47 year-old female patient Headheachs since 3 months Tired Too heavy word, end of the year…? Late...
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Transcript of 47 year-old female patient Headheachs since 3 months Tired Too heavy word, end of the year…? Late...
47 year-old female patient
Headheachs since 3 monthsTired
Too heavy word, end of the year…?
Late July 2008
Consultations
• Family doctor
• Neurologist
CT scanner followed by IRM
Primary brain tumor
Metastases
Abcess ???
• •
•
Post-operative MRI
Large tumor resection
Histopathological diagnose
50 year-old male patientFirst epilepsia in 2004
Periventricular fronto-basal lesion
Biopsy: grade II astrocytoma
Complication: hematoma
Clinical evolution: uncontrolled epilepsia
Radiotherapy in 2005
June 2008Clinical evolution: Frontal syndrom
Agressivity
Some confusion
• •
•
Oriented frontal lobectomy
2d tumoral
pieces
Per operative analysis
• •
•
Histopathological diagnose
Post-operative CTscan
WHO histopathological grading:
IPilocytic astrocytoma
Pleiomorphic xantoastrocytoma
well-circumscribed
II
Astrocytoma
IIIAnaplastic
astrocytoma
IV
Glioblastoma
diffusely infiltrative into normal brain parenchyma
Astrocytic Tumors
60-70 % of all gliomas about 5% of all solid tumors in adults 20% in children
Expected
survival
benign
Cure is expected by
surgery
malignant
10 – 20 years
highly malignant
3 – 5 years 0.5 - 3 years
WHO histopathological gradingII III IV
Angiogenesis
Current Treatment Against High-grade Malignant Gliomas
Surgery
Anaplastic Astrocytoma
(WHO Grade III)
Anaplastic Oligodendroglioma(WHO Grade III)
Glioblastoma(WHO Grade IV)
+
Chemotherapy(PCV)
Cytogenetic Analyses 1p19q Status
Radiotherapy at Recurrence+ Temodal
Radiotherapy
Followed byChemotherapy
(PCV, Temodal)
Radiotherapy+
Chemotherapy(Temodal)
Histopathological Grading
A B C
D E F
Cancer cell migration: A coordinated process between adhesion, motility and invasion
Cell movement
adhesion complexes
new adhesion complex
ADHESION
INVASION
cancercells
secreteproteases
proteasesmake holes
in tissuethat cancer
cells can cross
actincytoskeleton
Glioblastomas (GBM) are associated with dismal prognoses because:
New types of compounds are needed to efficiently combat
devastating cancers
PI3-K Akt/PKB (PTEN) mTOR,
NFkappaB and Ras/Raf/MEK/ERK
Lefranc et al., J Clin Oncol, April 2005
McCubrey et al., Advan Enzym Regul 2006
under press
Ras
Raf
SOS
PI3KPIP2 PI3P
Akt
Transcription factors
Grb2
MAPK/ERK
mTOR inhibitors(rapamycin) mTOR
nFkB
IkBIKK
P P
PTEN
Src
Resistance to cytotoxic insultsApoptosis
Invasion / Migration
Growth Factors
Akt inhibitorsPI3K inhibitors
they are resistant to apoptosis, and so to pro-apoptotic cytotoxic drugs,
because constitutive activation of distinct anti-apoptotic signaling
pathways including:
Lefranc and Kiss, Neurosurgical Focus 2006
Stupp and Colleagues (N Engl J Med, 2005): Long-Term Treatment with TMZ
TMZ offers greater therapeutic benefits to GBM patients when administered during radiotherapy
60Gy
TMZ 75 mg/m²
2GyN= 286, radiotherapy alone
N= 287, combined therapy
TMZ 200 mg/m²TMZ 150 mg/m²0-7 cycles, median 3 cycles
2-year survival rate
10.4%
26.5%
Ran
dom
izat
ion
Hegi and Colleagues (N Engl J Med, 2005): MGMT Gene Silencing and Benefit
from Temozolomide in Glioblastoma
Benefit from Temozolomide
Why Temozolomide Is It Active
In Glioblastomas, which Are Resistant
to Apoptosis?
TMZ 100µM induces autophagy in
apoptosis-resistant glioblastoma cells
(Kanzawa T et al., Cell Death Differ,
2004)
TMZ 100µM induces late apoptosis in
p53Wt glioblastoma cells (Roos WP et al.,
Oncogene, 2007)P P
mTOR inactivation
Anticancer therapies
DR
Caspase-8
Cas
pa s
e-8
Cas
pa s
e-8
FA
DD
FA
DD
Effector caspases
DISC
Lysosome
Autophagolysosome
Type II PCDAutophagy
Type I PCDApoptosis
LC3-I
LC3-II
Mitochondria
Growth FactorReceptor
Autophagosome
Caspase-9
Lefranc et al., The Oncologist, 2007
TMZ 100µM activates stress mechanisms that
include the angiogenesis-inducing
proteins HIF-1 and VEGF in glioblastoma cells (Fisher T et al.,
Cancer J, 2007)
Metronomic treatment of TMZ reduces angiogenesis in
orthotopic models of gliomas
(Kim JT et al., Oncology Reports,
2006)
Combining Avastin with Temozolomide Increases the Anti-Tumor Efficacy of Temozolomide in Human Glioblastomas Orthotopic Xenografts
(Mathieu et al., accepted for publication )
Angiogenesis
0.5 mm
GL5 human GBM
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Days post tumor graf
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cu
mu
lati
ve P
rop
orti
on S
urv
ivin
g
Ctrl PCV Avastin/Irinotecan Temodal
J0 J52.106GL5 GBM cells
PCV (4x1); 10/10/0.63 mg/Kg IV
Ava/IRI (5x1); 10/10 mg/Kg IV
TMZ (5x1); 40 mg/Kg PO
p 0.0007p 0.0006
p 0.002
From Yamanaka R, Trends in Mol Med 2008
Dentritic Cell Vaccinotherapy
From Parney et al., Neurosurgery 2000
Dentritic Cell Vaccinotherapy
From Yamanaka R, Trends in Mol Med 2008
Dr Steven de Vleeschouwer, « Clinical experience with DC vaccinotherapy at KUL hospital », May 25th 2009