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Transcript of European Commette for Genetic Cancer Research Dr. Francesco Graziano Medical Oncology Hospital of...
![Page 1: European Commette for Genetic Cancer Research Dr. Francesco Graziano Medical Oncology Hospital of Pesaro Biotecnologie ed Evoluzione della Terapia Medica.](https://reader038.fdocuments.net/reader038/viewer/2022110305/5542eb4c497959361e8ba1fb/html5/thumbnails/1.jpg)
GSEC - GENETIC SUSCEPTIBILITY TO ENVIRONMENTAL CARCINOGENSUNIVERSITY OF PITTSBURGH
European Commette for Genetic Cancer Research
Dr. Francesco GrazianoMedical Oncology Hospital of Pesaro
Biotecnologie ed Evoluzione della Terapia Medica dei Tumori Solidi
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Terapia dei tumori
chirurgia
Stadio I-II
chemioterapiaprimaria
chirurgia
Stadio III
chemioterapiadella malattia metastatica
radioterapia chirurgia
Stadio IV
guarigione
guarigioneprolungamento
della sopravvivenza
prolungamento della sopravvivenza
palliazione
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Obiettivi dellachemioterapiaantitumorale neglistadi avanzati(stadio IV)
Riduzione dellamassa tumorale
Aumento della sopravvivenza
Beneficio suisintomi
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Sviluppo storico della chemioterapia antineoplastica
1945
1950
1955
1960
1965
1970
Mecloretamina
Metotrexato6-MercaptopurinaBusulfan
ClorambucilCiclofosfamide
Vinblastina, vincristinaFluorouracile, actinomicina DMelfalan
Procarbazina, 6-tioguaninaCitosina arabinosideAdriamicina
• Prima chemioterapia adiuvante con actinomicina D nel tumore di Wilms
da G. Bonadonna, 1999 (modificata)
Bleomicina, dacarbazina
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Sviluppo storico della chemioterapia antineoplastica (II)
1975
1980
1985
1990
1995
CCNU, BCNU, cisplatino
Etoposide, mitoxantrone
CarboplatinoIfofosfamide + MESNA
Paclitaxel, docetaxelTopotecan, irinotecanGemcitabinaOxaliplatino
• Trapianto autologo con GM-CSF• Espansione chemioterapia primaria
da G. Bonadonna, 1999 (modificata)
• CMF adiuvante nel ca. mammario• Terapia adiuvante nell’osteosarcoma• Trapianto di midollo osseo• PVB nei tumori del testicolo
• Inizio chemioterapia primaria in vari tumori solidi resecabili
2000
• Terapia antiemetica
Targettherapy
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ACIDO FOSFONACETIL-L-ASPARTICOACIDO FOSFONACETIL-L-ASPARTICO•Inibisce la biosintesi purinica
5-FLUOROURACILE5-FLUOROURACILE•Inibisce la sintesi dell’acido timidilico
PENTOSTATINAPENTOSTATINA•Inibisce l’adenosina deaminasi
6-MERCAPTOPURINA6-MERCAPTOPURINA6-TIOGUANINA6-TIOGUANINA
•Inibisce la biosintesidell’anello purinico
•Inibiscono le intercorversioninucleotidiche
DACTINOMICINADACTINOMICINADAUNORUBICINADAUNORUBICINADOXORUBICINADOXORUBICINAMITOXANTRONEMITOXANTRONE
•Si intercalano nel DNA•Inibiscono la sintesi dell’RNA
METOTREXATOMETOTREXATO•Inibisce la riduzionedell’acido diidrofolico
•Blocca la sintesi purinicae dell’acido timidilico
BLEOMICINABLEOMICINAETOPOSIDEETOPOSIDETENIPOSIDETENIPOSIDE
•Danneggiano il DNA e ne impediscono il riparo
IDROXIUREAIDROXIUREA•Inibisce la ribonucleotide reduttasi
CITARABINACITARABINAFLUDARABINAFLUDARABINA
2-CLORODEOXIADENINOSINA2-CLORODEOXIADENINOSINA•Inibiscono la sintesi del
DNA
AGENTI ALCHILANTIAGENTI ALCHILANTIMITOMICINA CMITOMICINA CCISPLATINOCISPLATINO
PROCARBAZINAPROCARBAZINADACARBAZINADACARBAZINA
•Formano addotti con il DNA
L-ASPARAGINASIL-ASPARAGINASI•Deamina l’asparagina
•Inibisce la sintesi proteicaPACLITAXELPACLITAXEL
ALCALOIDI DELLA VINCAALCALOIDI DELLA VINCACOLCHICINACOLCHICINA
•Inibiscono le funzioni dei microtubuli
Sintesipurinica
Sintesipirimidinica
ribonucleotidi
desossiribonucleotidi
DNA
RNA(transfer, messaggero,
ribosomiale)
proteine
enzimi (ecc.) microtubuli
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Tossicità arigenerativa dei chemioterapici antitumorali
•Amenorrea, azoospermiaGONADI
•Alopecia CUTE ED ANNESSI CUTANEI
•Stomatite•Enterite arigenerativa•Colite mucosa-membranosa•Diarrea
MUCOSA GASTRO-INTESTINALE
•Leucopenia, immunodepressione, •Piastrinopenia •Anemia
MIDOLLO OSSEO EMATOPOIETICO
Farmaci NON target!
