Your Advocacy at Work: The DoD Academy, Karen McLean, MD, PhD
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Presented July 9, 2016 at the Ovarian Cancer National Conference in Washington, DC
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Your Advocacy at Work: The DoD Academy, Karen McLean, MD, PhD
- 1. Targeting Ovarian Cancer Tumor Microenvironment Signaling for Therapeutic Effect Karen McLean, MD, PhD Assistant Professor, Gynecologic Oncology Department of Defense - Early-Career Investigator July 9, 2016
- 2. “Seed in the Soil” Hypothesis Steven Paget - 1889 Tumor Microenvironment Cancer cells are the seeds and the microenvironment is the soil. 2
- 3. The Ovarian Cancer Microenvironment Messages/Signals Back and Forth Cancer Stem Cell Tumor Cell Mesenchymal Stem Cell (MSC)Stromal Cell Blood Vessel 3
- 4. Mesenchymal Stem Cell Signals Increase Ovarian Cancer Growth Cancer Cells + Mesenchymal Stem Cells Cancer Cells Tumorweight(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.
- 5. Two Pathways Estrogen IL6/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
- 6. 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
- 7. Microenvironment IL6 and LIF Signals Activate Cancer Cells SKOV3 aloneNoTx anti-LIF400ng/ml anti-IL6150ng/ml anti-LIF+IL6 SKOV3+ Pt 324 CM SKOV3+ Lot 2155 CM NoTx anti-LIF+IL6 NoTx anti-LIF+IL6 anti-LIF400ng/ml anti-IL6150ng/ml anti-LIF400ng/ml anti-IL6150ng/ml pSTAT3 tSTAT3 actin SKOV3 + CA-MSC Cond. Media SKOV3 + MSC Cond. Media More Growth Signals 6 NoTx Anti-IL6 Anti-LIF Anti-IL6+LIF NoTx
- 8. IL6/LIF Increase Cancer Stem Cells 7 0 0.5 1 1.5 2 2.5 3 3.5 Percentageof CancerStemCells SKOV3 Ovarian Cancer Cells
- 9. The Ovarian Cancer Microenvironment Cancer Stem Cell Tumor Cell Mesenchymal Stem Cell (MSC)Stromal Cell Hormone signals: Estrogen Blood Vessel 9
- 10. 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 E E E Estrogen Receptor Cancer Cell 10 GROWTH
- 11. Estrogen Receptor Positive Estrogen Receptor Negative Finding: Some patients with cancers that do not express estrogen receptor will still respond to anti- estrogen therapy. Anti-Estrogen Therapy in Ovarian Cancer Patients Treatments: tamoxifen, letrozole, anastrozole Int J Gynecol Cancer. 2015;25:222-8. 11
- 12. Blocking Our Two Pathways Estrogen IL6/LIF Cytokines 12 X X Ruxolitinib Anti-Estrogens: Tamoxifen Letrozole
- 13. Blocking Both Pathways –IL6/LIF and ER 0 20 40 60 80 100 120 140 OVCAR3 Ovarian Cancer Cells PercentageLivingCells 13
- 14. 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
- 15. 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 15
- 16. • Support to carry out my research • Network of collaborators and mentors • Motivation and accountability Your advocacy makes a difference – THANK YOU! 16
- 17. Acknowledgements • McLean Lab Lijun Tan Marina Stasenko, MD Kari Hacker, MD, PhD Dani Rastedt, PhD Jake Erba • Ronald Buckanovich, MD, PhD University of Michigan • Steffi Oesterreich, PhD University of Pittsburg 17
- 18. Acknowledgements Ovarian Cancer Academy Award – Early-Career Investigator DOD W81XWH-15-0194 Patients and Families Private Donors 18
Editor's Notes
- Thank you to the program organizers for the opportunity to speak today. I am a gynecologic oncologist at the University of Michigan. I have a clinical practice that includes surgery, chemotherapy and followup for women with ovarian and other gynecologic cancers. For me, clinical medicine is rewarding and serves as a constant reminder of our need for improved treatment strategies for our cancer patients. I therefore dedicate a significant portion of my time to running a research laboratory, and today I’m going to talk with you about my research that is supported by the Department of Defense Ovarian Cancer Academy.
