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Strategies to improve anti tumor effectiveness of
radiotherapy
Eric Deutsch MD PhDInstitut Gustave Roussy
Villejuif, France
RadiosensitizationRadiosensitization....
DNA damageDNA damagemodificationmodification
ApoptosisApoptosisinductioninduction
IncreaseIncrease in PA02in PA02NucleotideNucleotidedepletiondepletion
InhibitionInhibitionof DNA of DNA repairrepair
CellCell cycle cycle redistributionredistribution
Classical view : radiosensitization….
Radiosensitization
Hypoxic targeting
Tyrosin kinaseinhibition
Tumor suppresor genesreplacement
COX-2 inhibition
Apoptosisinduction
Antiangiogenesis
Biological view..
« Intrinsic »radiation response
Anti EGFr, mTOR, PI3K.. COX-2, Proteasome inhibitors, TNFr inducers
« extrinsic »micro environment
Anti VEGFr, FGFr
More than 60 new agents tested in phase I or II trials
*Source : www.clinicaltrials.gov
MAPK
MEK
Gene transcriptionCell cycle progression
PI3-K
RAS RAF
SOSGRB2
PTEN AKTSTAT
R
KpY
R
pY
pY
K
proliferation/maturation
survival/anti-apoptosis angiogenesis
metastasis
DNAmyc
Myc
cyclin D1 Cyclin D1
Jun Fos
P P
chemotherapy/ radiotherapy resistance
EGFrEGFr
R R
K K
Ligand
Tyrosine kinase inhibitors
ZD1839, Cp-358, PKI166
Monoclonal AB
C225..C225..
Signal transduction
SPECIFIC EGFr INHIBITORS :SPECIFIC EGFr INHIBITORS :
C225 + irradiation
in vitro
L. L. MilasMilas, T. , T. AkimotoAkimoto, , Int J Int J RadiatRadiat OncolOncol BiolBiol PhysPhys 5252 (2002), (2002),
EGFr expression : Dose EGFr expression : Dose effecteffect relationshiprelationship
C225 & irradiation :
transfert from bench to clinic
EGFR & radiotherapy :First clinical evidence of the value
of target agentscombined to radiotherapy
C225 + radiotherapie : Bonner NEJM 2006
On the other side :the endothelial cell
Wachsberger, Clinical Cancer Research Vol. 9, 1957-1971, June 2003
Tumor Neovasculature: Comparative Tortuosity and
Disorganization
From Konerding et al. In Molls and Vaupel, eds. Blood Perfusion and Microenvironment of Human Tumors, 2002.
Normal colorectal mucosa Nearby colorectal cancer
Antivascular agents :a way to increase RT efficacy?
Wilett, Nature Medicine 05
Toxicities of new agents
Budach W, New England Journal of Medicine, 2007
Anti EGFr + Radiotherapy : One (unusual) case of grade IV skin necrosis
Modulation of lung injury
Abdollahi JEM 2005
DEVELOPMENTS in RADIOTHERAPY
TECHNICAL BIOLOGY
BALISITICS OPTIMIZATION : IMRT
IMRTIn HNSCC
IMRT allows better accuracy
1) Normal tissues sparing
2) Dose escalation
OPTIMIZED RADIOTHERAPY in GI TUMORS :Toward a bettertherapeutic index..
The usefulness of functionnal imaging :the example of tyrapazamine
• Bioreductive agent whenhypoxic
• Radiosensitizer
Randomized phase III
RT + CDDP
RT + CDDP + Tyrapazamine
Overall results : 2 arms similar!!
Tirapazamine : Hypoxia PET to select the patients?
Rischin, JCO 2006
THE NEXT STEP :IMAGE GUIDED RADIOTHERAPY (PET as a tool for radiotherapy)
DEVELOPMENTS in RADIOTHERAPY
TECHNICAL BIOLOGY
Tumor stem cells :
Stem cells radioresistance : G2/M arrest
Induction polyploidy in p53-/-HCT116 cells by AZD1152
cycle HCT116 24h exposure to AZD1152
-10
0
10
20
30
40
50
60
70
80
sub-G1 G1 S G2-M >4N
%
control
AZD1152
p53-/- control
08/02/06.011
0 200 400 600 800 1000Cycle
s - G1
G1
S
G2
>4N
08/02/06.011
0 200 400 600 800 1000Cycle
s - G1
G1
S
G2
>4N
14/02/06.025
0 200 400 600 800 1000Cycle
s - G1
G1
S
G2
>4N
14/02/06.025
0 200 400 600 800 1000Cycle
s - G1
G1
S
G2
>4N
p53-/- AZD1152
Figure 6 HT29 cells IR and AZD1152 in vivo
0
200
400
600
800
1000
1200
1400
1600
1 4 8 11 15 18 22 25 29 32 36 39 43 46 50 53
days
Tum
or V
olum
e m
m3
controlIRAZD1152IR+AZD1152
6b
6d
6c
6a
p53wt HCT116 IR and AZD1152 in vivo
0
200
400
600
800
1000
1200
1400
1600
1800
1 4 8 11 15 18 22 25 29 32 35
days
volu
me
(mm
3) controlIRAZD1152IR+AZD1152
p53-/-HCT116 cells IR and AZD1152 in vivo
0
200
400
600
800
1000
1200
1400
1600
1800
2000
1 6 11 16 21 26 31 36 41 46
days
volu
me
(mm
3) controlIRAZD1152IR+AZD1152
p53-/- and wt HCT116 tumour growth delay by IR and AZD1152 in vivo
0
5
10
15
20
25
p53wt p53-/-
HCT116 cells xenograft
days IR alone
IR + AZD1152
Tao et al BJC 2008, Tao et al Oncogene 2008
Cell death mecanims as targets for radiosensitizationMorphology of mitotic catastrophe (MC)
control
micronuclei
MC
Hoechst/β-tubulin
multinucleation
Morse et al, 2005
Preferential mitotis entry for P53 deficient cells after irradiation
Different HCT116 cell lines mitosis index 24h after X and IR
0
1
2
3
4
5
6
ctrl Chir IR Chir+IR
MPM
2 +
cells
%
14-3-3-/-Mad2+/-wtp53-/-
• Oncogenes– Activated from protooncogenes– Usually enhance cell proliferation
• Tumor suppressor genes– Inactivated by mutation or
deletion– Usually arrest cell proliferation
• Genes regulating apoptosis– Control cell survival– Overexpression,mutation or
deletion can enhance cell survival• Genes regulating metastasis
– Control cell motility and interaction with the environment
– Both activating and inactivating mutations
Hanahan and Weinberg 2000The hallmarks of cancer
Cell 100, 57-70.
