AKT as a therapeutic target in
Multiple Myeloma
Noopur Raje, MD
Objectives
· Biological Relevance
· Pl
Prec ili i
n
l
ca S d
tu i
dies
· Clinical Studies
· Future Directions
AKT Signaling
gg
IL-6 induced signaling
gg in MM
IL-6 induces p-AKT in a
dose and time dependent
fashion
AKT and itits downstream targets are
stimulated via PI3-K activation
Hideshima et al. Oncogene 2001;20 5991
IL-6 and PI3K/AKT: Effects on
proliferation and dex-induced
apoptosis
PI3K inhibition
overcomes
protective effects
of IL-6
Lichtenstein lab, Can Res 200,
Oncogene 2002, 2004
Hideshima et al. Oncogene 2001;20 5991
IGF-1 signaling and AKT
IGF-1 induced
phophorylation
and kinase
activity of AKT
in MM Cells
Ge and Rudikoff, Blood 2000;96
Activated AKT results in drug
resistance
Apo2L/TRAIL
Doxorubicin
Velcade
Mitsiades et al. Oncogene 2002, and PNAS 2002
MM Cell migration via
via PI3K/AKT
CD40 triggers AKT activity via PI3K activation
CD40 induced MM
migration is
PI3K/AKT
dependent
Tai et al, Blood 2003; 101: 2762-
Effects of PI3K/Akt Signaling in
MM
IL-6
IGF-1
TNF-
BAFF/APRIL
CD40
MIP1-
PI3K/AKT
Growth &
Adhesion
proliferation
Survival
Migration
Cell Cycle
Drug
y
Drug
Progression
Resistance
MM Patients have increased
AKT
p
·Activated AKT on MM
cells.
·Correlates with Stage
Hsu et al. Blood 2001;98, 2853-2855
Preclinical studies with novel
agents targeting PI3K/AKT and
their downstream targets
· Novel agents targeting cytokines
· Small molecules targeting
gg upstream
p
proteins,
p, downstream proteins
p
and AKT
· Combination strategies
Preclinical validation of NVP-
ADW742
42 in MM
IGF-1R
inhibition
results in
anti-tumor
activity in
part by
down
regulation
of AKT
Mitsiades CS et al. Cancer Cell 2004;5
SGN 40 induces cytotoxicity in
MM
ll
ce s
SGN 40, a humanized anti-CD40
Ab results in growth arrest and
apoptosis of MM. Pretreatment
with SGN results in inhibition of
AKT phosphorylation by CD 40
stimulation
Tai et al. Cancer Research 2004;64
BAFF Inhibitor Blocks Adhesion
Adhesion--Induced
Induced
MM C l
ell G
th
row
d
an Survi l
va
TACI
BCMA
BAFF-R
MM
BAFF inhibitor AMG 523
MM adhesion
BAFF inhibitor AMG 523
NF-Bt
B t
t
arge genes, i.e.,
BAFF, IL6, VEGF
BMSCs
BAFF secretion
mRNA transcription
protein synthesis
Tai et al. C`ancer Res
2006; 66:6675-82
Tai et al #3452 ASH2006
Anti-BAFF Neutralizing Ab Prolongs Survival and
Inhibits Osteoclasts in SCID-Hu Model of MM
Control Animal
Anti-BAFF Ab-Treated
Survival in Days
70
CNT Isot.
