PATOGENESI MOLECOLARE E POSSIBILI TARGET TERAPEUTICI NEL MIELOMA MULTIPLO

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PATOGENESI MOLECOLARE E POSSIBILI TARGET
TERAPEUTICI NEL MIELOMA MULTIPLO
Alberto Rocci Ospedale San Giovanni Battista di
Torino Università degli Studi di Torino
Mediterranean School of Oncology Orvieto, 20
novembre 2009
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MULTIPLE MYELOMA
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Hematological Neoplasia Pathogenesis
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MM PATHOGENESIS
GENOMIC INSTABILITY
MICROENVIRONMENT ALTERATIONS
IMMUNE SYSTEM IMPAIRMENT
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GENOMIC INSTABILITYIN MULTIPLE MYELOMA
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BM and PB
Lymph Node
Naive B lymphocyte
Extra GC-maturation
Memory B lymphocyte
B-cell precursor
Marginal zone
Mantle-zone
Germinal Centre
GC-maturation
Memory B Lymphocyte
plasmacells
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VDJ RECOMBINATION
somatic hypermutation
IgH switch recombination
Alterations regarding these three mechanisms are
commonly involved in the pathogenesis of
hematological malignancies. In particular it is
involved the 14q32 chromosomal region
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PRIMARY Translocations
TRASLOCATION
ONCOGENE
ROLE
t(4p1614q32) 15 FGFR3 GF
rec TK MMSET Transcription
regulator TACC3 ND
t(6p2114q32) 5
CICLINA D3 Cell cycle regulator t(6p251
4q32) 5 MUM/IRF4 Regulation of
IFN transc. t(14q3216q23) 5-10
c-maf Transcriptional factor t(14q3
220q12) 5 b-MAF
Transcriptional factor t(11q13,14q32)
15-20 CICLINA D1 Cell cycle
regulator MYEOV
ND
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PRIMARY Translocations
Almost all the genetic aberrations identified in
MM are present in MGUS
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THE MM STORY PROBABLY STARTS HERE
Marginal zone
Mantle-zone
Germinal Centre
MM
GC-maturation
Memory B Lymphocyte
plasmacells
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Two pathway hypotesis
Multiple Myeloma and MGUS
Chromosome 13 monosomy/deletion is an early event
that can occur in both groups
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Cyclin D disregulation
Virtually all MM and MGUS plasmacells have
increased levels of Cyclin D1, D2 or D3, despite
the low proliferative rate
Nonhyperdiploid pathway
Cyclin overespression does not lead to a growth
improvement, however it seems that this
situation can make plasma cells more prone to
growth stimuli
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TC classification
FGFR3
MMSET
C-MAF
MAFB
CCND3
CCND1
CCND2
RB1
4p16 14
Maf 8
11q13 16
D1 32
D2 19
D1 D2 7
None
6p21 2
2
Bergsagel PL, Blood 2005
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Alteration of Rb pathway
Bergsagel PL and Kuehl WM, JCO 2005
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GENOMIC INSTABILITY
ONCOGENIC EVENTS
Bergsagel PL, Blood 2005
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FROM MGUS TO MULTIPLE MYELOMA
Supervised analysis
263 genes are differentially expressed
between healthy and MGUS
380 genes are differentially expressed
between healthy and MM
74 genes are differentially expressed
between MGUS and MM
There are fewer differences at the gene
expression level between MGUS and MM than between
healthy and MM or healthy and MGUS
Davies FE et al., Blood 2003
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SECONDARY Translocations
Occurres as progression event
Rare or absent in MGUS patients
Can be mediated by mechanisms that do not involve
the three B-cell-specific DNA-modification
mechanisms
Bergsagel PL and Kuehl WM, JCO 2005
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GENOMIC INSTABILITY
ONCOGENIC EVENTS
Bergsagel PL, Blood 2005
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Disease stages and timing of oncogenic events
Bergsagel PL and Kuehl WM, JCO 2005
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GENOMIC INSTABILITY and Prognosis
ONCOGENIC EVENTS
Karyotypic abnormalities
Secondary (Ig) TLC
N-ras (codon 12,13,61) K-ras (40-55) FGFR3
MAPK pathway activating mutations
TRAF3 cIAP1/2 CYLD NIK
NFkB pathway activating mutations
RB1 pathway
p18INK4c inactivating muts
MYC dysregulation (45)
DEL 17p DEL 1p
TP53
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GENOMIC ALTERATION AND EFS OS
Avet-Loiseau H et al., Blood 2007
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GENOMIC ALTERATIONS AND NEW DRUGS
BORTEZOMIB
