IGF-1R: A key linker between chemoresistance and cancer stem cells in epithelial ovarian cancer cells
IGF-1R: A key linker between chemoresistance and cancer stem cells in epithelial ovarian cancer cells Ram Kumar Singh, Ankit Jinager, Ajit Dhadwe, Abh...
IGF-1R: A key linker between chemoresistance and cancer stem cells in epithelial ovarian cancer cells Ram Kumar Singh, Ankit Jinager, Ajit Dhadwe, Abhijit De and Pritha Ray*
Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India 5th Asia Pacific Summit on Cancer Therapy, 20th – 22nd July 2015
Ovarian Cancer Ovarian cancer (OC) is the 4th leading cause of gynecological deaths around the world. (Siegel et al., Cancer J Clin, 2012) As per the Tata Memorial Center, Mumbai’s registry India, it is the third most lethal cancer amongst women. Types Germ cell OC (3-5%) Epithelial OC (85-90%) Sex-cord stromal cell OC (5-7%) Subtypes: Epithelial Ovarian Carcinoma
Chemotherapy Platinum (cisplatin and carboplatin) Taxane (paclitaxel)
Though the patients show response to 1 st line therapy, 50-60 % ultimately exhibit recurrence and finally succumb to the disease.
Key players behind drug resistance
There are subset of cells within the heterogeneous tumor designated as cancer stem cells. These CSCs have high DNA repair efficiency and chemo resistance property.
Ovarian cancer and chemoresistance
Ovarian cancer-stem-like side population cells are tumorigenic and chemoresistant. (Hu et. al., British Journal of cancer, 2010) In vivo and in vitro studies have showed the role of Insulin Growth Factor -1Receptor (IGF-1R) cross-talk in chemoresistance and have proven that IGF-1R inhibitors can overcome cytotoxic resistance. (Wong et. al., Gynecologic Oncology, 2012).
Neoadjuvent therapy Debulking Surgery Adjuvant Chemotherapy
Tumor Relapse
Tumor Relapse
Chemo resistance
Early detection of Chemo resistance
Targeting Right population
Chemo resistance
Cancer Stem Cells
IGF-1R Axis
Schematic representation of development of cellular resistant models in A2780 cells
Understanding the role of the biological and molecular players during induction of drug resistance CSC characterization • SP assay • Biomarker assay • Spheroid assay • Tumor xenograft assay
Cell line used • A2780/APFT • OAW42 • SKOV3 • Hey
Side population assay Paclitaxel Model
25
Combination Model
p = 0 .0 0 0 2
P e r c e n t S id e P o p u la tio n
Cisplatin Model
20
p = 0 .0 0 5 4
15
p < 0 .0 0 0 1 p = 0 .0 0 0 4
10
p = 0 .0 0 0 2 p < 0 .0 0 0 1
5
0
A
P
F
T C
IS
-E
R C
IS
-L
R P
A
C
-E
R P
A
C
-L C
R
O
M
B
I-
E
C
R
O
M
B
I-
L
R
Self Renewal and Chemoresistance Property B
110
* * * = P < 0 .0 0 1
***
110
***
90
100
80
90
P=0.0005 P=0.0004
70
***
60
Number of spheroids
N u m b e r o f s p h e r o id s
100
***
*** ***
50 40 ***
30 20
P=0.0008
80 70
P=0.0082
60
P=0.0014
50 P=0.0093
40 30 20
10 10
C
P
P
I
L
R
S
S
R L
7 A2
ER
S CI
LR
S CI
I
B
80
M
B
M C
O
O C
M O
0
N
P
P N
R
S
S
R E
I
E
I
B
B
M O C
P
C
A
C
A P
P
P
P
S
S L
C
C C A
A
N
R
L
R
P
P E
R
N
S
S
E
R
P
P
S
S
N P
C
IS
IS
L
R
L
R
S
P
100
*
80
*
*
40
20
R
R
I-
L
-L
B
C
C
O
M
A
C
IS
-L
F
R
T
0
P
SP NSP
60
A
P e r c e n t V ia b ilit y
MP
*
P
P R
N C
S
R
E
IS
IS
C
C
7 2 A
E
N
0
0
8
8
7 2
S
S
P
P
0
A
A
ER
C PA
LR
C PA
ER
LR
B MB OM C CO
Stemness gene expression across the resistant models 0.020 *** ***