Strategies to improve anti tumor effectiveness of radiotherapy. Eric Deutsch MD PhD Institut Gustave Roussy Villejuif, France

Transcription

1 Strategies to improve anti tumor effectiveness of radiotherapy Eric Deutsch MD PhD Institut Gustave Roussy Villejuif, France

2 Classical view : radiosensitization. DNA damage modification Inhibition of DNA repair Cell cycle redistribution Radiosensitization.. Nucleotide depletion Increase in PA02 Apoptosis induction

3 Biological view.. Hypoxic targeting Apoptosis induction Antiangiogenesis Radiosensitization COX-2 inhibition Tumor suppresor genes replacement Tyrosin kinase inhibition

4

5 More than 60 new agents tested in phase I or II trials «Intrinsic» radiation response Anti EGFr, mtor, PI3K.. COX-2, Proteasome inhibitors, TNFr inducers «extrinsic» micro environment Anti VEGFr, FGFr *Source :

6 EGFr R R RAS RAF PTEN PI3-K AKT py K K py STAT SOS py GRB2 MEK MAPK proliferation/ maturation chemotherapy/ radiotherapy resistance DNA Gene transcription Cell cycle progression PP Jun Fos myc Myc survival/anti-apoptosis cyclin D1 Cyclin D1 angiogenesis metastasis

7 SPECIFIC EGFr INHIBITORS : Monoclonal AB Ligand C225.. R R Tyrosine kinase inhibitors ZD1839, Cp-358, PKI166 K K Signal transduction

8 C225 + irradiation in vitro

9 EGFr expression : Dose effect relationship L. Milas,, T. Akimoto, Int J Radiat Oncol Biol Phys 52 (2002),

10 C225 & irradiation : transfert from bench to clinic

11 EGFR & radiotherapy : First clinical evidence of the value of target agents combined to radiotherapy C225 + radiotherapie : Bonner NEJM 2006

12 On the other side : the endothelial cell Wachsberger, Clinical Cancer Research Vol. 9, , June 2003

13 Tumor Neovasculature: Comparative Tortuosity and Disorganization Normal colorectal mucosa Nearby colorectal cancer From Konerding et al. In Molls and Vaupel, eds. Blood Perfusion and Microenvironment of Human Tumors, 2002.

14 Antivascular agents : a way to increase RT efficacy? Wilett, Nature Medicine 05

15

16 Toxicities of new agents Anti EGFr + Radiotherapy : One (unusual) case of grade IV skin necrosis Budach W, New England Journal of Medicine, 2007

17

18 Modulation of lung injury Abdollahi JEM 2005

19 DEVELOPMENTS in RADIOTHERAPY TECHNICAL BIOLOGY

20

21 BALISITICS OPTIMIZATION : IMRT

22 IMRT allows better accuracy IMRT In HNSCC 1) Normal tissues sparing 2) Dose escalation

23 OPTIMIZED RADIOTHERAPY in GI TUMORS : Toward a better therapeutic index..

24 The usefulness of functionnal imaging : the example of tyrapazamine Bioreductive agent when hypoxic Radiosensitizer RT + CDDP Randomized phase III RT + CDDP + Tyrapazamine Overall results : 2 arms similar!!

25 Tirapazamine : Hypoxia PET to select the patients? Rischin, JCO 2006

26 THE NEXT STEP : IMAGE GUIDED RADIOTHERAPY (PET as a tool for radiotherapy)

27 DEVELOPMENTS in RADIOTHERAPY TECHNICAL BIOLOGY

28 Tumor stem cells :

29 Stem cells radioresistance : G2/M arrest

30 Induction polyploidy in p53-/-hct116 cells by AZD1152 p53-/- control 14/02/ cycle HCT116 24h exposure to AZD1152 G1 80 G s-g1 S >4N 50 % control AZD Cycle p53-/- AZD /02/ G1 0 sub-g1 G1 S G2-M >4N -10 s-g1 G2 S >4N Cycle

31 p53-/- and wt HCT116 tumour growth delay by IR and AZD1152 in vivo HT29 cells IR and AZD1152 in vivo 25 Figure 6 6a 20 6d days IR alone IR + AZD1152 Tumor Volume mm control IR AZD1152 IR+AZD p53wt HCT116 cells xenograft p53-/ days p53wt HCT116 IR and AZD1152 in vivo p53-/-hct116 cells IR and AZD1152 in vivo 6b c volume (mm3) control IR AZD1152 IR+AZD1152 volume (mm3) control IR AZD1152 IR+AZD days days Tao et al BJC 2008, Tao et al Oncogene 2008

