September 18 th , 2012 3-4 p.m. Presenters: Cecelia Fisher-Dahms Peter Mangione Osnat Zur
Osnat Ashur-Fabian 1,Keren Cohen 1,Aleck Hercbergs 2,Martin Ellis 1 1 Translational Hemato-Oncology,...
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Osnat Ashur-Fabian 1 ,Keren Cohen 1 ,Aleck Hercbergs 2 ,Martin Ellis 1 1 Translational Hemato-Oncology, The Hematology Institute, Meir Medical Center & Sackler Faculty of Medicine, Tel-Aviv University, ISRAEL 2 Department of Radiation Oncology, The Cleveland Clinic, Cleveland, Ohio, USA Tetrac, a small molecule integrin ligand cooperates with bortezomib and enhances cellular response in myeloma cells: A novel chemosensitizing approach in myeloma A novel chemosensitizing approach in myeloma
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Transcript of Osnat Ashur-Fabian 1,Keren Cohen 1,Aleck Hercbergs 2,Martin Ellis 1 1 Translational Hemato-Oncology,...
Osnat Ashur-Fabian1 ,Keren Cohen1 ,Aleck Hercbergs2 ,Martin Ellis1
1Translational Hemato-Oncology, The Hematology Institute, Meir Medical Center & Sackler Faculty of Medicine, Tel-Aviv University, ISRAEL
2 Department of Radiation Oncology, The Cleveland Clinic, Cleveland, Ohio, USA
Tetrac, a small molecule integrin ligand cooperates with bortezomib and enhances cellular response in myeloma
cells:
A novel chemosensitizing approach in myelomaA novel chemosensitizing approach in myeloma
Multiple Myeloma (MM)
First described in 1844 * Sarah Newbury* Dr. Samuel Solly
Plasma cell (PC)
* Bone Marrow
Multiple Myeloma (MM)
Plasma cells * Antibodies (Ab) producing cells
Plasma cell neoplasm * Abnormal plasma cells
proliferation * Excess Ab production * Bone damage, Kidney
Multiple Myeloma (MM)
10% of hematological malignancies
Incurable
* Median survival 3-5 years
* Most patients refractory/relapse
Novel “targeted” therapies
Treatments
* Steroids/Chemotherapy
* Bone-marrow
transplantation
Multiple Myeloma timeline (MM)
Bortezomib (Velcade)Proteasome inhibitorProteasome inhibitor
The concept
* 80% of proteins are destroyed by proteasome
system* Balanced degradation (cell cycle/anticancer proteins,
p53)
* Proteasome inhibition
* Promotes apoptosis
* Increased proteasome activity in multiple myeloma,
Bortezomib
* The first FDA approved proteasome inhibitor
* Dysregulated proteasome activity in cancer
Bortezomib in multuple myeloma
Preclinical and clinical trials in myeloma
bortezomib
* Inhibited proliferation
* Enhanced apoptosis
* Synergism with chemotherapies
Improved outcome
The problem
* Side effects
* Resistance Demand for discovery of new drugs/combination
Thyroid function and cancer
Cancer patients with hypothyroidism
* Increase sensitivity to chemotherapy
* Increased sensitivity to radiation therapy
* Prolonged survival
Dr. Aleck HercbergsHypothyroidism and tumor regression.N Engl J Med. 319(20):1351-2. 1988
Clinical supportive data Hypothyroidism reduces cancer incidence and improves survival
Clinical supportive data Hyperthyroidism increases cancer risk
Thyroid function and cancerThe biological process?
V3Plasma membrane
Nucleus
RGD
Proliferation
PKC, MAPK
Angiogenesis
VEGF
T3/T4 Metabolic rate?
Oxygen consumption ATP formation IGF-1/EGF
TR1
“Classical” function
Thyroid function and cancerMimicking selective hypothyroidism
V3Plasma membrane
Nucleus
T3/T4
ProliferationAngiogenesis
Tetrac
Sensitizes
Chemo/radiation therapy
TR1
Thyroid function and cancerThe biological process
Clinical supportive dataChemically induced subclinical hypothyroidism
prolongs cancer patients survival
PTU
Methimazole
Official consensus statement- Cleveland Clinic, USA
* Evidence for T3/4 involvement in cancer * No thyroid hormones supplements in subclinical hypothyroidism (Supported by “The American Thyroid Association”)
* Advocate conservatism in replacement therapy in hypothyroid patients who harbor a diagnosis of solid cancer
* Signed by hospital oncologist/endocrinologist
Importance ofv3 in MM and cancer
Thyroid function and multiple myeloma (MM)
Effect of thyroid hormones in MM?
Thyroid function and multiple myeloma (MM)
V3Plasma membrane
Nucleus
T3/T4
0
50
100
150
200
control 0.1nM 1nM 10nM 100nM
Pro
lifer
atin
g c
ells
(% o
f co
ntr
ol)
T3
0
50
100
150
200
control 0.1nM 1nM 10nM 100nM
Pro
lifer
atin
g c
ells
(% o
f co
ntr
ol)
T4
T3/T4 increases myeloma cells proliferation
** *
* * * *
S phase
G2M
Effect of thyroid hormones in MM
Will blocking thyroid hormones binding to v3 induce
* cell proliferation?
