1 Translational research with small animal IGRT Andrew Hope, MD Staff Radiation Oncologist Radiation Medicine Program Princess Margaret Hospital Assistant Professor Department of Radiation Oncology University of Toronto “Good” models for translational research • Should assess both tumor control and normal tissue effects – Relevant tumor model • Orthotopic tumor • Carcinogenesis – Normal tissue endpoints in conjunction with tumor • Longitudinal studies with non-invasive endpoints • Physiologic measures • Imaging μCT μSPECT μPET MR – 7T Pre-clinical imaging modalities Gruene et al., Gamma Medica, Nature Medicine μUS μOptical Pre-clinical imaging modalities Images courtesy of Visualsonics, Xenogen
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Translational research with small animal IGRT · 2009-08-04 · Translational research with small animal IGRT Andrew Hope, MD Staff Radiation Oncologist ... µUS Optical Pre -clinical
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Translational research with small animal IGRT
Andrew Hope, MD
Staff Radiation OncologistRadiation Medicine ProgramPrincess Margaret Hospital
Assistant ProfessorDepartment of Radiation Oncology
University of Toronto
“Good” models for translational research
• Should assess both tumor control and normal tissue effects– Relevant tumor model
• Orthotopic tumor• Carcinogenesis
– Normal tissue endpoints in conjunction with tumor
• Longitudinal studies with non-invasive endpoints
• Physiologic measures• Imaging
µµµµCT µµµµSPECT µµµµPET MR – 7T
Pre-clinical imaging modalities
Gruene et al., Gamma Medica, Nature Medicine
µµµµUS µµµµOptical
Pre-clinical imaging modalities
Images courtesy of Visualsonics, Xenogen
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Biologic variation is a significant factor in the clinic
• Inherent radiosensitivityand/or response to treatment may be as important as the dose itself
• Small animal irradiation can minimize biologic variation– inbred strains
• Evaluation of radiotherapy, chemotherapy, and biologic agents without confounding genetic heterogenity
Yuan et al., JCO, 2009
A challenging problem
• Glioblastoma– Very poor long-term
prognosis – Radiotherapy alone
insufficient– Some improvements with
addition of temozolomide(~10% OS @ 5y)
• New treatments required– Novel targets continuously
being explored– How to test to see if they
improve outcomes?
Stupp, R. et al. N. Engl. J. Med 352, 987-996(2005).
A potential target
• Many brain tumors gliomas express CXCR4– G-protein coupled receptor
that drives cAMP levels
• Inhibition of CXCR4 with targeted agents slows tumor growth– Multiple cell lines
• Possible target for further clinical exploration?
Rubin, J.B. et al. Proc. Natl. Acad. Sci. U.S.A 100, 13513-13518(2003).
An exploitable mechanism
• Tumors drive cAMP down via CXCL12/CXCR4 to sustain growth
• Growth can be tracked longitudinally with non-invasive imaging
• Tumor growth is slowed, but not halted
• What’s the next step?
Yang, L. et al. Cancer Res 67, 651-658(2007).
A rationale for pre-clinical IGRT
• High RT doses are needed to effectively treat brain tumors
• Concurrent chemotherapy with temozolomide is the current standard of care
• High RT doses in previous mouse model attempts was poorly tolerated– Adjacent critical structures! (Pharynx, esophagus, eye)– Concurrent chemotherapy
microRTmicroRTP
Kiehl, E.L. et al. Med Phys 35, 4735-4743(2008).
Experimental schema
• RT – 30 Gy / 6 (pragmatic, ~66 Gy equiv)• Temozolomide (21 mg/kg/d x 5d per month)• Rolipram (5mg / kg continuously)
RT: 6x5Gy MWFx2
TMZ TMZTMZ TMZ
Rolipram
Imaging Imaging Imaging Imaging Imaging Imaging
Goldhoff, P. et al. Clin Cancer Res 14, 7717-7725(2008).
An important observation in vivo
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A translatable result?
Goldhoff, P. et al. Clin Cancer Res 14, 7717-7725(2008).
Bench to mouse… to clinic?
• Translational path– From basic science observation– Clinical relevant (staining patient samples)– Shown to be effective alone in vivo– When added to ‘standard’ therapy in vivo cured
tumors
• Next stop…. the clinic?– Novel agent in trials of pediatric patients with
Acknowledgements:Washington University in St. Louis
• Daniel Low• Strahinja Stojadinovic• Enrique Izaguirre• Simon Powell• Joseph Deasy• Issam El Naqa• Jeffrey Bradley• Sasa Mutic• James Alaly• Divya Khullar• Aditya Aapte• Kate Malinowski• Erich Kiehl• And many more…
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Acknowledgements:Princess Margaret Hospital
• Patricia Lindsay• David Jaffray• Dick Hill• Amudha Venugopal• Steve Ansell• Salomeh Jelveh• Doug Moseley• James Chow• Graham Wilson• Precision X-ray, Inc.• (many more)