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

14

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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Acknowledgements

Ovarian Cancer Academy Award –Early-Career InvestigatorDOD W81XWH-15-0194

Patients and Families

Private Donors

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