2004
53
9 SD gt 6 mths
Tarceva
EGFR
II
Rec MG
45
1 PR/6SD PFS 8-12 wks
Raizer ASCO 2004,1502
Tarceva
EGFR
II
Rec GBM
24
5 PR/5SD gt 6 mths
Vogelbaum ASCO 2004,1558
Tarceva
EGFR
II
Rec GBM
31
6 PR/5 SD
Prados ASCO 2003,
Tarceva
EGFR
II
Rec GBM
48
1 CR/1 PR/11 SD
Yung ASCO 2004, 1555
II
Rec GBM
51
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
31
No rad response
Galanis ASCO 2004, 1503
PTK787
VEGF
I
Rec GBM
47
2 PR/31 SD PFS12.1 wks
Conrad ASCO 2004, 1512
I
Rec GBM
28
5 PR
LY317615
PKC-?2
Fine ASCO 2004, 1511
I
Rec MG
51
2 CR/3 PR/13 SD
?V?3
Cilengitide
Nabors SNO 2004, TA 39
56Targeted 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
57Research Interests
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59SUMMARY
- 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.