“Good” models for translational
research
Translational research with
small animal IGRT
• Should assess both
tumor control and normal
tissue effects
– Relevant tumor model
• Orthotopic tumor
• Carcinogenesis
– Normal tissue endpoints in
conjunction with tumor
Andrew Hope, MD
Assistant Professor
Department of Radiation Oncology
University of Toronto
Staff Radiation Oncologist
Radiation Medicine Program
Princess Margaret Hospital
• Longitudinal studies with
non-invasive endpoints
• Physiologic measures
• Imaging
Pre-clinical imaging modalities
µCT
Gruene et al., Gamma Medica, Nature Medicine
µSPECT
µPET
MR – 7T
Pre-clinical imaging modalities
µUS
µOptical
Images courtesy of Visualsonics, Xenogen
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Biologic variation is a significant
factor in the clinic
• Inherent radiosensitivity
and/or response to treatment
may be as important as the
dose itself
• Small animal irradiation can
minimize biologic variation
A challenging problem
• Glioblastoma
– Very poor long-term
prognosis
– Radiotherapy alone
insufficient
– Some improvements with
addition of temozolomide
(~10% OS @ 5y)
– inbred strains
• Evaluation of radiotherapy,
chemotherapy, and biologic
agents without confounding
genetic heterogenity
Yuan et al., JCO, 2009
• 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
• CXCR4 suppression
elevates cAMP
– Elevated cAMP suppresses
tumor growth
• Rolipram (generic drug)
elevated cAMP as well as
more expensive ‘targeted’
agent
Yang, L. et al. Cancer Res 67, 651-658(2007).
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An in vivo model
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
• Intracranially implanted
bioluminescent tumors
– U87-luc/NCR nude
• Growth can be tracked
longitudinally with noninvasive imaging
– Adjacent critical structures! (Pharynx, esophagus, eye)
– Concurrent chemotherapy
• Tumor growth is
slowed, but not halted
microRTP
microRT
• What’s the next step?
Yang, L. et al. Cancer Res 67, 651-658(2007).
Kiehl, E.L. et al. Med Phys 35, 4735-4743(2008).
Experimental schema
An important observation in vivo
RT: 6x5Gy MWFx2
Imaging Imaging Imaging Imaging Imaging Imaging
TMZ
TMZ
TMZ
TMZ
Rolipram
• RT – 30 Gy / 6 (pragmatic, ~66 Gy equiv)
• Temozolomide (21 mg/kg/d x 5d per month)
• Rolipram (5mg / kg continuously)
Goldhoff, P. et al. Clin Cancer Res 14, 7717-7725(2008).
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A translatable result?
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
unresectable (and universally fatal) brain stem
gliomas
Goldhoff, P. et al. Clin Cancer Res 14, 7717-7725(2008).
A related clinical problem
An in vivo normal tissue model
• Using a micro-IGRT
device, sub-totally
irradiate murine brain
– 60 Gy / 10 fractions
• Radiation necrosis
– Imaging methods currently don’t clearly differentiate from tumor
– TMZ addition appears to make this effect more common
• Monitor with small
animal MR
• Up to 10% rate
– Biopsy is usually required to prevent futile re-operation
Peca, C. et al. Clin Neurol Neurosurg 111, 331-334(2009).
Jost, S.C. et al. Intl J Rad Onc Bio Phys In press,
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Contrast-enhanced, T1-weighted, gradient-echo images
Histology confirms necrosis
2 months
4 months
6 months
Mouse
Human
T2-weighted spin-echo images
Jost, S.C. et al. Intl J Rad Onc Bio Phys In press,
Tools for translation research
•
Biologic (targeted) agents
Chemotherapy
Timing
Combinations
Modeling outcomes
–
–
•
Modulate dose to adjust TCP and NTCP
Model uncomplicated control
Imaging questions
–
Novel imaging methods and modalities (PET tracers,
MR sequences, etc)
•
•
Carcinogenesis models
Orthotopic tumor and normal tissue models
–
–
–
–
•
Jost, S.C. et al. Intl J Rad Onc Bio Phys In press,
Imaging biomarkers to distinguish tumor from necrosis
Therapy questions
–
–
Hypoxia targeting?
Sub-volume boosts to ‘resistant’ areas
Garbow et al., Clin Can Res 2008
5
Respiratory correlated small animal
CBCT and 4D IGRT
Amplitude 0
• Clinical
Amplitude 0.2
5
Endpoints:
Pre-clinical and Clinical
–
–
–
–
–
5
10
10
15
15
5
10
15
20
Amplitude 0.4
25
5
5
10
10
15
5
10
15
20
Amplitude 0.6
25
5
10
25
Symptoms
Histology
Laboratory
Physiology
Imaging
• Pre-clinical
–
–
–
–
Histology
Laboratory
Physiology
Imaging
15
5
10
15
20
25
15
20
• Anatomic
• Functional
Amplitude 1
5
2
1.5
1
0.5
Amplitude 0.8
5
• Anatomic
• Functional
0
-0.5
-1
2
-1.5
1. 5
0
0.864
1.728
1
2. 592
3.456
Sit e3-WBP1: Flow
0. 5
4.32
WB FDP:Time
0
-0.5
-1
10
– Tumor
endpoints
10
15
15
5
10
15
20
25
5
10
15
20
25
– Tumor
endpoints
-1.5
0
0. 938
1.876
2. 814
Sit e1-WBP1: Flow
3.752
4.69
WB FDP:Time
Moseley D., Lindsay, P. 2009
Acknowledgements:
Washington University in St. Louis
Conclusions
•
Potential for exploration with small
animal IGRT is immense
– Internal normal control tissue for
experiments
•
Many issues to consider for each
potential application
– Biology
• Species/strain
• Tumor model
• Endpoints
– Radiotherapy
•
•
•
•
Fractionation
Dose distribution
Motion
Validation
– Drugs
• Timing
• Sequencing
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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)
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