47 year-old female patient Headheachs since 3 months Tired 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 patient First epilepsia in 2004 Periventricular fronto-basal lesion Biopsy: grade II astrocytoma Complication: hematoma Clinical evolution: uncontrolled epilepsia Radiotherapy in 2005 June 2008 Clinical evolution: Frontal syndrom Agressivity Some confusion

Oriented frontal lobectomy 2d tumoral pieces Per operative analysis

Histopathological diagnose

Post-operative CTscan

WHO histopathological grading: I Pilocytic astrocytoma Pleiomorphic xantoastrocytoma well-circumscribed II Astrocytoma III Anaplastic astrocytoma IV Glioblastoma diffusely infiltrative into normal brain parenchyma Astrocytic Tumors  % 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 years WHO histopathological grading IIIIIIV 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 by Chemotherapy (PCV, Temodal) Radiotherapy + Chemotherapy (Temodal) Histopathological Grading

A B CDEF

Cancer cell migration: A coordinated process between adhesion, motility and invasion Cell movement adhesion complexes new adhesion complex ADHESIONADHESION INVASIONINVASION cancer cells secrete proteases make holes in tissue that cancer cells can cross actin cytoskeleton

 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  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 2Gy N= 286, radiotherapy alone N= 287, combined therapy TMZ 200 mg/m²TMZ 150 mg/m² 0-7 cycles, median 3 cycles 2-year survival rate 10.4% 26.5% Randomization 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) 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

J0J GL5 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 p 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