Znane i nowe cele terapeutyczne w raku jajnika Katarzyna Kamińska, Aleksandra Klemba

Znane i nowe cele terapeutyczne w raku jajnika Katarzyna Kamińska, Aleksandra Klemba

Znane i nowe cele
terapeutyczne w raku
jajnika
Katarzyna Kamińska, Aleksandra Klemba
Klinika Onkologii
Laboratorium Onkologii Molekularnej
Molecular Mechanisms of Cancer
ECMs
Cytokines
Oncogene
Growth
Factors
Tumor
Suppressor
Energy
Depletion
Hormones
GRB2
C3G Crk
GRB2
SOS
Oncogene
SOS
Oncogene
EPAC1
NF1
Tumor
Suppressor
Src
cAMP
Oncogene
Gb
Gg
Ga
PI3K
SHC
RasGAP
MEK1/2
Akt
Abl
ATR
Tumor
Suppressor
Tumor Suppressor
Chk2
CcFo
Ju
s
Oncogene
n
Chk1
BclXL
PUMA
BIM
BAK
CDC25A
A
CD
Cc
HP
Oncogene
CD
K2
nE
Vcyclin
Oncogene
p53
Oncogene
C2
Regulation
P18(INK4C)
E6
CTumor
Wee1
Tumor VHL
Fo
Suppressor
Oncogene CD
P19(INK4D)
Suppressor
P21(CIP1)
s
cK4,
MD
Tumor
Cc
WNT, Ptc, BMP
Ju
Oncogene
6
Cell cyclie
M2
Suppressor
nD
Regulation
n
Regulation
MIZ
P15(INK4B)
Cc
Gli
Tumor
1
CD
MA
P14(ARF)
Suppressor
nE
Oncogene
P16(INK4A)
K2
My X
P27(KIP1)
Angogenesis
Tumor
HIF1a
c
P21(CIP1)
Tumor
Suppressor
Tumor
Oncogene
Suppressor
MIZ
Suppressor
Cell Survival
1
SMAD
SO
RA
2,3,4
Cell Survival
RBPJ-k
X
R
SMAD2,3
p300
HAT1
CBP
CIAP
Caspase9
Apoptosis
APAF1
Caspase3,6,7
MKK-7
SMAD
1,5,8
TCF3,4
BID
Caspase8,10
MKK3;6
n
SMAD6
SuFu
Fu
NLK
Gli
SMAD4
SMAD2,3
TAB1TAK1
FLi
P
Oncogene
Suppressor
APC
AXIN
Ctn
n
NUMB
G-Proteins
TAB2
SMAD SMAD4
1,5,8 Tumor
Oncogene
bTumor
Suppressor
CytoC
Ctn
Oncogene
Microtubules
Gli
BA
X
Oncogene
SMAC
p38
LEF1
b-
tBID
MMP
NF-k B
HP
Tumor
Oncogene
VSuppressor E7
DNA Breakage
Rb
E2Fs
Ladder-Like DNA
CDC25
B/C
Bcl2Suppressor
Noxa
Fo
x01
Cell
Survival
Cyclins, CDKs and
CKls Gene Expression
Aur
ora
Oncogene
Tumor
Tumor
Ik-Bs Suppressor
BAD
Cc
nD
Regulation and
Oncogenesis
BRCA1
C-Raf
p53
Oncogene
cCJuOncogene
Fo
Cell
n
s cycle
NBS1
DNA-PK
MD
M2
Oncogene
mTOR Pathway
JNK
FANCD2
ATM
ERK1/2
PAK1
GSK3
Autophagy and
Translation
Elk
Rad51,
52
Tumor
Suppressor
Ra
c
Oncogene
mTORC1
Cell Proliferation
DNA Repair
Akt
RHEB
ERK1/2
JNK
Ra
s
Oncogene
PTEN
Tumor
Suppressor
Oncogene
Akt Signaling
Oncogene
MP1
ERK1/2
HIPK2
RalGAP
PI3K
c-Raf
TSC1/2
Oncogene
MP1
Oncogene
RasGRF
MEK1/2
PI3K
RasGEF
SynGAP
PDK-1
RalA/B
PIP3
PKC
C
a
2
RasGRP
+
Oncogene
RalGEF
Oncogene
CamK2
PI3K
AMPK
Rap
IP3
LKB1
PIP3
Oncogene
Oncogene
DAG
Fy
n
Oncogene
Rh
o
Oncogene
BRaf
PKA
GSK3b
FADD ASK1
SMAD7
TAB1,2
TAK1
MKK-7
TRADD
SMAD7 SMAD
1,5,8 ERK
SMAD2/3
Dsh
Oncogene
b-
Ctn
a-Ctnn
ADAM
17/
TACE
n
WN
T1
Tumor
Suppressor
Src
P120
Ctn
Frizz
ied
WNT5A
Tumor
Suppressor
Ra
s
Oncogene
BMPs
Cd2+
TGFb
Wpływ beta endorfiny na proliferaję komórek rakowych
AlamarBlue
OvBH1
lamraraa
jaja
Ca-1
er
lamraraa
END
β edrfa
Wyniki analizy mikromacierzy ekspresyjnej
Bezpośredni wpływ β-endorfiny na komórki
nowotworowe skutkuje zmianami w ekspresji
genów związanych z podziałami komórkowymi
(proliferacją) oraz przyleganiem (adhezją)
komórek, co przekłada się na proces
nowotworzenia i przerzutowania. Dodatkowo,
β-endorfina wpływa na ścieżki przekazywania
sygnałów wewnątrz komórki, odpowiedzialnych
za stan zapalny.
Nowotwór jajnika – typy histologiczne
A o granicznej złośliwości
B surowiczy
C endometrioidalny
D jasnokomórkowy
E, F śluzowy
Lancet2014; 384: 1376–88
Odpowiedź na leczenie w raku jajnika
Różnice molekularne a odpowiedź na terapię
Int J Clin Exp Pathol. 2014 Mar 15;7(4):1502-13.
Szlak Nrf2–Keap1
PLoS One. 2014 Dec 23;9(12)
Znane cele terapeutyczne w raku jajnika cz.1
http://www.spandidos-publications.com/or/28/2/395
Znane cele terapeutyczne w raku jajnika cz.2
vintafolide
Vintafolide
http://www.spandidos-publications.com/or/28/2/395
LY2606368
LY2606368
Potencjalny cel terapeutyczny w raku jajnika
ARID1A
Proliferacja
Transformacja onkogenna
Apoptoza
Inwazyjność
Angiogeneza
Pluripotencja
Nowotworowe komórki macierzystopodobne
http://hylostet.pl/igm/article/27/
Marker Method
CD133 percentage of
Association
No correnpondence was found.
Sample size
Ref.
41 samples of OC
Ferriadin
a 2008
50 samples stained positive for CD133.
No prognostic information
Expression of both markers was correlated with
 reduced disease free survival

