National Cancer Institute Milan, Italy University of Milano Bicocca, Monza, Italy Molecular Mechanisms of Resistance to Imatinib (STI571, CGP57148B)
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National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Molecular Mechanisms of Molecular Mechanisms of Resistance to Imatinib Resistance to Imatinib (STI571, CGP57148B)(STI571, CGP57148B)
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Structure of Imatinib Structure of Imatinib (STI571, CGP 57148B)(STI571, CGP 57148B)
Class: Phenylaminopyrimidines, 589.7 mwClass: Phenylaminopyrimidines, 589.7 mw
CH3SO3H
O
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Cellular Selectivity of STI571: Cellular Selectivity of STI571: ICIC5050[µM][µM]
Kinases InhibitedKinases Inhibited Kinases Not InhibitedKinases Not Inhibitedv-ABLv-ABL 0.1–0.30.1–0.3 Flt-3Flt-3 >10 >10
p210p210bcr-ablbcr-abl 0.250.25 c-Fms, v-Fmsc-Fms, v-Fms >10 >10
p185p185bcr-ablbcr-abl 0.250.25 EGF receptorEGF receptor >100 >100
TEL-AblTEL-Abl 0.350.35 c-erbB2c-erbB2 >100 >100
PDGF receptorPDGF receptor 0.10.1 Insulin receptor >100Insulin receptor >100
TEL-PDGF TEL-PDGF IGF-1 receptor >100IGF-1 receptor >100
receptorreceptor 0.150.15 v-Srcv-Src >10 >10
c-kitc-kit 0.10.1 JAK-2JAK-2 >100 >100
Druker BJ et al. Nat Med. 1996;2:561-566; Personal communication 4/00. B Druker, E Buchdunger.
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Effect of STI571 on Growth ofEffect of STI571 on Growth ofBcr-Abl–Positive and –Negative Cell LinesBcr-Abl–Positive and –Negative Cell Lines
Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380.
*Bcr-Abl-negative cell lines
†Bcr-Abl-positive cell lines
U937*KG1*KCL22*K562†
KU812†
SU DHL1†
STI571 Concentration (M)
% Control CPM
0 0.1 0.3 1 3 10
0
20
40
60
80
100
120
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
LAMA84 Control
LAMA84 24h 1uM
LAMA84 44h 1 uM
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Cytogenetic response of Chronic Phase patients during XXII therapy month
% patients without response
(20%)
% patients with major response(13,33%)
% patients with complete response(66,67%)
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Chronic Phase patients
30.00
20.0023.08
45.16
32.0028.57
44.83
30.00
96.77
76.9280.00
70.0073,68
54.84 55.17
71.43 68.00
3.230.00
20.00
40.00
60.00
80.00
100.00
0 3 6 9 12 15 18 21 24
Therapy, month
% p
ati
en
ts
% pt without response % pt with major or complete response
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Cytogenetic response of Accelerated Phase patients during XXII therapy month
% patients with complete response(35,71%)
% patients with major response
(0%)
% patients without response(64,29%)
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Hematological Response in Blast Crisis patients
00.00
25.00
100.00
75.00
0000
44.44
66.67
44.44
55.56
33.33
55.56
1
11
21
31
41
51
61
71
81
91
1 21 41 61 81 101 121 141 161
Giorni di terapia
% p
azie
nti
% pt con risposta completa % pt con risposta parziale % pt senza risposta
National Cancer Institute Milan, Italy
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Hematologic failureCytogenetic failureIFN intolerant
= Censored observations
% w
ithou
t los
s of
MC
yR
0
10
20
30
40
50
60
70
80
90
100
Months since MCyR0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Resistance to ImatinibResistance to Imatinib
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Cytogenetic and hematological response of patient 506
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12Therapy, month
% of Ph+ cells WBC (* 1000) % of blasts PLT(*1000)
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
IIDiscontinuous InhibitionDiscontinuous Inhibition
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
0
20
40
60
80
100
120
140
ctrl 6h 7h 20h 21h 30h 30h
time of drug exposure
% c
pm
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
bcr/abl
bcr/abl
anti-phosphotyrosine
anti-abl
i.p. 2h p.o. i.p. 5h p.o. i.p. 9h p.o.