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Changing of the Guard
A Paradigm Shift in the Treatment of Cancer
• Conventional cytotoxic drugs interact with DNA to prevent cell replication but are not specific to cancer cells
• We are moving to targeted therapies which specifically target cancer cells
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Target therapy:1) Identificazione del bersaglio
2) Sopravvivenza e crescita delle cellula tumorale dipendono dal bersaglio
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…. la comparsa degli “inib” e degli “umab” ...
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Targeted Therapies
• Monoclonal antibodies: proteine che si legano a recettore o altra molecola di segnale extracellulare
• Tyrosine Kinase Inhibitors: molecola che lega e inibisce attività enzimatiche intracellulari
• Gli “umab
• Gli “inib”
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Dalla biologia alla biotecnologia ai nuovi farmaci
From JB Gibbs, 2000, modified
umab
umab
Second messanger……….inib
Transcription Translation Proteolysis
I
I
I
I
I
I
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Lo sviluppo degli “umab” e degli “inib” segue quello dei
chemioterapici antitumoraliAcquisizione
Screening
Produzione e Formulazione
Studi clinici di fase I
Studi clinici di fase II
Studi clinici di fase III
Pratica medica
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Valutazione farmacologico-clinica dei chemioterapici
antitumorali (I)FASE I TOLLERABILITA’
•Dose massima tollerata •Tipo della tossicità limitante
•Schema di somministrazione ottimale•Dose consigliata per la fase II
FARMACOCINETICA
FASE II ATTIVITA’ ANTITUMORALE•Spettro di attività•Relazione dose-risposta
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Valutazione farmacologico-clinica dei chemioterapici
antitumorali (II)
FASE III-IV EFFICACIA TERAPEUTICA•Valutazione comparativa con terapia standard •Integrazione della chemioterapia nel trattamento primario
•Monitoraggio farmacocinetico
TOLLERABILITA’•Farmacovigilanza •Monitoraggio farmacocinetico
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Drug Development Timeline
2-4 yrs 3-6 yrs
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Anticorpi monoclonali….gli “umab”
Inibitori della trasduzione del segnale…” gli “inib”
Rituximab (CD20) Imatinib mesilato ( bcr-abl -, c-kit-, PDGF-TKs)
Trastuzumab (HER2) Gefitinib ( EGFR-TK)
Erlotinib ( EGFR-TK)
Cetuximab (EGFR) Bortezomib ( proteasoma)Sorafenib, Sunitinib
Bevacizumab (VEGF)
Farmaci a Berasglio Molecolare
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Targeted Therapies
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Carcinoma Renale
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The Von-Hippel Lindau Gene
• Located in the short arm of chromosome 3
• Tumor suppressor function
• Found in up to 80% of sporadic (non-hereditary) renal cell cancers
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Sporadic Renal Cell Cancer: VHL Two-Hit Hypothesis
At birth First Hit Second Hit:
Cancer
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Inactivation of VHL: An Early Step in Kidney Carcinogenesis
VHL (+/-) VHL (-/-):
Cysts
VHL (-/-):
Tumor
Loss of remaining VHL allele
Mutation/s at non-VHL loci
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Consequences of Consequences of VHL GeneVHL GeneMutationMutation
UbiquitinLigase ComplexDisrupted
HIFAccumulation
VEGF, PDGF Glut-1,
Erythropoietin TGF-, CXCR4
