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Solo 96 TKs in tutto il genoma umano!

Solo 96 TKs in tutto il genoma umano!. SHC. GRB2. GAB2. SOS. RAS GTP. RAS GDP. ERK. JUN. Nucleus. SHC. GRB2. GAB2. PI3K. mTOR. Apoptosis block. Perché esiste una specificità di risposta se tutti i segnali attivano le stesse vie?

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Solo 96 TKs in tutto il genoma umano!

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  1. Solo 96 TKs in tutto il genoma umano!

  2. SHC GRB2 GAB2 SOS RAS GTP RAS GDP ERK JUN Nucleus

  3. SHC GRB2 GAB2 PI3K mTOR Apoptosis block

  4. Perché esiste una specificità di risposta se tutti i segnali attivano le stesse vie? • Perché gli stessi segnali possono attivare risposte diverse?

  5. ABL is a “shuttle” TK Radiatons->genetic damage ABL NUCLEUS Cell Cycle Rb, p53,p73 ABL Block in G1

  6. Scaffold protein

  7. Intensità del segnale • Durata del segnale • Possibilità di spegnerlo più o meno rapidamente

  8. Meccanismi di attivazione • Riarrangiamenti • Amplificazioni • Mutazioni puntiformi • ……….

  9. Riarrangiamenti • Spesso conseguenza di traslocazioni cromosomiche (BCR-ABL, NPM-ALK) o di delezioni intracromosomiche (FIP1-PDGFRa) • Meccanismo più frequente nelle neoplasie ematologiche che nei tumori solidi

  10. BCR BCR P ABL ABL Tyr Tyr Autophosphorylation by dimerization Phosphorylation of substrates

  11. Amplificazioni • Più frequenti nei tumori solidi che nei tumori ematologici (ERB2 nel Ca mammario etc…) • Più frequente per recettori di membrana • Meccanismo di attivazione: l’aumento delle molecole in superficie ne favorisce il contatto anche in assenza di ligando

  12. * P P * P P P P * P P P P Mutazioni puntiformi • Numerosi esempi sia nei tumori ematologici (JAK2 in DMPC-Ph-negativi) che nei tumori solidi (KIT nei GIST) • Meccanismo di attivazione: meccanismo di attivazione diretto del dominio TK amino acid substitutions

  13. FLT3 activation in AML (30% of cases) P P P P P P P P ITD D835Y STAT JAK RAS

  14. BCR/ABL ABL is a “shuttle” TK Radiatons->genetic damage ABL NUCLEUS Cell Cycle Rb, p53,p73 ABL Block in G1 Deacreased DNA repair= genomic instability Jane Wang, Paolo Vigneri et al.

  15. Proteina P Tir ATP P P Imatinib Mechanism of action Bcr-Abl ATP binding pocket STI

  16. Chronic phase Accelerated Myeloid IFN failure phase Blast crisis (n=532) (n=235) (n=229) Haematological response 95% 83% 31% Complete 95% 54% 8% No evidence of leukaemia - 12% 4% Return to CP - 17% 18% Major cytogenetic response 60% 26% 15% Complete 41% 18% 7% Partial 19% 8% 8% Imatinib Response and Disease Phase

  17. N N N N N N Ph+ N N N N N N N N N Ph+ Ph+ N N N N N N N Ph+ N N N N Ph+ Ph+ Ph+ N N N N N N N N Ph+ Ph+ N N N N N N N Ph+ Ph+ N Ph+ Ph+ N N N N Ph+ N N N Ph+ Ph+ N N N Ph+ N Ph+ N Ph+ N N Ph+ Ph+ N N Ph+ Ph1 Ph+ N Ph+ N N N Ph+ Ph+ N Ph1 Ph1 N Ph+ N Ph+ Ph1 N Ph1 Ph1 Ph+ Ph1 N Ph+ Ph1 Ph+ Ph1 Ph+ N Ph+ Ph+ Ph1 Ph+ Ph1 Ph+ Ph+ Ph+ Ph+ Ph1 Ph1 Ph+ Ph+ Ph+ Ph1 Ph1 Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph1 Ph+ Ph+ Ph1 N N

  18. Cumulative Best Response at 12 and 60 months on First-line Imatinib in IRIS study 96% 96% 98% 98% 92% 92% 85% 85% 87% 69% 69%

  19. Event-free Survival and Survival Without AP/BC on First-line Imatinib 98% 84% Estimated rate at 60 months (with 95%CI) (90-96) 93% 83% (80-87) Actual Events 6.3% AP/BC (n=35) 5.1% loss of MCyR (n=28)2.5% loss of CHR (n=14)1.6% CML-unrelated deaths (n=9)