- This story begins in the late 1800s, when the English surgeon Stephen Paget published his 'seed and soil' hypothesis. Dr. Paget believed that locations where a cancer spreads are not due to chance, but rather certain tumor cells (which he called the 'seed') have specific affinity for certain organs (which he equated to the 'soil'). He concluded that metastases formed only when the seed and soil were compatible. We now believe that the soil is also important when a cancer is first developing and growing. Today, we consider this soil to be the “tumor microenvironment”, wherein the cancer cells grow.
- There are many cell types that make up the ovarian cancer microenvironment and build the soil that promotes cancer growth. I’d like to take a bit of time to tell you about each of these cells… We have the tumor cells or cancer cells. A subset of these cells are called cancer stem cells, which are a small percentage are believed to lead to cancer recurrence. My research focuses specifically on the mesenchymal stem cells. These cells do not make a cancer themselves, but contribute to the soil that feeds the cancer cells. They also divide into stromal or structural cells. All of these cells are talking to each other by sending messages back and forth. Let me show you an example of how these MSC talk to the cancer cells. Remember CSC and MSC – both are important for how we might devise improved treatments for patients
- This slide shows one of the important take home points of my talk today. This is an experiment where we put either cancer cells alone into mice or we put in cancer cells plus mesenchymal stem cells into mice. We then allow the tumors to grow and measure their size over time, as shown on this graph. As you can see, adding the mesenchymal stem cells causes the tumors to grow larger. This is because of messages from the mesenchymal stem cells to the cancer cells. I believe if we can block these messages in the cancer cell soil or microenvironment in addition to targeting the cancer cells, we can improve treatment response.
- I am going to talk with you about two pathways that I believe are important in the way the microenvironment and the mesenchymal stem cells specifically feed the cancer. The first… The second… Studies suggest that these pathways may influence each other’s messages. Thus, the overall hypothesis of my research supported through the Department of Defense Ovarian Cancer Academy is that IL6 and LIF in the tumor microenvironment promote tumor growth and resistance to hormonal therapy. I will talk with you a bit about IL6/LIF and then estrogen, and finally the result of blocking both pathways.
- Let us first look at the cytokine signals. Interleukin-6 (IL-6) and leukemia inhibitory factor (LIF). IL6 and LIF are made by the mesenchymal stem cells and float in the liquid of the microenvironment. They then attach to receptors on a cancer cells and activate messages INSIDE the cell that lead to the cancer growth. Thus the mesenchymal stem cells form a soil that feeds the cancer cells. When we are doing research, we can look at how strong these messages are inside the cell to determine how much the IL6 and LIF are promoting growth. We can also block these messages inside the cell to try and slow the growth. One medicine I want to talk about today is Ruxolitinib, which blocks the messages from IL6 and LIF in the cancer cells.
- This is a western blot, which is a type of experiment that looks at proteins in cells. Ovarian cancer cells are grown in a plastic dish in the laboratory, and then the proteins are collected and run on a gel, and then we can see the amount of a specific protein present. Let me walk you through what I am wanting to show you… We are interested in the pSTAT3, or phosphorylated STAT3, that shows how active the growth signals from IL6 and LIF are. First, on the left, we have ovarian cancer cells SKOV3. They have a very small amount of pSTAT3 signal. The next set of pictures is what happens when we add the liquid from around mesenchymal stem cells. This liquid increases the pSTAT3 growth signals in the cancer cells. Finally we can block specifically IL6 and LIF in this liquid, and the growth signal decreases again, suggesting that it is IL6 and LIF in the liquid that are causing this change.