Angiogenesis Increased Metabolism Autocrine GrowthMetastasis
Elongin B/CCul2Rbx1
pVHL-E pVHL-AX XHIF HIF HIF HIF HIF HIF
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Sunitinib
Inhibition of RCC pathogenesis and progression
↑ VEGF ↑ PDGF
Vascularpermeability
Cell survival, proliferation, migration
Vascularformation, maturation
VEGFR PDGFRVEGFVEGF PDGFPDGF
Vascular Endothelial CellVascular Endothelial Cell Pericyte/Fibroblast/Vascular Smooth Muscle
Pericyte/Fibroblast/Vascular Smooth Muscle
SunitinibSunitinib
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Horizontal “Targeted” Strategy
pVHLHIF
VEGF PDGF TGF
KDR PDGFR EGFR
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TARGETsSingle, Planned Progression-Free Survival* Analysis
Pro
po
rtio
n o
f p
atie
nts
pro
gre
ssio
n f
ree
0
0.25
0.50
0.75
1.00
Time from randomization (weeks)
0 6 12 18 24 36 48 60 66
Median PFS**
Sorafenib = 24 weeks
Placebo = 12 weeks
Hazard ratio = 0.44
p-value <0.000001
54
Censored observation
Placebo
Sorafenib
Escudier B et al. Oral presentation, ASCO, 2005 *Independently assessed **PFS analysis performed March, 2005 (data cut-off Jan 28, 2005)
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TK Intracellular Domain
Transmembrane Domain
Extracellular Domain
EGFR
Epidermal Growth Factor Receptor
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TK TKTK
erbB1HER1EGFR
erbB2HER2neu
erbB3HER3
erbB4HER4
No specific ligands - often acts as dimer partner Heregulins
NRG2NRG3
Heregulinsβ-cellulin
EGF, TGF Cellulin
Amphiregulin, HB-EGF
Human Epidermal Growth Factor Receptor Family
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Normal Cell Cancer Cell
Epidermal Growth Factor Receptor
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EGFR expression in solid tumors
LungLung(NSCLC)(NSCLC)
ColorectalColorectal
Head & NeckHead & Neck(SCC)(SCC)
Colorectal cancer (advanced)
75-82%
Lung cancer (NSCLC) 40-91%
Head & neck cancer (SCCHN)
90-100%
Gastric cancer 33-74%
Ovarian cancer 35-70%
EGFR is expressed in a variety
of solid tumors
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Extracellulardomain
Tyrosine kinase domain
C-terminusdomain
P
P
P
P
P
P
ATPATP
Cell membrane
Ligand(e.g. EGF, TGF)
1. receptor dimerization
2. tyrosine kinase domain activation
Cytoplasmaticregion
• signal transduction
• transphosphorylation
• phosphorylation of substrate tyrosines
Inactive monomers
EGFRHER2HER3HER4
Structure of the EGF receptor and its mechanism of activation
From E. Raymond et al., 2000 (modified)
PP
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EGFR: FUNZIONE FISIOLGICA
Una delle principali vie molecolari attivate dall’EGFR è quella di ras. Ras viene reclutata attraverso il legame con la molecola SOS.
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A sua volta, ras determina l’attivazione della serina/treonina chinasi raf, delle MAPKK 1 e 2 e delle MAPK ERK 1 e 2.
EGFR: FUNZIONE FISIOLGICA
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Il risultato dell’attivazione di questa via molecolare è l’espressione di varie proteine nucleari, inclusa la ciclina D1 (necessaria per il passaggio G1-S nel ciclo cellulare).
EGFR: FUNZIONE FISIOLGICA
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Un altro target di EGFR è il PI3K
EGFR: FUNZIONE FISIOLGICA
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Il reclutamento di PI3K porta all’attivazione di Akt, una serina/treonina kinasi con forte attività antiapoptotica.
