Targeting NF-kB in Multiple Myeloma
Marta Chesi, Jonathan Keats, Leif Bergsagel
Mayo Clinic
Scottsdale,
Scottsdale Arizona
A
Arizona
Rochester,
Rochester Minnesota
M
Minnesota
Jacksonvill
Jacksonvil e
l ,
e Florida
Continuous improvement in 5-year survival: 1950-2000
35
35%
ival
rsurva
5-ye
Year of diagnosis
0
1950
1960
1970
1980
1990
2000
ACTH
Merphalan Melphalan
Thalidomide Lenalidomide
GW Thorne NB
N
l
Bl k
o hi
khin
DE Bergsagel
BB
B Barl
i
og e
KC A d
n erson
1950
1957
1962
1999
2002
Prednisone
Bortezomib
M Scafi
RZ Orlowski
R Baldassari
Baldassari
2002
1957
SEER Cancer Statistics Review 1975-2005
Clinical progression of plasma cell neoplasia
Multistep pathogenesis of
of MM
MM
Primary
Secondary
Late
Indolent
Aggressive
PC
MGUS
MM
MM
Hyperdiploidy
p18 deletion
Ras mutation
IgH translocations
p53 mutation
Myc dysregulation
NFKB mutation
Primary events
events in MM
Primary
Indolent
Aggressive
PC
MGUS
MM
MM
Hyperdiploidy
IgH translocations
MMRC Genomics Portal
Integrated Genomics Viewer
Hyperdiploid vs
vs Non
Non-Hyperdiploid MM
MM
TC Classification: universal dysreg
ygulation of cyclin D
FGFR3
MMSET
C-MAF
MAFB
CCND3
CCND1
CCND1
CCND2
RB1
D1 N
4p16 Maf
11q13
D1
+
D2
o
6p21
Hyperdiploid
D2 n
e
Primary event
event generates two
two genetic
subtypes of MM
Progression of MGUS to MM
Secondary
Indolent
Aggressive
PC
MGUS
MM
MM
Ras mutation
Myc dysregulation
BM restricted plasmacy
pytosis in Vk*MYC mice
wt
Vk*MYC
albumin


50w 20w
30w 40w 50w 60w 70w
wt
Vk*MYC
spleen
BM
spleen
BM
0.37
0.74
0.72
0.56
1.06
1.69
25.2
0.26
CD138
44.8
54.1
69.6
29.2
70.9
26.3
68.8
5.66
B220
Chesi et al, Cancer Cell, February 2008
MYC upregulation MGUS > MM
Chesi et al, Cancer Cell, February 2008
MYC rearrangements
rearrangements
Late progression of MM
Late
Indolent
Aggressive
PC
MGUS
MM
MM
p18 deletion
p53 mutation
NFKB mutation
p53 deletions on 17p
Activation of NFkB in MM
· Induced by interaction of MM with BM
microenvironment
· Protects MM from drug-induced apoptosis
· Inhibited by bortezomib
Chauhan D et al. Blood 1996 87:1104
Hideshima T et al. Cancer Res 2001 61:3071
BAFF & APRIL & Receptors
Receptors in
in MM
MM
BAFF and APRIL elevated in serum of MM patients, and are
produced mainly in the BM microenvironment by monocytes and
osteoclasts.