* cell death?
Thyroid function and multiple myeloma (MM)
V3Plasma membrane
Nucleus
T3/T4
Tetrac
020406080
100120
Control 6.25 25 100
mM
Su
rviv
ing
cel
ls
(% o
f co
ntr
ol)
Tetrac
0
20
40
60
80
100
120
control 6.25 25 100
mM
Pro
lifer
atin
g c
ells
(%
of
con
tro
l)
Tetrac ** *
Tetrac reduces myeloma cell
proliferation/survival
Cell proliferation Cell survival
*
0
50
100
150
200
250
Control 6.25 25 100
mM
Nec
roti
c ce
lls
(% o
f co
ntr
ol)
Tetrac
0
50
100
150
200
250
Control 6.25 25 100
mM
Ap
op
toti
c ce
lls
(% o
f co
ntr
ol)
Tetrac
* * *
Apoptosis Necrosis
Tetrac induces myeloma cell death
RGD but not RGE blocks tetrac activity in MM
cells
V3Plasma membrane
Nucleus
T3/T4RGD
Tetrac
0
20
40
60
80
100
120
control Tetrac Tetrac+RGD Tetrac+RGE
Pro
lifer
atin
g c
ells
(%
of
con
tro
l)
Tetrac **
Effect of thyroid hormones in MM
Will blocking thyroid hormones binding to avb3 induce
* cell proliferation?
* cell death?
Will blocking thyroid hormones sensitize bortezomib action?
Thyroid function and multiple myeloma (MM)
0
20
40
60
80
100
120
Control 6.25 25 100
nM
Su
rviv
ing
cel
ls
(% o
f co
ntr
ol)
Bortezomib
Bortezomib+tetrac 100 Mm
* *0
20
40
60
80
100
120
control 6.25 25 100
nM
Pro
lifer
atin
g c
ells
(%
of
con
tro
l)
Bortezomib
Bortezomib+tetrac 100 Mm
* *
Tetrac sensitizes bortezomib action
0204060
80100120
control 6.25 25 100
nM
Pro
lifer
atin
g c
ells
(%
of
con
tro
l)
Bortezomib
0
20
40
60
80
100
120
Control 6.25 25 100
nM
Su
rviv
ing
cel
ls
(% o
f co
ntr
ol)
Bortezomib
cell proliferation cell survival
Drug “sparing effect”
Supra additive
0
50100
150
200
250300
350
Control 6.25 25 100
nM
Ap
op
toti
c ce
lls
(% o
f co
ntr
ol)
Bortezomib
Bortezomib+tetrac 100 M
*
m
0
50100
150
200
250300
350
Control 6.25 25 100
nM
Ap
op
toti
c ce
lls
(% o
f co
ntr
ol)
Bortezomib
0
50
100
150200
250
300
350
Control 6.25 25 100
nM
Nec
roti
c ce
lls
(% o
f co
ntr
ol)
Bortezomib
Bortezomib+tetrac 100 M
**
m
0
50
100
150200
250
300
350
Control 6.25 25 100
nM
Nec
roti
c ce
lls
(% o
f co
ntr
ol)
Bortezomib
Bortezomib+tetrac 100 M
**
m
0
50
100
150
200
250
300
350
Control 6.25 25 100
nM
Nec
roti
c ce
lls
(% o
f co
ntr
ol)
Bortezomib
Supra additive/additive
Apoptosis Necrosis
Tetrac sensitizes bortezomib action
Combined tetrac-bortezomib and cell cycle
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
17%
A
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
17%
A
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
17%
A
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
17%
A
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
17%
A
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
17%
A
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
25%
SubG1
BG0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
47%
C
SubG1
G0/G11
G2/M1
G0/G12
G2/M2
Control Bortezomib
Bortezomib
+ tetrac
Current/future work
* Biological pathways activated by t3/t4 in MM
* MAPK
* VEGF
* v3 role in myeloma* Level* SiRNA
* Tetrac prior to bortezomib
* Tetrac effect on Ab production
* Co-culture with stroma cells
* Tetrac Nanoparticle
Thyroid function and multiple myeloma (MM)
Thyroid hormones induce proliferation in myeloma cells
Tetrac, mimics selective hypothyroidism
* Reduce proliferation
* Induce death
* Sensitized bortezomib action*Supra-additive
* Drug sparing effect
Thyroid function and multiple myeloma (MM)
Summary
Novel Novel adjunctadjunct therapy in myeloma and cancer in therapy in myeloma and cancer in
generalgeneral* Low risk* Low risk* Bench to bed-side* Bench to bed-side* Low cost* Low cost* Combined with any chemotherapy* Combined with any chemotherapy
מרכז רפואי מאיר ד"ר אשר אלחיאני
המעבדה האונקוגנטית פרופ' מיקי לישנרד"ר ליאת דרוקר ד"ר שלי מטלון ...בקרוב ד"ר ויקי זיסמנוב
צוות הפקסחווה שפירא רחל שיקלר
קרן כהן
The Cleveland Clinic Cleveland, Ohio, USA
Department of Radiation Oncology Dr. Aleck Hercbergs
Ordway Research InstituteAlbany, NY, USA
Signal Transduction Laboratory Prof. Paul J. Davis
ד"ר מרטין אליס