N.B. la via di segnale di Akt svolge un ruolo nel determinare la chemioresistenza/ sensibilità della cellula neoplastica.
EGFR: FUNZIONE FISIOLGICA
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N U C L E U S
Targeting Cellular Signal Pathways
Ras
Raf MEKK
ERK sek
MAP kinase
jnk/sapkC-myc
C-jun
PI3K
Akt
intermediates
Apoptosis
YEGFR
PP
Rho-B
Ki-67
inib
umab
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Anti-EGFRCetuximab Panitumumab
cetuximab matuzumab panitumumab100% Mouse 34% Mouse 10% Mouse 100% Human
Mouse Fully HumanHumanizedChimeric
Anti EGFR antibody
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Colorectal cancer: cetuximab BOND Trial
• Cunningham et al. ASCO 2003– Randomized trial in 329/577 pts screened for
EGFR+ tumors refractory to 5-FU/CPT-11
CPT-11+cetuximab
cetuximab
R
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0
0,2
0,4
0,6
0,8
1
0 2 4 6 8 10 12
MONTHS
PR
OP
OR
TIO
N
Mono ComboN 111 218
No. events 92 152Median 1.5 4.1
HR (95% CI): 0.54 (0.42; 0.71)
log rank p-value < 0.0001
0
0,2
0,4
0,6
0,8
1
0 2 4 6 8 10 12 14 16
MONTHS
PR
OP
OR
TIO
N
Mono ComboN 111 218
No. events 75 140Median 6.9 8.6
HR (95% CI): 0.91 (0.68; 1.21)
log rank p-value = 0.48
Cetuximab vs. CPT-11+Cetuximab in CPT-11 refractory CRC
Pati
en
ts s
urv
ivin
g (
%)
Pati
en
ts f
ree o
f p
rog
ressio
n (
%)
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KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab
Monoclonal antibodies
R
K
K-ras mutato è sfavorevole
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TKTK
Survival(anti-apoptosis)
PI3-K
STAT3
AKTPTEN
MEK
Gene transcriptionMAPK
Proliferation/maturation
Chemotherapy /radiotherapyresistance
Angiogenesis Metastasis
pYpY
RAS RAFSOS
GRB2pY
G1
SM
G2
Anticorpi monoclonali
Piccole molecole anti-TK
Strategie anti-EGFR
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Gefitinib (piccola molecola anti-EGFR TK) Gefitinib (piccola molecola anti-EGFR TK)
Farmaco studiato nei carcinomi Farmaco studiato nei carcinomi polmonari non a piccole cellule polmonari non a piccole cellule
(esprimono EGFR) (esprimono EGFR) Small molecule
TKIs
R
K
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Differenze di risposta al gefitinib
Group Response p value Study
Women vs men
19% vs 3% 0.001 IDEAL 21
Japanese vs caucasian
27.5% vs 10.4%
0.0023 IDEAL 12
Adenocarcinoma vs others
13% vs 4% 0.046 IDEAL 21
Non-smokers vs former/current
36% vs 8% < 0.001 MSKCC3
1Fukuoka et al., JCO 2003; 2Kris et al., JAMA 2003; 3Miller et al., JCO 2004
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Normal Cell Cancer Cell
Overexpression+
mutation
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• l’effetto delle mutazioni di EGFR sulla funzione della proteina è ancora oggetto di ricerca;
• le cellule che presentano forme mutanti di EGFR, vanno incontro a massiva apoptosi sotto l’azione di farmaci inibitori della via di segnale Akt e STAT-mediata.
MUTAZIONI DI EGFR
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85% circadi queste mutazioni
delezioni multinucleotidiche “in-frame” (ESONE 19)
mutazioni puntiformi (ESONE 21)
MUTAZIONI DI EGFR
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MUTAZIONI DI EGFR
• > frequenza nel sesso femminile;
• > frequenza nei non fumatori;
• > frequenza nel tipo istologico adenocarcinoma.