LENALIDOMIDE
Del(13q)
T(414)
Sagaster V et al, Leukemia 2007
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GENOMIC ALTERATION AND TARGET THERAPY
Clin Cancer Res 2009
Leukemia 2009
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GENOMIC INSTABILITY CONCLUSIONS
MM seems to include several diseases that have
differences in early events, global gene
expression patterns, clinical features,
prognosis and response to therapy
IgH translocation are common in half of MM and
MGUS patients whereas other patients display
trisomies
Common translocations have a major prognostic
role in patients treated with standard or high
dose chemotherapy, their role in patients
treated with novel drugs is still under
investigation
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MICROENVIRONMENT ALTERATION IN MULTIPLE MYELOMA
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HOW MICROENVIROMENT SUSTAINS MALIGNANT GROWTH
A TYPICAL CASE OF MM DOES NOT HAVE ALL THESE
FEATURES
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MICROEVIRONMENT AND MM(main actors)
Plasma cell Osteoclast Endothelial
cell Hematopoietic cells Mesenchymal
cells Osteoblast ECM Dendritic cells Natural
immunity cells T-cells B-cells
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MM cells and bone marrow interaction
Hideshima T et al., Nat Rev Canc 2007
Hideshima T Anderson KC Nat Rev Cancer
2007585-598
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Molecular modification due to cell-to-cell
interaction
Hideshima T Anderson KC Nat Rev Cancer
2007585-598
Hideshima T et al., Nat Rev Canc 2007
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HGF/MET in Multiple Myeloma
HGF
Met
ß-actin
Normal BM Cells
Normal PB Cells
Primary myeloma cells
Börset M et al, Blood 1996
Seidel C et al, Blood 1998
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RESULTS MET and PFS - OS
The two groups display no differences
about beta2microglobulin and albumin levels or
FISH feature
Rocci A. et al, ASH 2009
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MICROEVIRONMENT AND MM(How does it plays)
IL-6 TNF-? RANK-L VEGF TGF-? Prostaglandins
Multiple role and indipendence to growth
stimuli resistance to apoptosis homing and
migration angiogenesis replication and
proliferation resistance to inhibition stimuli
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MULTIPLE ROLE OF IL-6 IN MALIGNANT PC
IL-6 induces expression and secretion of VEGF
Hideshima T and Anderson KC, Nat Rev Cancer 2002
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ROLE OF VEGF IN Myeloma
Laminin, fibronectin
BMSCs
VEGF IL-6
MM cell
IL-6 VEGF
VEGF, IL-6
VEGF
Inhibition of maturation
Proliferation, migration
Dendritic Cell
MM PC
Lin et al. Cancer Res 2002
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BONE DISEASE
Scheletal involvment is observed in approximately
80 of newly diagnosed multiple myeloma patients
Very debilitating aspect of multiple myeloma due
to pain Dangerous due to pathological fractures
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Bone Physiology
OSTEOBLAST
OSTEOCLAST
TNF?, IL-1, IL-6, PGE2, IFN?, RANKL
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Bone in Multiple Myeloma
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MICROEVIRONMENT AND MM(role of RANK/RANKL)
RANK is found on the surface of
osteoclast precursors
RANKL is expressed on marrow stromal cells
and osteoblasts
RANKL binds to RANK Inducing osteoclast formation
OPG is produced by osteoblasts and can
antagonize RANKL activity
Myeloma cells - downregulate expression of OPG
- upregulate expression of RANKL
Myeloma cells produce DKK-1 that antagonize the
Wnt signaling, vital for osteoblast
differentiation
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DRUGS ACTIVITY ON BONE
Terpos E. et al, Leukemia 2007
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CONCLUSIONS
Treatment paradigm in MM concurrent targeting
of both tumor cells and bone marrow
microenvironment to overcome drug resistance
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IMiDs in myeloma treatment
Richardson P. et al, JCO 2004
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Bortezomib in myeloma treatment
PROTEASOME INHIBITOR
Triggers MM cell apoptosis by the accumulation
of improperly folded proteins
Reduce growth factors Decrease cytokine levels
Antiangiogenic effects reduce cell adesion and
IL-6 production
Bone remodelling Reduce resorption Increase
formation
Increase Immunity disrupts tumor-DC interaction
and enhances DC-mediated immunity