3. Typical Treatment Course for Gliomas 1. Surgery-biopsy or resection 2. Radiation with low dose temozolomide (TMZ) 3. High dose or metronomic TMZ alone 4. F/u with MRI scans every two months 5. If MRI documented progression: Avastin, repeat resection, radiosurgery, or clinical trials
15. Targeting the Perinecrotic Rim in Glioblastoma Multiforme via Modulation of the Endoplasmic Reticulum Stress Response Vascularized Periphery Perinecrotic Rim (Pseudopalisades ) Necrotic Area Thrombotic Vessel
16. Targeting the Perinecrotic Rim in Glioblastoma Multiforme via Modulation of the Endoplasmic Reticulum Stress Response
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19. Targeting the Perinecrotic Rim in Glioblastoma Multiforme via Modulation of the Endoplasmic Reticulum Stress Response
32. TMZ treatment with 15% BSA Treatment in 6well plate and transfer to 96well plate for MTT analysis 2009-10-01 TMZ (uM) % O.D. at 490nm TMZ (uM) % O.D. at 490nm Conclusion: TMZ is not cytotoxic to CSC. U251 w/ 15% BSA CSC w/ 15% BSA 0 20 40 60 80 100 120 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 120 0 10 20 30 40 50 60 70 80
33. Is DMC Cytotoxic To Glioma Cancer Stem Cells (GCSC) ? U87 U251 CSC (single) CSC (sphere) DMC (uM) % O.D. at 490nm Condition: Medium +10% BSA, 48hr treatment 0 20 40 60 80 100 120 140 0 10 20 30 40 50 60 70 80 90 100
34. Does DMC Enduces ER Stress in Glioma Cancer Stem Cells (CSC) ? 1 2 3 4 5 GRP78 Chop Actin 1: No treatment 2: DMC 20uM 3: DMC 40uM 4: DMC 60uM 5: DMC 80uM
35. Does DMC Induce ER Stress in Glioma Cancer Stem Cells (CSC) ? 1 2 3 4 5 GRP78 Chop Actin Parp MGMT Conclusion: ER stress upregulated at DMC 60 uM in CSC. DMC at 60 uM reduces MGMT levels. 24hr treatment Cl. parp Parp 1: No treatment 2: DMC 20uM 3: DMC 40uM 4: DMC 60uM 5: DMC 80uM CSC-D431
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40. May/2006 Dec/2006 Fibrillary Astrocytoma grade II ______________________________________________________________________________________________________________________________________ May/2008 Jun/2007
41. JAN / 2007 MAY / 2008 Recurrente Anaplastic Oligodendroglioma ______________________________________________________________________________________________________________________________________ NOV / 2008
42. Disease-free survival (6 months) ______________________________________________________________________________________________________________________________________ The median PFS rate was 48.2% for patients with GBM, 60% for patients with AA, and 66.6% for patients with AO.
50. www.pharmaco-kinesis.com Convection Enhanced Trials 1. Some success in Phase I/II trials 2. No clear success in Phase III trials (Neopharm, Transmid) 3. Question: Lack of success from delivery or from drug?
63. Cir. And Reservoir Pump ( Bartels ) Active Valve ( Bartels ) Flow Sensor ( Sensirion ) Pressure Sensor Temperature Sensor ( GE ) pH Sensor ( WPI ) Reservior ( Metal Bellows ) www.pharmaco-kinesis.com
64. www.pharmaco-kinesis.com Wireless Radio High level goals High level tasks Internal states Growth signal Intracranial pressure Tissue condition Tissue metabolism Table of parameters Circulate Inject 1 Inject 2 Inject 3 Pump Pump-valve Pump-valve Pump-valve VEGF Spectrometer Pressure sensor pH sensor Oxygen sensor Solid Tumor Microcontroller Medication Tumor Fluid
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66. www.pharmaco-kinesis.com Avastin in 28-day pump Implantated IP CPT-11 D7 – D11 D14 – D118 D21 – D25 D28 – D32 1 st dose of Avastin 2nd dose of Avastin
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70. U87 intra-cerebral glioma model for in vivo analysis of RCR vector-mediated suicide gene therapy Establishment of tumor 1 x 10 t.u. ACE-CD injected into tumor 4 Intraperitoneal injection of 5-FC H&E / IHC Survival analysis virus spread 2 x 10 U87 tumor cells injected into nude mice 5