Chapter 13: Mesenchymal Stem Cell Treatment for Ewing’s Sarcoma; Harnessing Autophagy to Reduce Tumors
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Description
In this chapter, Dr. Kleinerman talks about her interest in the rare cancer, Ewing’s sarcoma. She first sketches the research questions she poses, based on the tumor’s reliance on blood vessels. She sketches how she focused on mesenchymal stem cells and a pathway to block to successfully prevent angiogenesis, turning this cancer into a chronic disease. Dr. Kleinerman notes some challenges to doing clinical trials, then comments on her approaches to clinical problems and the importance of funding for basic research.
Next Dr. Kleinerman talk about a new area of research she has undertaken harnessing the process of autophagy.
Identifier
KleinermanES_03_20140604_C13
Publication Date
6-4-2014
City
Houston, Texas
Interview Session
Eugenie Kleinerman, MD, Oral History Interview, June 04, 2014
Topics Covered
The Interview Subject's Story - The ResearcherThe Researcher Overview Definitions, Explanations, Translations Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care Discovery and Success
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Tacey Ann Rosolowski, PhD:
Now, I wanted to make sure that we had a chance to talk about the Mesenchymal stem cells, too, and I didn’t really have—that also, I guess, uses Interleukin-12. So maybe you could give me just the background [unclear].
Eugenie Kleinerman, MD:
Okay. The other pediatric bone cancer that I’m interested in is Ewing’s sarcoma, very rare tumor, probably, I don’t know, two, three hundred cases a year. This is a tumor that has a genetic etiology. There’s two chromosomes that have combined, and they produce an abnormal protein that has been shown to be the etiology of the malignant phenotype. So, again, my philosophy is let us understand the biology of Ewing’s sarcoma, and Ewing’s sarcoma is a very vascular tumor. And at this point in my career, there was a lot of interest in tumor vessel formation. Judah Folkmann had made his observation about vascular endothelial growth factor, which is a protein that tumors produce that stimulate expansion of the tumor vascular network, because as the tumor grows, it needs to also grow a blood supply.
Tacey Ann Rosolowski, PhD:
What year was this when you started working on Ewing’s?
Eugenie Kleinerman, MD:
Oh, I don’t know. Well, certainly probably twelve years ago, probably. So, again, my thought was, okay, if the tumor, if Ewing’s tumors need vessels as they grow, if we could interfere with this vessel formation, maybe that is a way we could augment the activity of chemotherapy. So we began to study how are these vessels formed, what are the signals, what are the proteins that the tumor produces. And at the same time, people had been starting to use anti-VEGF in the clinic and found that it didn’t cure patients, that the tumors were able to circumvent and still do that, and we found the same thing with Ewing’s sarcoma. We could block the EGF and yet the tumor would figure—it would stop growing, then all of a sudden it would take off. And to make a long story short, what we found was that VEGF comes in several forms, and one of them is a soluble form and one of them is a membrane-bound form. Why would it produce a soluble form? And so what we found is the soluble form was going to the bone marrow and stimulating the migration of Mesenchymal stem cells to migrate into the tumor area, and these cells would then differentiate into endothelial cells and help make the vessels. So there not only was a local component, which is what Dr. Folkmann had shown, that there were the local endothelial cells. The tumor was stimulating the local endothelial cells. What we found with Ewing’s is that there was that, but there was also the stimulation of the bone marrow to send cells, you know, “I need help!” “Okay. Emailing you or Fed Ex-ing you cells that can help you in your quest to grow, to grow the blood vessels.” And what we found is that if we blocked the local, the VEGF, if we did not block the soluble one, this could rescue the tumor, but we also found a way—and we studied the signals, the molecular pathways that control this, and found the specific agent that could block this. That sort of stalled the tumor growth, so the tumor was there, but it never grew and it never metastasized. So it sort of turned this disease from a disease that metastasizes and kills to a chronic disease, and I like to think of it like diabetes. You never get rid of diabetes. You always have to take insulin.
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
But if you take your insulin, you’re fine.
Tacey Ann Rosolowski, PhD:
So in this—
Eugenie Kleinerman, MD:
So in this, what we found is as long as we gave the animals this agent that interfered with the ability of the bone marrow to participate, the animals had a tumor, they were fine. So, again, the idea was can we use the biology to identify ways to interfere with the tumor. So that’s the Ewing’s story. And we studied the pathways. We’ve identified specific agents that can block it. We don’t have clinical trials yet to do it. I think it’s going to be tough, because it’s such a rare tumor, that I don’t think any pharmaceutical company is going to be interested. But the drug that we identified has already been produced, but it’s still a matter of how do you form a clinical trial, get enough patients, and get the company to give you the drug to do the trial.
Tacey Ann Rosolowski, PhD:
What is the drug?
Eugenie Kleinerman, MD:
It’s called AMG-100, I think it is, and it specifically blocks a pathway called NOTCH, and it blocks one of the specific receptors. It’s called DLL4. And I had a very creative graduate student who really did this work.
Tacey Ann Rosolowski, PhD:
And that person’s name is?
Eugenie Kleinerman, MD:
Keri, K-e-r-i, Schadler, S-c-h-a-d-l-e-r.
Tacey Ann Rosolowski, PhD:
An MD or—
Eugenie Kleinerman, MD:
She’s a PhD. She’s presently doing a postdoc at the University of Pennsylvania, and actually she’s going to come back and be an instructor in pediatrics in January, so we can continue some of our vessel work.
Tacey Ann Rosolowski, PhD:
Great. Wow. Amazing.