overall survival on cancer patients
160 samples with
stage III, IV OC
Ferrandin
a 2009
56 stage III,IV
samples of epithelial OC
Silva
2011
CD133-1+ /CD133-2
CD133
Immunostaining of
CD133-1+ cells
CD133/
ALDH
Tissue microarray,
immunofluorescenc
e
CD133
Tissue microarray
Expression (>0% of slide) found in 31% of cancers.
CD133 expression was associated with:

high-grade serous carcinoma (p=0.035)

late-stage disease (p<0.001) • ascites level (p=0.010)

non-response to chemotherapy (p=0.023)

shorter overall survival time (p=0.007)

shorter disease-free survival time (p<0.001)
CD133 expression was an independent predictor of

shorter disease-free survival time (p=0.024).
400 ovarian
carcinomas samples
Zhang
2012
Nestin,
but
not
CD133
Immunohistochemical staining
Nestin-positive (in comparison to negative cases) correlated
 cisplatin chemotherapy resistance (55.0% vs. 20.1%, p=0.001)
 shorter overall survival (p=0.001)
Nestin expression was an independent predictor of shorter
overall survival time (HR=2.501, p=0.007).
123 samples from
stage III/IV serous
ovarian carcinoma
patients
Qin 201
ALDH1,
Indirect
CD44
Immunohistochemic
al staining
Patients with higher ALDH1 expression (>50%) had (compared
with those with lower ALDH1): poor overall survival (p=0.004)
 yielded an odds ratio of death of 2.43 (95% CI = 1.12 to 5.28)
ALDH1 expression correlated with CD44 expression.
84 samples of OC
Wang
2012
CD44+/
CD24-
Percentage of such
cells found in ascites
by FACS
Threshold of 25 % CD44+/CD24- ovarian cancer cells found in
ascites. Patients with >25 % CD44+/CD24- :
 were significantly more likely to reoccur (83 vs.14 %, p=0.003)
 had shorter median progression-free survival (6 vs.18 m, p=0.01)
ascites from
19 patients with
stage IIIC/IV papillary
serous ovarian cancer
Meng
2012
Threshold of 25 % CD44+/CD24- ovarian cancer cells found in
CD44+ Percentage of
CD24- such cells found ascites. Patients with >25 % CD44+/CD24- :
in ascites by
 were significantly more likely to reoccur (83 vs.14 %, p=0.003)
FACS
 had shorter median progression-free survival (6 vs.18 m, p=0.01).
CD44+ Tissue
CK19 + microarray
Immunofluorescene
staining
CD44
tissue
microarray
CD117 Immunostaining
High frequency cells with CD44+ or CD44+/CK19+ was associated

with chemoresistance (p=0.033 and p=0.02, respectively).
High frequency of CD44+/CK19+ cells was associated with:

short disease-free interval (7.9 vs. 20.9 months, p=0.019)
Significant predictor variables were:

the frequency of CSLCs (p=0.019)