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
0
1
2
3
4
5
6
7
8
9
0 10 20 30 40
days
tumor weight mg x 1000 ctrl
2x50 mg/kg i.p.
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 5 10 15 20
days
tumor weight mg x 1000
ctrl
3x160 mg/kp p.o.
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
0102030405060708090
100
0 10 20 30 40 50days
tumor free survival
ctrl
3x50 mg/kg i.p.
3x160 mg/kg p.o.
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
IIIIInsufficient Tissue LevelsInsufficient Tissue Levels
(Beware of Plasma Concentrations)(Beware of Plasma Concentrations)
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
1 2 3 4
alpha 1 acidic glycoprotein
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
AGP
0
20
40
60
80
100
120
0 0.5 1 1.5 2 2.5 3
µM STI571
% o
f co
ntr
ol 0 mg/ml
0.1 mg/ml
0.2 mg/ml
0.4 mg/ml
0.8 mg/ml
1 mg/ml
2 mg/ml
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
205 kd Anti-Abl
205 kd Anti-Ptyr
Day 1 Day 5
Patient 001
205 kd
47 kd
Day 1
Anti-Ptyr
Day 2
Anti-Actin
Patient 504
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Day 1 Relapse
No
ST
I571
in v
ivo
> 3
µM
ST
I571
in v
ivo
+ 3
µM
S
TI5
71In
vit
ro
+ 3
µM
ST
I571
in v
itro
205 kd
Anti-Abl
Anti-Ptyr
Patient 001
205 kd
Patient 505
Anti-Abl
Anti-Ptyr
Patient 002
Anti-Abl
Anti-Ptyr
205 kd
205 kd
205 kd
205 kd
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
>3 µM S
TI571 in vivo +
100 µM E
ryth
rom
ycin
in vitr
o
>3µM S
TI571 in vivo
3 µM S
TI571 in vitr
o
205 kd
205 kd
Patient 008
Anti-Abl
Anti-Ptyr
Patient 009
Anti-Abl
Anti-Ptyr
>3 µM S
TI571 in vivo +
100 µM E
ryth
rom
ycin
in vitr
o
>3µM S
TI571 in vivo
3 µM S
TI571 in vitr
o
205 kd
205 kd
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Effect of the administration of Clindamycin (900 mg i.v. over 20 minutes) on STI571 plasma concentrations
0 10 20 300.0
0.1
0.2
0.3
0.4
Patient 008Patient 00213
Patient 00241
2
3
4
5
6
7
8
Time (min)
ST
I571
Pla
sma
con
cen
trat
ion
(g
/ml)
ClindamycinClindamycin
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
0 4 8 12 16 20 240
1
2
3
4
5
6
7
8
9001 day 4502 day 4
Time (h)
STI
571
conc
entr
atio
n(
g/m
l)
0 1 2 3 40
1
2
3001 day 5502 day 5
4 8 12 16 20 24
Time (h)
0 4 8 12 16 20 240.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5002 day 4503 day 4502 day 4
Time (h)
STI
571
conc
entr
atio
n(
g/m
l)
0 1 2 3 40.0
0.5
1.0
1.5002 day 5503 day 5501 day 5
6 10 14 18 22
Time (h)
Effect of Clindamycin (C) administration Effect of Clindamycin (C) administration on steady state STI571 plasma levelson steady state STI571 plasma levels
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
BCR/ABL
STI571STI571
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
BCR/ABL
AGP
STI 571
AGP
STI 571
AGP
STI 571
AGP
STI 571
In the presence of alpha 1 acidic glycoprotein (AGP)
STI571STI571
National Cancer Institute Milan, Italy
University of MilanoBicocca, Monza, Italy
Trattamento con STI571 + Eritromicina (E)
BCR/ABL
STI 571
STI 571
STI 571
STI 571
AGP
AGP
AGP
AGPE
E
E E
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