Chapter 05: Recent Research: A Focus on Brain Metastasis

Chapter 05: Recent Research: A Focus on Brain Metastasis

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Description

Dr. Fidler discusses his research focus for the last four years: brain metastasis. He emphasizes that very few researchers focus on brain metastasis, largely due to the complexities presented by the blood-brain barrier. Dr. Fidler explains that the blood-brain barrier is already compromised in metastasis, a fact that has implications for treating as well as studying the condition. He discusses his work on astrocytes, which protect tumor cells from chemotherapy, until he and his group discovered a drug (now patented) that interrupts the astrocyte’s protective activity.

Identifier

FidlerIJ_02_20110927_C05

Publication Date

9-27-2011

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The ResearcherThe Researcher Definitions, Explanations, Translations Overview Inspirations to Practice Science/Medicine Professional Practice Career and Accomplishments Discovery, Creativity and Innovation Influences from People and Life Experiences Industry Partnerships Understanding Cancer, the History of Science, Cancer Research On Research and Researchers Character, Values, Beliefs, Talents

Transcript

Tacey Ann Rosolowski, PhD:

OK, let me just -- today this is Tacey Ann Rosolowski interviewing Dr. Fidler for the Making Cancer History Voices Oral History Project. Today is our second session. It is September 27th, and the time is just about five after 2:00.

Isaiah J Fidler, DVM, PhD:

Thank you.  

Isaiah J Fidler, DVM, PhD:

So the finding that the organ microenvironment influences the behavior of cancer had a significant influence on the design of animal models to study a cancer. Basically that development of what you call orthotopic models or models in the correct organ environment versus ectopic which means incorrect. Ectopia is incorrect, orthotopia is correct. Came from the observation that when we wanted to study the biology and metastasis of colon cancer we received a specimen from surgery. And the question was can we design an animal model that will predict whether the specimen that we receive are going to produce metastasis or not a year or two or three later in a patient. And if we could then the advice will be “Why don’t you do a very aggressive therapy? Because this cancer will metastasize and it will be a disaster two years, four years down the line.” And we literally did close to 80 or 90 different specimen. And not in single one did we see a metastasis when we implanted it into a mouse that had no immune system, so it couldn’t reject it. The problem was we injected it, like anybody else, under the skin. And it’s very easy to do. And all these tumors, whether they were metastatic in the patient, we even had example of already metastases that theoretically should have metastasized in the mouse. They did not. They grew locally into a quite large tumor where we either had to surgically resect the tumor or simply sacrifice the mouse. But we never found metastases. And then it dawned on me that perhaps injecting tumors under the skin is not exactly the correct model. And we began to inject human colon cancer cells into the cecum or appendix of a mouse. Into the wall of the cecum. The cecum in a mouse is almost equivalent to the appendix of man. And to my great surprise the tumors grew locally and produced metastases.

Tacey Ann Rosolowski, PhD:

Can I ask you how you came up with the idea to shift procedures?

Isaiah J Fidler, DVM, PhD:

Well, I began to think about Paget seed and soil. I said, “Subcutaneous is the wrong soil.” And colon cancer in patient, we don’t see under the skin. We see it in the colon. And we then followed with renal cancer in the kidney. Pancreatic cancer in the pancreas. Lung cancer in the lung. Breast cancer in the mammary fat pad or breast of mice. And in all those examples malignant tumors were distinguished from nonmalignant by the fact that they produced metastases. The implication of that orthotopic model was enormous, because the subcutaneous tumors by and large were very sensitive to chemotherapy, but the same tumor growing in the correct organs were not sensitive. And once again patient who have kidney cancer, they don’t have it growing in the skin. And whether the tumor in the skin is sensitive or not to chemotherapy is irrelevant because you never see it. You see it in the kidney. You see it metastasize to the lung and so on. And when we duplicated the correct organ environment we found that we were mimicking the resistance or we were duplicating, a better word, the clinical situation. So again this microenvironment, seed and soil, was translated to something extremely practical. That is can you predict the metastatic potential of individual cancers from patient and can you predict the therapeutic sensitivity or resistant.

Tacey Ann Rosolowski, PhD:

Why were the cancers that ended up in the organs themselves so resistant to chemotherapy?

