your advocacy at work: the dod academy, karen mclean, md, phd
TRANSCRIPT
Targeting Ovarian Cancer Tumor Microenvironment Signaling for Therapeutic Effect
Karen McLean, MD, PhDAssistant Professor, Gynecologic Oncology
Department of Defense - Early-Career InvestigatorJuly 9, 2016
“Seed in the Soil” Hypothesis
Steven Paget - 1889
TumorMicroenvironment
Cancer cells are the seeds and the microenvironment is the soil.
2
The Ovarian Cancer Microenvironment
Messages/Signals Back and Forth
Cancer Stem Cell
Tumor Cell
Mesenchymal Stem Cell (MSC)Stromal Cell
Blood Vessel
3
Mesenchymal Stem Cell Signals Increase Ovarian Cancer Growth
CancerCells +
Mesenchymal Stem Cells
CancerCells
Tum
or
wei
ght
(g)
1.00
0.75
0.50
0.25
0.00
J Clin Invest. 2011;121:3206-19.4
I believe that blocking signals from the non-cancer neighbor cells to cancer cells in addition to targeting the cancer cells can improve treatment response.
Two Pathways
EstrogenIL6/LIF
Cytokines
Hypothesis: Cytokines IL6 and LIF produced by mesenchymal stem cells in the tumor microenvironment function in parallel to promote tumor growth and resistance to hormonal therapy.
5
Cytokine Signals
• Interleukin-6 (IL6)Leukemia Inhibitory Factor (LIF)
5
Ruxolitinib:Medicine that blocks these messages
Outside Cell
Cell Membrane
Inside Cancer Cell
IL6/LIF
Receptor
JAK
STAT
GROWTH
Microenvironment IL6 and LIF SignalsActivate Cancer Cells
SKOV3alone
No
Tx
an
ti-L
IF4
00
ng/
ml
an
ti-I
L61
50
ng/
ml
an
ti-L
IF+
IL6
SKOV3+Pt 324 CM
SKOV3+Lot 2155 CM
No
Tx
an
ti-L
IF+
IL6
No
Tx
an
ti-L
IF+
IL6
an
ti-L
IF4
00
ng/
ml
an
ti-I
L61
50
ng/
ml
an
ti-L
IF4
00
ng/
ml
an
ti- I
L61
50
ng/
ml
pSTAT3
tSTAT3
actin
SKOV3 +CA-MSC
Cond. Media
SKOV3 +MSC
Cond. Media
More Growth Signals
6
No
Tx
An
ti-I
L6
An
ti-L
IF
An
ti-I
L6+L
IF
No
Tx
IL6/LIF Increase Cancer Stem Cells
7
0
0.5
1
1.5
2
2.5
3
3.5
Perc
enta
ge o
fC
ance
r St
em C
ells
SKOV3 Ovarian Cancer Cells
The Ovarian Cancer Microenvironment
Cancer Stem Cell
Tumor Cell
Mesenchymal Stem Cell (MSC)Stromal Cell
Hormone signals: Estrogen
Blood Vessel
9
Anti-Estrogen Therapy
• Well-studied in estrogen receptor (ER) positive breast cancers– Excellent side-effect profile
• Clinical use in ovarian cancer patients less clear
E
EE
E
EstrogenReceptor
CancerCell
10GROWTH
Estrogen ReceptorPositive
Estrogen ReceptorNegative
Finding: Some patients with cancers that do not express estrogen receptor will still respond to anti-estrogen therapy.
Anti-Estrogen Therapyin Ovarian Cancer Patients
Treatments: tamoxifen, letrozole, anastrozole
Int J Gynecol Cancer. 2015;25:222-8. 11
Blocking Our Two Pathways
EstrogenIL6/LIF
Cytokines
12
X
X
Ruxolitinib
Anti-Estrogens:TamoxifenLetrozole
Blocking Both Pathways –IL6/LIF and ER
0
20
40
60
80
100
120
140 OVCAR3 Ovarian Cancer Cells
Perc
enta
ge L
ivin
g C
ells
13
Predicting Patients for Anti-Estrogen Therapy
• Collaboration with Dr. Steffi Oesterreich at the University of Pittsburg
• In our ER+ cancer samples, determining what other genes are expressed and how they correlate with response to anti-estrogens
• Goal: To identify biomarkers of response
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Conclusions
• Ovarian cancer mesenchymal stem cells in the tumor microenvironment promote tumor growth
• IL6/LIF cytokine messages and estrogen are important microenvironment signals
• Blocking IL6/LIF signals may make anti-estrogen therapy more effective in ovarian cancer patients
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• Support to carry out my research
• Network of collaborators and mentors
• Motivation and accountability
Your advocacy makes a difference – THANK YOU!
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Acknowledgements
• McLean Lab
Lijun Tan
Marina Stasenko, MD
Kari Hacker, MD, PhD
Dani Rastedt, PhD
Jake Erba
• Ronald Buckanovich, MD, PhDUniversity of Michigan
• Steffi Oesterreich, PhDUniversity of Pittsburg
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