  20. Annual Event Rateson First-line Imatinib Year All events* AP/BC 1st 3.3% 1.5% 2nd 7.5% 2.8% 3rd 4.8% 1.6% 4th 1.5% 0.9% 5th 0.9% 0.6% * All deaths or loss of response including progression to AP/BC

  21. Survival Without AP/BC by Molecular Response at 12 months on First-line Imatinib Estimated rate at 60 months Response at 12 months  n=136 100% n= 94 95%n=138 88%  CCyR with >=3 log red. p=0.007 p<0.001 CCyR with <3 log red. No CCyR Druker et al., ASCO 2006

  22. The BCR/ABL amount measured by RQ PCR mirrors the number of cells less sensitive to Imatinib PhR PhR PhR PhR PhR Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Imatinib Imatinib BCR/ABL reduction The persistent Ph-positive cells less sensitive to imatinib may potentially become prone to progression Higher the number, higher the risk!

  23. Two major problems with imatinib therapy • Resistance/Loss of Response and Progression • Persistence of small amount of leukemic cells

  24. Pathophysiology of imatinib resistance Pathophysiology of imatinib resistance Imatinib Other defects BCR-ABL Imatinib not able to suppress the BCR-ABL TK proliferation BCR-ABL BCR-ABL proliferation proliferation Clonal evolution • Point mutations • BCR-ABL amplification • Insufficient IMA in cells

  25. The map of mutations 4 Critical regions a.a. that control the kinase activation step ATP binding loop Gate keepers P-loop Catalyticdomain Activationloop M244V D276G V289A M343T E355G/D H396R/P S417Y L248V T277A M351T/V L387M/F G250E E255K/V F311L/I F317L F359V F382L E459K Q252R/H F486S V379I T315I Y253F/H A380T

  26. P-loop Most frequent mutations 22 21 20 19 18 17 16 15 14 13 12 no. of mutations 11 10 9 8 7 6 5 4 3 2 1 0 G250E Q252R/H Y253F/H E255K/V D276G T277A P296H M351T/V E355G/D F359V/I V379I A380T F382L L387F/M H396R/P M244V L248V F311L/I T315I F317L M343T S417Y E459K/Q F486S *Soverini et al GIMEMA-CML WP data on 297 matinib resistant patients (CML, Ph+ ALL)

  27. Soverini et al., JCO 2005

  28. Dual Inhibitors Imatinib derivative

  29. Wild-type T3151 Mutant Wild-type T3151 Mutant Gorre et al., Science. 2001

  30. Imatinib Clone without mutations Clone with Mutation LBH or ON012380 Clone with T315I Dasatinib or nilotinib

  31. PhU PhU PhU PhU PhU PhU PhU PhU PhU PhU PhU PhU PhU PhU PhU Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Ph+ Imatinib Imatinib PhU PhU PhU PhR Ph+ Ph+ Ph+ PhR Ph+ Ph+

  32. Blood 2006

  33. Molecular response in IRIS trial Base line 1.0 CCR 2.0 Log reduction of BCR-ABL 3.0 92% BCR-ABL positive 4.0 Not detected Pre 3 6 9 12 18 24 27 30 Months

  34. Less sensitive progenitor Ph+SC Ph+SC Ph+SC Imatinib Ph+ progenitors Normal SC Normal SC Normal SC Normal SC Normal SC Normal SC CML cells Ph+ mature cells

  35. Most patients who stop imatinib therapy, even when PCR neg, relapse!

  36. Differentiated Progenitors Michor et al., Nature 2005

  37. Punish the Parent not the Progeny Bcr-Abl off? Bcr-Abl on? The Imatinib concentration in the progenitor cells, due to the action of influx (OCT-1) and efflux (ABCB1) proteins seems to represent a major determinant for the persistence-resistance of Ph-positive progenitors Tessa Holyoake and Deb White Holyoake TL, Blood 2004

  38. The persistence of Ph-positive cells may be due to: - cells more resistant to imatinib - cells in which the BCR-ABL TK activity may be suppressed without a great damage The persistence of Ph-positive cells may be due to: - cells more resistant to imatinib - cells in which the BCR-ABL TK activity may be suppressed without a great damage BCR-ABL inhibition BCR-ABL inhibition Imatinib Apoptosis Ph+ cells Imatinib Ph+ cells that survive and return to “normality”

  39. The strategy to eradicate the persistence of this tricky Ph+ population must be appropriate • Combination therapy? • Immunotherapy?

  40. University of Turin Daniela Cilloni Giovanna Rege Cambrin Francesca Messa Carmen Fava Francesca Arruga Ilaria Defilippi Emanuela Messa Alessandro Morotti Enrico Gottardi Emilia Giugliano Anna Serra Milena Fava San Luigi Hospital-University of Turin

  41. ICSG on CML

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