7/15/2011
Imaging organ injury
Stem cell cell depletion
Planning Radiation Protection Clinical trials
•
•
•
•
•
•
Dennis Hallahan, MD, FASTRO
McDonnell Distinguished Professor
Washington University, St. Louis
Mallinkrodt Institute of Radiology
Siteman Cancer Center
(BJH/BJC/WUSM)
Medulloblastoma
Medulloblastoma
Whole Brain irradiation
Hair follicle vs basal layer
Intestinal crypts
Brain: hippocampal neuronal progenitors
Salivary
T cells including Treg
Hematologic
Ionizing Radiation Induces Significant Neurocognitive
Deficits
Estimated decline in full-scale, verbal
and performance IQ
(FIQ, VIQ, and PIQ, respectively) over
time after childhood cranial radiation.
IQ
Time Since Diagnosis (years)
J Clin Oncol 22:4, 706-713,2004
1
7/15/2011
Pattern of Intellectual Dysfunction
Radiation-induced apoptosis in neuronal
progenitor cells: SGZ
0 Gy
Fund of Factual Knowledge
7 Gy
Verbal Abstract Thinking
Nonverbal Abstract Thinking
Conclusion: Decline in IQ may be 2/2 to slower rate of acquisition of new skills and info
compared with healthy peers.
Palmer JCO 2001
Hippocampal neuronal apoptosis
Neurocognitive deficit
Mallinckrodt Institute
Washington University St Louis
Siteman Cancer Center
Neuronal apoptosis
β-tubulin (immature neurons, green), GFAP
(astrocytes, red) and
NG2 (immature oligodendrocytes, blue)
0.25
% apoptosis
0.2
control
3Gy
LiCl
3Gy+LiCl
0.15
0.1
0.05
0
8
16
24
Hours post irradiation, hours
FIKE & PALMER Nature Medicie, 2002
0 Gy
2 Gy
10Gy
2
7/15/2011
a.
TUNEL staining of hippoampal neurons
a
b
c
b.
d
e
f
0
0
40
80
0
80
Radiation (Gy): 0
LiCl (mg/kg):
3
3
5
5
5
Lithium increases phospho-GSK3
And alters expression of bax & Bcl2
LiCl, 3 mM
IR, 3 Gy
-
+
+
-
+
+
Lithium prevents
neurodegeneration
in bipolar patients
P-GSK3b Ser9
GSK3b
actin
Bax
Bcl-2
actin
Beaulieu,and Caron, Cell 2008
3
7/15/2011
Mechanisms
of action: lithium
LiCl - - +
3Gy - + -
+
+
NIAP
Thotala, Cancer Research 2008
4
7/15/2011
Apoptosis in intestinal crypts
TUNEL staining
Intestinal crypts
• 0 Gy
4 Gy
8 Gy
5
7/15/2011
GSK3 inhibitor prevents intestinal injury
Cytoprotection: GSK3 inhibition
IJROBP 2010
GSK3 inhibition alters Bax & Bcl2
in intestinal crypt cells
Intestinal Irradiation
6
7/15/2011
Prevention of brain necrosis
Mouse models of brain necrosis
• Prevention vs. Mitigation
• Gammaknife on mouse models
Screen Cage
Stereotactic Mount Ring
Quick Attach/Release Connections
7
7/15/2011
Film Dosimetry
Histology of Irradiated Mouse Brain
A
B
D
C
E
Development/Progression of Radiation Necrosis
(60 Gy, single fraction GK irradiation)
H&E Staining
Week 3
Hemosiderin in
Macrophages
Fibrinoid
Necrosis
Vessel
Week 5
Telangiectases
Week 7
8
7/15/2011
Neuroprotection by SB415286
(60 Gy, single fraction GK irradiation)
Neuroprotection by SB415286
(45 Gy, single fraction GK irradiation)
7 weeks
18 – 22 weeks
Mitigation: slowing progression of
brain necrosis
Mitigation of Radiation Necrosis by SB415286
• “Stroke patients on lithium showed less brain injury”
• Presently brain necrosis is treated with steroids
• GSK3 inhibitors could minimize (attenuate/mitigate)
radiation induced necrosis
9
7/15/2011
Status
• Lithium Phase I: 3 patients accrued to half
dose: advance to full dose
• fMRI & neurocognitive studies of irradiated
children
• Aposense ML10 protocol for imaging
radiation-induced apoptosis
• SBIR funding for topical formulations
• Noscira: oral cytoprotective agent
Conclude
• Inhibition of apoptosis within normal cells can
reduce tissue injury
• Cytoprotection can mitigate brain necrosis
• Imaging is needed for clinical trials:
• MRI, PET/ML10
Acknowledgements
Hallahan Lab__
•
•
•
•
•
•
•
•
•
Dinesh Thotala
Girdhar Sharma
E. Yazlovytsia
Ling Geng
Keith Jacobs
Jeff Craft
Kathy Leahy
Rhon Hu
Jerry Fong
Imaging Team
• Joel Garbow
• Bob Dryzmala
• Xiaoyu Jiang
Clinical Protcols
• Cliff Robinson
• Bo Lu
10