BAFF
60
50
40
p=0.048
30
Ab(+)
20
10
Ab(-)
P<0.05
0
0
5
10
15
20
25
30
Days from treatment
Neri et al, Clin Can Res 2007 in press
MIPI-induced MM cell migration is
blocked by MLN3897
MLN 3897, a small molecule CCR1
specific inhibitor blocks
blocks MIPI
MIPI -
induced MM cell migration which is
PI3K/AKT dependent
Vallet et al. Blood 2007 submitted
Enzastaurin induces apoptosis
in MM
MM celllls by i h
n ibi
hibiting AKT
Rizvi MA et al. Mol Cancer Ther 2006;5(7)
Perifosine inhibits phosphorylation of Akt and its
downstream target proteins
Hideshima et al, Blood 2006 15;107
Perifosine induces cytotoxicity in cell lines
and patient
patient cells
Hideshima et al, Blood 2006 15;107
Perifosine inhibits phosphorylation of Akt and growth
stimulat
ation triggered by IL-6/IGF-1
G
and
ad BMSCs
SCs
Hideshima et al, Blood 2006 15;107
Perifosine Inhibits MM cell growth associated with
inhibition of Akt phosphorylation in
in vivo
vivo
Hideshima et al, Blood 2006 15;107
Perifosine enhances Bortezomib-induced cytotoxicity
Hideshima et al, Blood 2006 15;107
In vivo anti-tumor effects of
mTOR i hibi
n
tors
Frost et al. Blood 2004; 104: 4181-4187
Anti-
Anti angiogenic effects
effects of
of CCI 779
CCI779 an mTOR inhibitor induces
apoptosis in MM cells in part by
antiangiogenic effects
Frost et al. Blood 2004; 104: 4181-4187
Combination of Revlimid and
Rapamycin
Apoptosis
ls
CC-5013 Rapamycin Combination
40
cel 35
I- 30
+/P
25
xin
Ras
20
nne
Jak
15
eA 10
Raf
PI3K
tagn 5
cen 0
Per
048
Mek
Akt
Time (hrs)
Erk
mTOR
CC-5013
Ri
Rapamycin
Cb
Com ii
bination
Rapamycin/Rad001
hours
02
4
8
02
4
8
02
4
8
Stat
Revlimid
pMEK 1/2
pERK
MM Cell growth and survival
ERK
pSTAT3
pP65 NFB
Actin
Raje N et al. Blood 2004,104;4188-93
Cyclin D1 inhibition by P276-00 demonstrates
preclinical activity
py in Multiple
p Myeloma
48 Hour Cytotoxicity of MM Pt Cells
120
100
lor
Control-D1 Control-D15
P276.00-D1 P276.00-D15
80
ontC
of
60
tage
40
ercenP 20
0
0 nM
200 nM
400 nM
1000 nM
P276.00 Dose (nM)
1
P276.0
.8
0
.6
.4
Control
P<0.05
.2
0
0
5
10
15
20
25
30
35
Raje et al. Blood 2006; 108 Abst#3454
Cli i
n cal St
Studi
dies Targeting AKT
IL-6R inhibitors
IGF-1R inhibitors
Cytokine Receptor
BAFF-R
antagonists
SGN40
PI3K
PKC
PIP3
Enzastaurin
PDK1
RAD001
AKT
Perifosine
CCI779
mTOR
mT
GSK3
Cyclin D
P276
Results of Phase I study of SGN-
40 in
l
re
d/
apse refractory MM
MM
· 32 patients treated
treated
· Median 4 prior regimens and 4.8 yrs since
diagnosis
· 4 wkly infusions (0.5,1,2mg/kg/wk)--
ti
asep c
i
men i
n i
g ti
itis
d
an HA
HA in 2 t
p s
· Protocol ammended allowing intrapatient
dose escalation--max 8mg/kg
· 16% patients
p
had stable disease
Husssein MA, et al. Blood 2006 Abstr#3576
Phase II Study of Perifosine (KRX-
0401) Alone and in Combination with
Dex for Patients with Relapsed MM
· Perifosine 150 mgs qd
qd x 21 days
· Dex added at progression: 20 mgs twice
wky
· 25 patients evaluable for response
· 24%: Stable Disease
· 15/25had dex added with MR in 33% and
SD in 22%
· GI toxicity was the
the major AE
Richardson PG, et al. Blood 2006 Abstr#3582
Ongoing and planned future
cli i
n cal
di
stu es
· Enzastaurin in MM
· mTOR RAD001
in MM
· Combination with mTOR:
RAD001 and lenalidomide
CCI779 and bortezomib
· Pi
Per fifosine + bt
bortezomib
ib
· Cyclin D inhibitors
Acknowledgements
·
Ken Anderson
·
Members of the Jerome Lipper Multiple
Myeloma Disease
Disease Center
Center and MGH
Cancer Center