Isaiah J Fidler, DVM, PhD:

Well, there are many explanations for that. And I want to focus on the last four years of my research. And there is a personal reason why I became so committed to work on brain metastases, and I don’t want to discuss it. It was not -- it was a death in the family from brain metastases. And when I realized that in the United States almost 250,000 patients are going to die a year from brain metastases, 50% to 60% of all lung cancer patient, which is the most common cancer now, will develop brain metastases, 25% of breast cancer, 20% of melanoma, I can go on and on and on. It’s very difficult to diagnose brain metastases because you depend on MRI and CT, etc. And you cannot identify tiny little lesions. They have to be of a certain size. And it’s not like mammography where you do it routinely, or colonoscopy, or prostate examination, which are very relatively easy to do. And consequently in the majority of patients if you don’t treat them, the median survival after diagnosis is one to two months. 250,000 people. Actually it’s 230,000. Well, OK, close. And with chemotherapy, surgery, radiotherapy and on and on and on we can increase survival to a median of four to six months. But that’s about it. Very few -- out of 250,000 or 230,000, I can’t think of a number of survivors. And yet when you read the literature you see that very few people, very few laboratories work on brain metastases. Very few. In the world I’d say -- in therapy yes, because they have no choice. But research, pure research, maybe ten.

Tacey Ann Rosolowski, PhD:

The difficulty level is preventing people or --

Isaiah J Fidler, DVM, PhD:

It’s the difficulty level and the point, the strong belief that something called the blood-brain barrier which I’ll explain in a minute is the culprit. The blood-brain barrier consists of blood vessels that are very tightly attached surrounded by other cells called pericytes and astrocytes. And the role of the blood-brain barrier in the brain is to prevent toxic substances from entering the brain, to protect our neurons. Because our neurons don’t divide. If we’re going to start losing neurons, it’s irreversible loss, it’s not like skin cells or lung cells, colon cells that constantly are replaced. Neurons are not replaced. So we have protection called the blood-brain barrier. The thing is that in primary tumors of the brain like glioblastoma and in metastases a very telling symptom is headache. And turns out that these patients have edema in the brain. Edema means that the vessels are leaky. I can tell you clinically the blood-brain barrier when you would diagnose metastases is leaky. It cannot be intact. But we did a lot of experiments. You can inject fluorescent material into mice. And check whether the fluorescent material is inside the vessel or outside the vessel. And in a normal brain it always is retained in the vessels. In the brain metastases that we establish it leaks out. Now oh, 20, 25 years ago, a neurosurgeon by the name of Gabi G-A-B-I Schackert S-C-H-A-K-E-R-T Schackert came to do a fellowship with me. And she introduced me to brain metastases. At the time I was working with colon cancer and prostate cancer and pancreatic cancer and ovarian cancer. You name it. And it was one thing. OK, brain metastases. And then there was another fellow came from Japan to continue her work. But it wasn’t that captivating. I don’t know how to explain it. It was difficult. And I said, “OK, fine.” But she developed a method to introduce tumors through the carotid artery which is right here to the brain of mice. And we published, I don’t know, half a dozen to a dozen paper on models for brain metastases. And we have shown in these metastases that there were the same cell melanoma injected into the brain was resistant to chemotherapy, the identical clone injected subcutaneously was sensitive. In the lung it was sensitive. But in the brain it was resistant. But I attributed it to the blood-brain barrier. So the chemotherapy can reach the tumor in the skin and in the lung, but not in the brain. But as I said, a few years ago it became very clear that that prevailing viewpoint of the field is absolutely wrong. And again similar to what I told you, how can metastases be random? If you can predict metastases. But it took me quite a few years to reach that conclusion. What are they talking about that metastasis is random? You can predict it. It’s a contradiction in terms. Same thing here. If a patient has edema, cerebral edema, what are you telling me about the blood-brain barrier? There is edema for God’s sake. So we had to look at something else. And here circumstantial evidence became extremely strong. And that is that any wound in the brain, any lesion, any inflammatory change in the brain involves a cell of the microenvironment called astrocyte. Astro like the ballplayer that don’t know how to play ball. Astrocyte C-Y-T-E-S. These stromal cells of the brain’s job in physiology is fascinating. They send a process to the blood vessel and another process to a neuron. And they transfer nutrients from the blood to the neuron, glucose, galactose. They participate in signal transmission. They do all the -- practically they help neuron do their job, etc. But they’re the main support cell of neurons. When metastases or primary tumor grow in the brain, we found -- I had a slide given to me by Dr. Ken Kenneth Aldape A-L-D-A-P-E. A neuropathologist, or head of neuropathology. And we’re looking at the slide. And here is lung cancer metastases to the brain. And it’s surrounded by huge number of activated or angry astrocytes. And I say to Ken, it’s true story, “What is that?” He said, “Well, these are astrocytes surrounding tumor.” And I say, “Is that new?” He said, “No. Everybody knows it.” “So how come it’s not published?” He said, “Everybody knows it.”