32 Cell death mecanims as targets for radiosensitization Morphology of mitotic catastrophe (MC) control MC multinucleation micronuclei Hoechst/β-tubulin Morse et al, 2005

33 Preferential mitotis entry for P53 deficient cells after irradiation Different HCT116 cell lines mitosis index 24h after X and IR MPM2 + cells % ctrl Chir IR Chir+IR /- Mad2+/- wt p53-/-

34 Genes involved in cancer 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 2000 The hallmarks of cancer Cell 100,

35 Drug NS398 From the benchmark to the patients Vitro + Vivo + Normal tissue +/- XRT Phase I Ongoing Publication J Urol 2003 AG /-?? BJC 2003 Omega Abbott BJC 2003 Tirapazamine Ongoing Sanofi BJC, IJROBP <1995 Cidofovir Ongoing Oncogene 2003 Lancet Oncol Ritonavir + + -?? Metastat AACR 2003 Roscovitine + + -?? Can Res 2003 Aurora B + +? Oncogene 2007 Statins Pfizer IJROBP CCR

36 What might Gène Brca1 K-RAS PIKCA APC p53 PTEN C-Kit RB Bcr-Abl FLT-3 PML-RAR B-RAF RET JAK Cancer Sein Colon Li Fraumeni Colon/Poumon GIST Retinoblastome LMC LAM LAM Mélanome Thyroïde Polyglogulies Future challenges : Organ specific drug targeting Shift Drogue What does cause cancer FTI PI3K inhibitors Akt inhibitors Gllevec, Sutent, Sorafenib Gleevec, Dasatinib CEP701 Sorafenib, Chiron 265 AZD compounds AZD compounds

37 «oncogene addiction»

38 Weinstein Can Res 08

39 Molecular pathology into radiation practice? TNM «ultra staging» -GI tumors -Cervical cancer -Lung tumors

40 Targeted therapies for RECTUM PRE OP RT? K-Ras 30% PI3KCA mutations : 20% HIGH EGFr AKT

41 PI3K AKT the main pathway for radiation response P AKT/PKB Tyrosine kinase receptor PDK1 P3 P(3,4,5) P PTEN P P2 P(4,5) P P P P SH2 P85 PI3K P110 PI3K Growth Factor EGFR PDGFR IGF-1R Ras GTP

42 AKT the main AKTor RAS Egfr Angiogenesis Cell cycle PI3K/AKT Apoptosis DNA repair

43 The PI3K and mtor inhibitor selectively sensizites «addicted tumor cells» Non tumor cells no/low PI3K activation Tumor cells with PI3K activation Cancer Res in press

44 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 & cases / year (3.700 in France)

45 Cidofovir (HPMPC) (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)Cytosine: [(S)-HPMPC] Phosphonates nucléoside acyclique Demi-vie de la drogue in vivo : 48 h Mécanisme d action du Cidofovir

46 Cervical cancer ADNh Epithelila cell HPV16/18 + Cidofovir (10 ug/ml)+9gy Abdulkarim B et al 2001 /2002 E6 ADNh/V E7 DNA viral persistence p53 prb p21 Cyclin E In situ cancer (Abdulkarim et al 2001 oncogene)

47 Abdulkarim et al. Oncogene, 2002 HPC positive : Me180 cell line

48 HPV postivie tumors : restoration of p53 and prb

49 Oncogenes alterated in lung cancer : NSCLC vs SCLC RAS C-Myc EGFR HER2/neu IGF1 C-myc Myb IGF-1 BCL2

50 Lung cancer : BCL2 inhibition : NSCLC : SCLC No moderate/zero effect T RC ASO RC+RT ASO+RT 0 J15 J21 J28 J35 J42 J49 J56 Increase in radiation response in SCLC Loriot et al NCI EORTC 2007

51 Looking toward the future..

52 Personalised medicine : Challenges rely on tumor response probability Poor prognosis : Tumor «response» profile Optimise radiotherapy Decrease late effects Radiation sensitizer

53 Toward molecular profiling? Preoperative Radiotherapy in rectal cancer responders non responders Watanade Can Res 2006

54 Toward molecular profiling? Preoperative Radiotherapy in rectal cancer responders non responders Watanade Can Res 2006

55 Increasing the antitumor efficacy of radiotherapy will require Drugs adapted to Molecular pathology High Tech RT, IGRT Radiation sensitizers (EGFr ) Fractionnation..integration of all aspects of radiation biology