FIGO stage (p=0.037)

residual tumor volume and were entered(and 0.005)
The frequency of CSLCs was the most promising predictor variable
compared with the other 2 variables (hazard ratio=2.344, p=0.052),
however no independent significant predictor was found.
ascites from
Meng E
19 patients with 2012
stage IIIC/IV
papillary serous
ovarian cancer
33 patients with Liu 2013
epithelial ovarian
cancer
CD44s expression in 38% of the ovarian carcinoma samples.
CD44s expression was associated with:
 high-grade carcinoma (p=0.013)
 advanced stage FIGO (III-IV; p<0.001)
 age at diagnosis less than 60 years (p=0.011)
 transitional cell carcinoma (p=0.039)
CD44s expression was not associated with
 overall survival (p=0.529) & disease-free survival (p=0.218)
There was no statistical difference in CD44s expression between
the primary and recurrent ovarian carcinomas
27 paired
primary and
recurrent
ovarian
carcinoma
samples
Zhang
2013
Immunostainings positive for CD117 in 40% of patients.
CD117 expression was statistically correlated with
 resistance to conventional chemtherapy (p=0.027)
25 samples of
advanced
ovarian serous
cancer
Lou 2011
Target molecules
Inhibitor
MEK
U0126
CXCR4
AMD3100
ETRA- endothelin
receptor A
BQ123
CD133
Anti CD133
targeted toxin
dCD133KDEL
Conventional
therapy and
fusion cells
CD44+
Phenotype of targeted
cells
Ovca 433 CD133+/
CD44+/CD117+
NOY1 cells (ovaria yolc
sac tumor) CD133+
CD133+
NIH:OVCAR5 CD133+
CD44+ cells
Claudine-4
Clostridium
CD44+ cells
perfringens
enterotoxin (CPE)
CD44
miR-199a
Survival-promoting
Mitochondria
complex of
hesokinase II and
VDAC
3 bromopyruvate SKOV3 cell of
CD44+/CD117+/ALDH1+
CD44
drug delivery
system (DDS)
CD44+ cells
Cells isolated from
primary tumors and
ascites
Finding
Reference
Inhibited ERK2 activation and partially suppressed cisplatin-induced EMT and Latifi 2011
CSC markers
Decreased migration, invasion and colonies formatting capacity
Mitsui
ETRA inhibition of CSC prevented chemotherapy induced increases in tumor Coffman 2012
stem cells.
ETRA inhibition in combination with chemotherapy reduced the formation of
tumor spheres.
In vitro inhibition of CD133+ cells
Skubitz 2013
Fusion cells (FCs) prepared by fusion of dendritic cells and OCIC to
specifically target the OCIC subpopulations activated T cells to express
elevated levels of IFN-γ with enhanced
killing of CD44(+) OVCA cells.
Multiple intraperitoneal administrations of sublethal doses of CPE in mice
Casagrande 2011
harboring xenografts of chemotherapy-resistant CD44(+) ovarian cancer stem
cells had a significant inhibitory effect on tumor progression leading to the
cure and/or long-term survival of all treated animals
miR-199a significantly increased the chemosensitivity of ovarian CICs to
Cheng 2012
cisplatin, pacitaxel, and adriamycin, and reduced mRNA expression of the
multidrug resistance gene ABCG2 as compared with miR-199a mutanttransfected and untransfected cells. The expression of stemness markers was
also significantly reduced in miR-199a-transfected CICs as compared with
miR-199a mutant-transfected and untransfected ovarian cells. Furthermore,
xenograft experiments confirmed that miR-199a suppressed the growth of
xenograft tumors formed by ovarian CICs in vivo.
Pretreated SKOV3 cells exhibited also upregulation of mitochondrial mass
Wintzell 2012
and cytochrome c suggesting that targeting survival-promoting mitochondrial
complex of hexokinase-II and VDAC might be efficient. Indeed, cell were
sensitive to combination treatment of 3-bromopuryvate and significantly
lowered doses of cisplatin.
nanoscale-based drug delivery system (DDS) containing
a modified polypropylenimine (PPI) dendrimer as a carrier;
anticancer drug paclitaxel as a cell death inducer; \a synthetic analog of
luteinizing hormone-releasing hormone (LHRH) peptide as a tumor-targeting
Shah 2013
Podsumowanie
Różnice molekularne a odpowiedź na terapię
L. Hunakova et al. / Toxicology Letters 230 (2014) 479–486