MM cells express the receptors BCMA and TACI but not BAFF-R
Moreaux, J. et al. Blood 2004;103:3148
Moreaux, J et al. Blood 2005;106:1020
Moreaux, J et al. Haematologica 2007;92:803
NFkB pathway mutations in MM
BAFF
APRIL
CD40
CD40L
TACI
LTßR
CYLD
TRAF2/3
MLN
cIAP1/2
NIK
Classical
Alternative
IKKß
IKK
P P
NF-kB
NFKB2
P P
NF-kB
Pathway
IkB
Proteasomal degradation
IkB
g
p100
Pathway
100
p65
BTZMB
p50
RelB
NFKB1
p105
p52
p65
p65
p50
RelB
Nucleus
NF-kB
Target genes
Inactivation of TRAF3
· Inactivating point mutations in 50% of patients with LOH of TRAF3
· ~13% of patients and ~18%
~18% of cell lines have TRAF3 inactivation
inactivation
· Inactivation predicted to abrogate TRAF3 interaction with NIK
· TRAF3 inactivation is known to activate the non-canonical NFKB
pathway (p100 to p52 processing)
Differential sensitivity of HMCL to IKKß inhibitor
Annunziata et al
Cancer Cell 2007
Sensitivity to IKKß inhibitor correlates with activation of NFKB
Annunziata et al
Cancer Cell 2007
Resistance to Dex in HMCL with NFkB mutations
1.20
1.00
TRAF3
0.80
TRAF3
BIRC
TRAF3
NIK
none
0.60
NFKB1
none
none
none
0.40
none
none
0.20
0.00
d0
0
1
5
20
78
313
1250
nM dexamethasone
Patients with low TRAF3 mRNA are resistant to Dex
and sensitive to Bortezomib
CR+PR
PFS
2/20
10%
83d
17/19
89%
193d
17/50
30%
140d
41/104
40%
145d
APEX (039 & 040) pharmacogenomic data courtesy of George Mulligan and Barb Bryant
Higher response rate to bortezomib of t(4;14) in Summit 025
32%
23%
18%
22%
5%
FGFR3
MMSET
Time to progression
100
MAFB
75
CCND3
4p16
50
CCND1 total
25
CCND1 long
Other
0
0
90
180 270 360 450 540 630
CCND2
Days
4p16
6p21+11q13
D1
D2
maf
median 296 vs 84 days (p=0.065)
PD
NC
MR
PR
CR/NCR
71% p=0.002
17% p=0.01
32%
RR 39% overall
Bergsagel, 10th IMW 2005
Extramedullary PC in Vk*MYC/EBCL2
spleen
BM
03
0. 9
39
0.4
13
1. 8
38
06
0.76
Monoclonal plasma cell
expansion in old C57Bl6
2.13
restricted to BM
0.88
WT
CD138
CD138
70w 90w
49.7
49.5
50.4
47.4
B220
B220
2.72
1.81
1.53
0.42
Polyclonal plasma cell
expansion in all lymphoid
Emu-Bcl2
organs.
CD138
CD138
20.8
74.7
33.1
65
40w 60w
B220
B220
0.38
0.26
15.4
0.55
Monoclonal plasma cell
0.97
5.39
Vk*MYC
expansion in 30w old mice
CD138
CD138
restricted to BM.
30.9
68.5
47.6
36.5
70w 90w
B220
B220
26.7
7.48
37.3
0.96
17.6
Monoclonal plasma
p
cell
Vk*MYC/Bcl2
expansion in 30w old mice
CD138
CD138
in all lymphoid organs.
31.2
34.6
28.7
33.1
20w 30w
B220
B220
Microenvironment activates NFkB
NFkB in
in PC,
PC, MGUS, MM:
but mutations in NFkB/other pathways increase autonomy of MM
NFkB
High
High
mutation
NFkBi
NFkBi
High
High
High
MM
HMCL
NFkBi
NFkBi
NFkBi
other
PC
MGUS
MM
Low/high
Low
mutation
NFkBi
NFkBi
Extrinsic activation
activation of
of NFkB
NFkB
BAFF,APRIL > BCMA,TACI, BAFF-R > NFkB activation
BCMA-Fc
Bortezomib
TACI-Ig
IKKß inhibitor
Bl
Bergsagel Lab
Marta Chesi, Ph.D.
Jonathan Keats, Ph.D.
Mayo Clinic Arizona
Myeloma Group
Keith
Rafael
Rodger
Jonathan
StewartMarta
Fonseca
Tiedemann
Chesi
Keats
Esteban Braggio, Craig Reeder, Ric Valdez, Joe Mikhael
Collaborators
Mike Kuehl (NCI)
Michael Barrett (TGen)
John Carpten (TGen)