- I next… We are able to determine the percentage of cancer stem cells in a cancer cell sample. Low percentage…
- A second microenvironment signal that I believe is important in ovarian cancer growth is that of the hormone estrogen.
- Anti-estrogen hormonal therapy has been shown to reduce recurrence and decrease mortality in estrogen-receptor positive breast cancers. Also, hormonal therapy has many fewer side-effects that conventional chemotherapy. The general model in breast cancer is that estrogens (shown here as green diamonds) bind to the estrogen receptor shown in blue and promote growth. Anti-estrogen therapy can decrease estrogen or block this binding block binding to this receptor depending on the specific medicine, either of which inhibits cancer growth. Although the use of anti-estrogen therapy is well proven in breast cancer, its use in ovarian cancer patients is less clear, as I will show you.
- We wanted to look at the effectiveness of anti-estrogen therapy for women with ovarian cancer. We identified women with ovarian cancer who had been treated with an anti-estrogen therapy including tamoxifen, letrozole, or anastroze at the University of Michigan over an approximately 15 year period. We determined how long each woman took the hormonal therapy. We also stained their tumors for estrogen receptor. This is what the staining looks like for tumor cells. Brown cells in the top panels indicate the presence of the estrogen receptor. The bottom panels show the overall structure of the cancers. Some of the cancers tested express estrogen receptor, while others did not. Surprisingly, and unlike breast cancer, whether or not the receptor was present did not always predict which patients would do well on hormonal therapy. We found that some patients with cancers that do not express estrogen receptor still responded to hormonal therapy. This may be because the anti-estrogen medicine is having effects on the tumor microenvironment.
- If we can block both of these signaling pathways, we may be able to improve ovarian cancer treatment.
- This slide is the second take-home point for my talk today. In this experiment, ovarian cancer cells are growing on a plate in the laboratory. They are treated with different medicines either alone or in combination. The different treatments, either used alone or in combination, include tamoxifen, letrozole, and ruxolitinib. The cells are exposed to the medicines for 2 days, and then the number of living cells determined. As shown at the far left, with no treatment we set the number of living cells at 100%. With Tamoxifen or Letrozole alone, approximately 50% of the cells are killed, and similarly with ruxolitinib alone. When we use an anti-estrogen treatment AND ruxolitinib, either tamoxifen + ruxolitinib or letrozole + ruxolitinib, 90% of the cells are killed and only 10% survive. This suggests the two kinds of medicine work better together. This is encouraging data to continue to investigate the use of these two kinds of medicine together.
- I’ve shown you that for ovarian cancer, whether or not the estrogen receptor is present on the cancer cells isn’t the only or best predictor of response to anti-estrogen therapy… However, we don’t yet know what patients would be best to treat with hormonal therapy. In collaboration with a colleague at the University of Pittsburg, Dr, Steffi Oesterreich (o-strike), we are looking at the levels of other genes related to estrogen signaling in the tumors from our patients treated with anti-estrogen therapy, to see if we can identify other ways to predict which patients will have the best response to this treatment approach.
- So, in summary, ovarian cancer mesenchymal stem cells in the tumor microenvironment make a rich soil that promotes tumor growth. #2 #3
- Finally, I’d like to make a few comments about my participation in the Department of Defense Ovarian Cancer Academy. This program has given me the critical support to carry out my research, and to establish and independent research program. It has provided me…. #2 #3 I want to say that…. Your advocacy on behalf of ovarian cancer research funding truly makes a difference. Thank you.
- In closing, I’d like to acknowledge the folks in my lab who have helped with the studies I showed today, as well as my mentor Dr. Buckanovich and my collaborator Dr. Steffi Oesterreich at Pittsburg.
- I’d like to acknowledge my funding sources, including the DOD, MIOCA, and private donor support. And in closing, I thank the patients and families, it is an inspiration to see all of you here, and you motivate us to make advances that improve patient lives. Targeting Ovarian Cancer Tumor Microenvironment Signaling for Therapeutic Effect