Tacey Ann Rosolowski, PhD:

When you say activated or angry what do you mean? What is it doing?

Isaiah J Fidler, DVM, PhD:

They express a certain protein so we --

Tacey Ann Rosolowski, PhD:

I see.

Isaiah J Fidler, DVM, PhD:

-- call them activated astrocyte.

Tacey Ann Rosolowski, PhD:

I see.

Isaiah J Fidler, DVM, PhD:

If you look at the normal brain the astrocytes are there attaching every neuron. But they don’t express the protein. Only when there is hypoxia. Any stress in the brain would lead to expression of this protein called GFAP. Doesn’t matter. It’s too complicated. But the astrocytes are activated. Well, I’m looking at that and I’m saying to my fellows, “Go ahead, and let’s produce this model in the brain of a mouse.” And we inject lung cancer, breast cancer, melanoma into the brain of mice. And what do you know? They’re surrounded by angry or activated astrocytes. I began to think about it. What does it mean? Well, if the astrocytes were anticancer, there’ll be no cancer. The fact that they are interacting with all the tumor cells could be two things. Either they are neutral, they don’t do anything, or God help us, they enhance cell growth, because their job is wound healing in the brain. I didn’t tell you at all about 15 years that I spent on macrophages. But we’re going to leave it alone. These are the cells that enhance wound healing in the body. And they’re also -- they can do everything under the sun. The phagocyte. Everything.

Tacey Ann Rosolowski, PhD:

And this was the research that basically enlisted their aid. To activate the macrophages so that they would attack. Both benign and malignant cells.

Isaiah J Fidler, DVM, PhD:

Right, right. So anyhow, we began to be very interested. And Robert Langley L-A-N-G-L-E-Y isolated mouse astrocytes and gave us a nice cell line and when Sun-Jin Kim who did all the work, Sun-Jin J-I-N Kim K-I-M. Sun-Jin Kim cocultured tumor cell and astrocytes, to make the story short, tumor cell were protected from chemotherapy. And we showed that the astrocytes must touch the tumor cells. You can separate them by a membrane. You can do all kind of things. Unless an astrocyte put an end foot on a tumor cell, the tumor cell is not protected. Well, remember, the astrocyte have an end foot on a blood vessel cell, an end foot on a neuron. They don’t talk in -- they touch everything. Well, if they touch a tumor cell, tumor cell is going to be protected. And we looked at every conceivable mechanism, and the most fascinating thing is when we looked at growth of lung cancer or breast cancer or melanoma with astrocytes, versus fibroblasts, we saw that when they grow with astrocytes, there are more than 250 genes common that are upregulated in all the cell line. So the astrocyte, well, they can upregulate 2,000 in this. But there were almost 250 genes that in every cell line the same genes were upregulated. Among them were three survival genes. So these survival genes or antideath genes resulted from the interaction of this so-called stromal cell with the tumor cell. And the tumor cells are resistant to chemotherapy. We submitted the paper for publication. And a reviewer said, “You didn’t prove anything. Knock those genes down and show me that the tumor cells are now sensitive.” Well, Sun-Jin and colleague discovered something very interesting. If you knock one gene, the cells are still protected. Any one of these three genes as a single gene, they’re still protected. But when we knocked out all three of those genes, OK, the tumors became sensitive to chemotherapy. And we did something else. Again Dr. Aldape gave us clinical specimen of multiple tumors from patient brain metastases. In every case those genes are expressed in the metastases in patient. Now we did it in mice. Turn it off. You’ll excuse me.

Tacey Ann Rosolowski, PhD:

I will pause the machine.

Isaiah J Fidler, DVM, PhD:

This is my wife. The recorder is paused.

Tacey Ann Rosolowski, PhD:

OK. We’re resuming recording at 2:25 after Dr. Fidler took a brief phone call.