• > frequenza nelle popolazioni dell’est asiatico;
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2 classi differenti di molecole anti-EGFR
Small molecule TKIs
Monoclonal antibodies
R
K
R
K
K-ras mutato è sfavorevole
Carcinoma del colonCarcinoma del polmone (NSCLC)
EGFR mutato è favorevole
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Drug-related adverse events in >5% of patients: IDEAL 1 (250 mg/day)
0
10
20
30
40
50All grades
Grade 3
Patients(%)
No grade 4 drug-related adverse events were recorded
Fukuoka et al 2003a
Rash Diarrhoea
Pruritus Dry skin Acne Nausea
Tossicità dei farmaci anti-EGFR
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Adverse skin effects after gefitinib (ZD1839) treatmentA
A. Mild (grade 1) acne-like rash in the breast area of a 52-year-old patient treated with 225 mg/d
B. More severe (grade 2) facial acne-like rash in a patient treated with 1,000 mg/d for 8 months
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Normal tissue Tumor tissue
Jain: Science; 307: 58-62, 2005
Neo-angiogenesi tumorale
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ANGIOGENESI:formazione di nuovi vasi sanguigninuovi vasi sanguigni
a partire da pre-esistentivasi capillari normali
aggressività della malattia
esito clinico sfavorevole
ridotta sopravvivenza globale
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Il controllo dello switch angiogenetico dipende dall’equilibrio tra fattori PRO- ed ANTI-ANGIOGENETICI
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VEGF
• è il più potente e specifico fattore mitogeno per le cellule endoteliali;
• è un fattore di sopravvivenza per le cellule dei vasi neoformati;
• induce un aumento della permeabilità vasale, facilitando l’immissione delle cellule neoplastiche
nel torrente circolatorio.
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Bevacizumab (Avastin™): rhuMAb VEGF
• Recombinant Humanized Monoclonal Antibody to VEGF
• 93% human, 7% murine
• Recognizes all isoforms of VEGF, Kd = 8 x 10-10 M
• Terminal half life 17-21 days
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Bevacizumab (Avastin™): rhuMAb VEGF
• Somministrato e.v. insieme a chemioterapci
• Approvato per il trattamento dei pazienti con carcinoma del colon-retto avanzato
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Sopravvivenza libera da progressione: IFL + placebo, 6,2 mesi; IFL + bevacizumab, 10,6 mesi (p<0,001)Risposta obiettiva: IFL + placebo, 34,8%; IFL + bevacizumab, 44,8% (p=0,004)
Bevacizumab + chemioterapia vs. Placebo + chemioterapia
Hurwitz e coll. New Engl J Med, 2004
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GIST: Gastrointestinal Stromal Tumors
• GI sarcoma
• Highest incidence in the 40-60 year age group
• Expression of c-KIT (CD117) in ~95% of cases
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ATP
ProliferationSurvival
AdhesionInvasion
MetastasisAngiogenesis
ADP
+
P
Kit Receptor Phenotype
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ATP
= imanitib contact point
ProliferationSurvival
AdhesionInvasion
MetastasisAngiogenesis
Imatinib
Kit Receptor Phenotype
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Formula: C30H35N7SO4
MW: 589.7
Imatinib Mesylate
CH3SO3H
N
N
N
NH NH
O
N
N
Inhibitor of selective tyrosine kinasesbcr-ablPDGF-Rc-kit
Potent (IC50 0.1M)
(STI 571: Glivec)
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PET Before and after Glivec for GIST
7/12/007/12/00 9/1/019/1/01
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Verweij, et al 2004
EORTC study: Imatinib for Advanced GISTSurvival Benefit
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Extracellular Domain (exon 9, 10.2%)
Juxtamembrane Domain (exon 11, 66.1%)
Tyrosine Kinase Domain I (exon 13/14, 1.2%)
Tyrosine Kinase Domain II (exon 17, 0.6%)
= common mutation site
ATP
c-Kit Receptor Structure
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Overall Survival by Genotype
Exon 11
Exon 9
No Mutation
Median Survival
Exon 11 Not reached
Exon 9 1347 days
No mut 250 days
0 250 500 750 1000 1250 15000
10
20
30
40
50
60
70
80
90
100
Exon 9 23 22 18 14 11 11No Mutation 9 5 3 3 3 3
Exon 11 86 82 81 73 64 53
P-value = 0.0012
Survival Number at Risk Days 0 250 500 750 1000 1250
Days
Ove
rall
Sur
viva
l (%
)
Exon 11
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Target therapy”? ….quale bersaglio?