Genes involved in cancer
From the benchmark to the patients…
Oncogene2007
?++Aurora B
IJROBPCCR
Pfizer++++Statins
Can Res2003
??-++Roscovitine
AACR 2003-++Metastat
??-++Ritonavir
Oncogene2003Lancet Oncol
Ongoing-++Cidofovir
BJC, IJROBP <1995
OngoingSanofi
-++Tirapazamine
BJC 2003Abbott+++Omega-3
BJC 2003
??+/-++AG1024
J Urol 2003Ongoing+/-++NS398
PublicationXRTPhase I
Normal tissue
VivoVitroDrug
Sorafenib, Chiron 265MélanomeB-RAF
AZD compoundsThyroïdeRET
DrogueCancerGène
Polyglogulies
LMCLAMLAM
Retinoblastome
GIST
Colon/Poumon
Li Fraumeni
Colon
Sein
Gllevec, Sutent, SorafenibC-Kit
Gleevec, DasatinibCEP701
Bcr-AblFLT-3PML-RAR
Brca1
AZD compoundsJAK
RB
Akt inhibitorsPTEN
p53
FTIPI3K inhibitors
K-RASPIKCAAPC
What mightmight What doesdoes cause cancerShift
Future challenges : Organ specific drug targeting
« oncogene addiction »
Weinstein Can Res 08
Molecular pathology into radiation practice ?
TNM « ultra staging »• -GI tumors
• -Cervical cancer
• -Lung tumors
Targeted therapies for RECTUM PRE OP RT?
HIGH EGFr
K-Ras 30%
PI3KCA mutations :20%
AKTAKT
EGFR EGFR PDGFRPDGFRIGFIGF--1R1R
Tyrosine kinase receptorGrowthFactor
SH2SH2
Ras GTPRas GTP
P3P(3,4,5)
P
PP2
P(4,5)
PP
P
PTEN
P85PI3K
P
PDK1
AKT/PKB
P
P110PI3K
PI3K AKT the main pathwayfor radiation response
Cell cycle
Apoptosis
Angiogenesis
PI3K/AKTPI3K/AKT
DNA repair
RAS Egfr
AKT the main AKTor
The PI3K and mTOR inhibitor selectivelysensizites
« addicted tumor cells »
Cancer Res in press
Non tumor cells no/low PI3K activation Tumor cells with PI3K activation
Virus related cancers (15% of cancers wordwide and 7% in western countries)…
Epstein-Barr virus (EBV) : Lymphoma, Nasopharynx…
Human papilloma virus (HPV) : Carcinoma of the cervix, HNSCC, anal cancer
Uterine cervix carcinoma : HPV 16 & 18 …
500 000 cases / year (3.700 in France)
Cidofovir (HPMPC)
Phosphonates nucléoside acyclique Demi-vie de la drogue in vivo : 48 h
(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)Cytosine: [(S)-HPMPC]
Mécanisme d’actiondu Cidofovir
ADNh
ADNh/V
Epithelila cell
+HPV16/18
DNA viral persistence
E6 E7
p53 pRb
In situ cancer
Cidofovir (10 ug/mL)+9GyAbdulkarim B et al 2001
/2002
Cervical cancer
p21 Cyclin E
(Abdulkarim et al 2001 oncogene)
Abdulkarim et al. Oncogene, 2002
HPC positive : Me180 cell line
HPV postivie tumors : restoration of p53 and pRB
Oncogenes alterated inlung cancer :
NSCLC vs SCLC
RASC-MycEGFRHER2/neuIGF1
C-mycMybIGF-1BCL2
Lung cancer :
0
500
1000
1500
2000
2500
3000
J15 J21 J28 J35 J42 J49 J56
T
RC
ASO
RC+RT
ASO+RT
BCL2 inhibition :
Loriot et al NCI EORTC 2007
Increase in radiation response in SCLC
NSCLC :
No moderate/zero effect
SCLC
Looking toward the future..
Personalised medicine : Challenges rely on tumor response
probability
Optimise radiotherapyDecrease late effects
Radiation sensitizer
Poor prognosis : Tumor « response » profile
Toward molecular profiling?
• PreoperativeRadiotherapyin rectal cancer
responders
non responders
Watanade Can Res 2006
Toward molecular profiling?
• PreoperativeRadiotherapyin rectal cancer
responders
non responders
Watanade Can Res 2006
Fractionnation
Radiation sensitizers (EGFr…)
High Tech RT, IGRT
Drugs adaptedto
Molecularpathology
Increasing the antitumorefficacy of radiotherapywill require…
..integration of all aspects of radiation biology