Isaiah J Fidler, DVM, PhD:

The fact that astrocytes protect tumor cell leads to a simple conclusion. Role of astrocytes in the brain is to support and protect neurons. Unfortunately they don’t distinguish between a tumor cell and a neuron. They’ll do it to any cell they touch. But it indicates again the relative importance of the organ microenvironment on cells’ growth and survival. I told you that previously we injected lung cancer into the lung of a mouse or to the brain. In the lung it’s sensitive to chemo. In the brain it’s not. Well, there are no astrocytes in the lung. There are astrocytes in the brain. Damage to the lung occurs every day of our life. And it’s being repaired. It’s not -- obviously total damage is a disaster. But every day you damage your lung when you breathe the air in Houston, OK? And it’s repaired with alveolar macrophages. Here we go to the macrophage. But damage to the brain is almost irreversible, OK? Because the only cell that will divide will be the stromal cell, not the neurons. And we lose neurons all the time. That’s why I don’t remember names. But if I wish I knew how to revive neurons so we will never grow old. But the blood-brain barrier and the astrocytes’ function in physiology is to protect the neurons from damage from circulating toxic molecules. Well, tumor cells need oxygen. Tumor cell need nutrients. And they release a molecule that -- all tumors in the brain we published release molecule called vascular endothelial growth factor or VEGF. VEGF was identified years earlier as vascular permeability factor. So when cells release that molecule, endothelial cell become not as tight, and things become porous, and things leak out. In edema. It leads to edema. And when you flood the tumor with oxygen and with nutrient, the tumor will grow better. It doesn’t depend on blood vessels. But when that happen, the astrocyte goes berserk. And it becomes activated. Because it means there’s something wrong. There is stress. I’m sorry to make a movie out of it. But I don’t know how to explain it any better. There’s a knee-jerk reaction here. They become stressed. And when they’re stressed their job is to protect, to protect, to protect. And they’re so stupid they don’t know if you are protecting neurons or tumors. And unfortunately they protect everything alike. And that’s why tumor cells are insensitive or resistant to chemotherapy. Now we have a patent on that now. Because we know the pathway by which astrocytes activate those genes. I can describe it. It’s too sophisticated in a way. But I don’t know what else to tell you.

Tacey Ann Rosolowski, PhD:

I’d like to hear.

Isaiah J Fidler, DVM, PhD:

How to do it. The signal that astrocytes send to tumor cell to say, “Upregulate these genes,” or they send it to neuron, is called endothelin-1, ET-1. Now the signal has to bind to a receptor. And the way I explain to my graduate student the relationship of a signal, a receptor and activation of a receptor is very simple. You take a key, that’s the signal. You put it in a keylock, in a keyhole, excuse me, that’s the receptor. Now you got to have the right key to go into the receptor but sometimes you can put anything you want. You can put a toothpick in it. But in order to turn the keylock and open the gate or the door, the key and the keylock must be absolutely matched, and you have to turn the key, and that’s called phosphorylation. You activate the receptor. And if the receptor is not activated, the door will not be opened, and it doesn’t matter whether you stick the key in the key, you look stupid when you just stand there with the key, and then you realize, “Oh my God, I put the wrong key in the wrong keyhole.” If you can stop the key from turning over, nothing else will fall down. We’re working with a small company in Switzerland. This is really just for you. Not -- OK?

Tacey Ann Rosolowski, PhD:

Shall I turn this off?

Isaiah J Fidler, DVM, PhD:

No. I’m just telling you. Don’t -- and we found that a drug that inhibits phosphorylation of the endothelin receptor which was developed to lower blood pressure can prevent the astrocytes from upregulating those genes. We wrote a patent on that and MD Anderson now has a patent together with the company. But it was our, my idea to do that, OK? In fact the company didn’t think that -- I said, “I’d like to try it,” and they said, “Go ahead.” I think they thought I was out there in left field. And I told my friends, “Don’t turn down my intuition, it’s pretty good.” “No, no, no.” Said, “Fine, then I’ll do it on my own. I don’t need your money to do it.” So it was our idea, and it works. So I say to you we have done therapy experiment in mice. And I present it now in many many symposia where I’m invited, and I end up by saying, “If you’re a mouse that has brain metastases, come to me. I’ll cure you.” Not therapy. Cure. In human we need to do clinical trials. And clinical trials are planned for the near future. And you’re going to say again, “Well, what gave you the idea?” Well, one and one and one is three. If you believe in the principle of the seed and the soil, then who cannot believe in that? Just ignorant people. Absolute ignorant. Don’t have to understand metastases, have to understand medicine. You really think that muscle and the kidney are the same? Probably some people maybe. You really think that the brain and the colon is the same? Maybe in some. But these are distinct organ with distinct molecule, with distinct cell. Yes, we all evolve from two cells. But that’s called differentiation.

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Chapter 05: Recent Research: A Focus on Brain Metastasis

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