Eugenie Kleinerman, MD:
So I think there are many ways you can come at a tumor. You can come from cytotoxic chemotherapy. You can come from an immune approach. You can come from saying we’re going to interfere with your ability to put down the building blocks that you need to grow. And that’s why I think funding for basic research and understanding tumor biology is so important. Not only the genetic pathways, but how does the tumor—and I’m sure Dr. Fidler told you this—how does the tumor grow in the microenvironment? What does it need? Does it need low oxygen, high oxygen, vessels, down-regulate proteins so it can sit in this environment that is foreign? I mean, bone cell in the lung. You don’t have bone cells in the lung. I think it’s critical.
Tacey Ann Rosolowski, PhD:
Mm-hmm. Mm-hmm. Is there any other research that you would like to talk about?
Eugenie Kleinerman, MD:
So the area that we’re getting into now, again, is we’re trying to understand how tumors become resistant, how tumor cells stimulate vessel expansion. So there’s a process called autophagy, a-u-t-o-p-h-a-g-y.
Tacey Ann Rosolowski, PhD:
Self-eating or—
Eugenie Kleinerman, MD:
Exactly. Exactly. And that was shown to be a really important defense mechanism for cardiac cells. When there’s a cardiac infarction or an ischemia attack, clearly oxygen doesn’t get to the cardiac cells and they’re going to die because they don’t get oxygen and nutrients. Well, it turns out that autophagy is a mechanism by which cardiac cells use to put themselves in sort of like a suspended animation, and so they self-eat to provide the amino acids to make the proteins that they need to sustain, and this allows the cell to survive for a small period of time, hopefully to get through that period of anoxia.
Tacey Ann Rosolowski, PhD:
The body sure is clever. (laughs)
Eugenie Kleinerman, MD:
Exactly. Exactly. So one of my former fellows who was in my lab, she went to the Scripps Clinic in California, and even though she was a pediatric oncologist, she started doing research in cardiac. And she came and gave a lecture, because I said, “Come back. Tell me what you’re doing.” And it was in autophagy. And listening to her lecture, I thought, “Gee, I wonder if this is a mechanism that tumor cells can co-opt to put themselves in a state of suspended animation to get rid of the noxious effects of chemotherapy and radiation.” So we’ve started to investigate autophagy, and we find that osteosarcoma cells, when they’re treated with Gemcitabine, for example, or other chemotherapy agents, you do stimulate autophagy. You get production of all the proteins that are linked to autophagy and you do get resistance. So again, if we could understand this, then maybe we could block this process and prevent the tumor cell. Now, it’s completely the opposite in cardiac. You want to help this process. But in tumor cells, you don’t want this going on. However, it’s not always true. Nothing is, you know, [unclear]. So in certain cells, yes, and with certain agents, when you block autophagy, you augment the activity. But with other tumors and with other agents, autophagy seems to be part of the death pathway, and you can see that. If you eat yourself for a long period of time or at a high rate—
Tacey Ann Rosolowski, PhD:
You run out.
Eugenie Kleinerman, MD:
—you run out and you’re going to die. So we’re trying to understand what’s the linchpin, what’s the point of no return. Is it the speed at which autophagy is going? Is it the pathways that’s [unclear]? So that’s something that we’re trying to understand. And this is also important, it turns out, to immune cells, because if you trigger autophagy in immune cells, they die.
Tacey Ann Rosolowski, PhD:
Oh, interesting. Huh.
Eugenie Kleinerman, MD:
And so one of the ways tumors do have an anti-immune effect is they become hypoxic. The tumor becomes hypoxic from the chemotherapy. You get inflammatory cells that come in, but then the tumor cell somehow—we don’t understand how—induces autophagy in the immune cells and so they die. So that’s the latest thing we’re getting in, but, again, it’s from the point of view “Let’s understand normal processes and see if they are applicable in the tumor.”
Tacey Ann Rosolowski, PhD:
Are there other areas that you plan to investigate? What are you looking ahead towards?
Eugenie Kleinerman, MD:
I’m very interested in going further in this tumor vessel physiology, understanding—because tumor vessels are very leaky. So if you delivery chemotherapy, you don’t get a high concentration into the center of the tumor. If we could understand the biology and the mechanisms by which the tumor vessels are leaky—I’ve been recently reading about, for example, multiple sclerosis. There’s been a protein on vessels that has been identified on endothelial cells in the brain, patients with multiple sclerosis. And in animal models, the high expression of this protein allows breakage in the blood-brain barrier. You know, normally when you give things in the blood, the brain is protected because of the blood-brain barrier. Well, apparently, the expression of this protein breaks down the blood-brain barrier and allows immune cells to get into the brain, and there is an increase in the animal model of the immune cells in the areas of the brain that are concomitant with multiple sclerosis. So I’m thinking maybe this protein has relevance to why the tumor cells are leaky, and if we could understand that, then we could down-regulate it, cause the tumor vessels to be less leaky, and we get better delivery of whatever your target therapy, chemotherapy, immune cells, whatever, into the center of the tumor, which is usually very difficult to treat.
Tacey Ann Rosolowski, PhD:
Interesting. Yeah. Yeah.
Eugenie Kleinerman, MD:
But that’s like pie in the sky. (laughter) Hopefully, Keri and I can start addressing that next year.
Recommended Citation
Kleinerman, Eugenie S. MD and Rosolowski, Tacey A. PhD, "Chapter 13: Mesenchymal Stem Cell Treatment for Ewing’s Sarcoma; Harnessing Autophagy to Reduce Tumors" (2014). Interview Chapters. 1409.
https://openworks.mdanderson.org/mchv_interviewchapters/1409
Conditions Governing Access
Open
