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

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600

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1000

1200

1400

1600

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2000

1 6 11 16 21 26 31 36 41 46

days

volu

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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