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