Chapter 18: Therapy to Block Angiogenesis

Chapter 18: Therapy to Block Angiogenesis

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In this chapter, Dr. Hortobagyi talks about research on anti-angiogenesis therapies funded by The Breast Cancer Research Foundation. He begins, however, by noting that once he had embraced the understanding that breast cancer is multiple diseases, rather than a single pathological phenomenon, he realized that other colleagues and basic scientists needed to undergo the same “epiphany.” “We all needed to learn more and go beyond our slice of the world” in order for diagnosis and therapy to progress. Dr. Hortobagyi then describes his work on anti-angiogenesis therapy. He defines angiogenesis and lists MD Anderson faculty who have contributed to understanding the process. He then describes early work with Endostatin and Angiostatin, early anti-angiogenesis agents, which never provided adequate results because of their very short half-life. Work on the subject revived when Genentech developed Avastin (bevacizumab), a drug that caused tumor regression, but that also created serious side effects. Dr. Hortobagyi next explains that, with the revival of the field, he and Dr. Hung developed the Endo-CD project (Endostatin-cytosine deaminase fusion protein) which was similar to gene therapy in that it involved molecular manipulations in vivo. He and Dr. Hung worked with molecular processes to make the earlier drug, Endostatin, more effective. He describes the chemical construct they created: a chemical compound with no activity was linked to Endostatin and used as a vehicle to deliver Endostatin directly to tumor vasculature. Another activating agent was then administered to activate Endostatin. With the drug so locally attached to the tumor, side effects were minimized.

Dr. Hortobagyi notes that during work on EndoCD, he was also conducting clinical trials on Avastin. He describes the disappointing results. He notes that the pharmaceutical industry had looked to the drug as a potential “cash cow,” and he explains how the drug became a political issue in insurance reimbursement.

Identifier

HortobagyiGN_03_20130123_C18

Publication Date

1-23-2013

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The ResearcherThe Researcher Discovery, Creativity and Innovation Overview Definitions, Explanations, Translations Professional Practice The Professional at Work On Research and Researchers The History of Cancer Research and Care On Pharmaceutical Companies and Industry

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 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

Gabriel Hortobagyi, MD:

Following this initial example with Dr. Hung, then it became increasingly clear to me, on my side as a clinician, that this same scientific epiphany that I had gone through really needed to happen to my other colleagues in the clinical area and similarly needed to happen to other basic science investigators in the institution—the colleagues of Mien-Chie Hung. So we talked briefly about this project of doing an inventory of what was going on in breast cancer research and the institution at that time. Then from that we put together some of the most exciting projects into the first application for SPORE. Then from then on, I sort of acquire this responsibility—some of it self-inflicted, some of it sort of rubber-stamped by those who worked with me—that one of my roles was to cheerlead this group and continuously develop this pattern of translational research. I felt and continue to feel very passionate about the fact that this is a process—a process that if not successful will put significant brakes on the development of important diagnostic and therapeutic approaches to cancer and that the only way we are going to really get to conquer this group of diseases is if we all wanted to learn more about them and wanted to really understand all aspects of it, not just our little world—our little slice of the world. So that went on and with each additional project that I shared or collaborated with Dr. Hung on, this became more of a passion. It became more of a challenge for me how to communicate my enthusiasm to my colleagues.

Tacey Ann Rosolowski, PhD:

So after the E1A project, then we went on to the BikDD project. The BikDD project actually continues. In fact, we have reformulated the project a number of times based on newer discoveries and improvements and tweaking of various aspects of it. We are planning to go on with an investigational new drug application to the FDA. This has to go through a special committee called the RAC—the Recombinant DNA Advisory Committee—because every gene therapy project that has some even theoretical risks of affecting our genes—our gene pool—has to go through this thing that was imposed on us by some previous government that was absolutely frantic about Nineteen Eighty-Four and some futuristic dangers to mankind. So that’s continued. Then our next projects with Mien-Chie were—again, it started out as a conversation—a loose conversation—about various things. That takes us back to the beginnings of angiogenesis as an area of research. At the very beginning of angiogenesis, there was this great hypothesis, which of course goes back to this pediatric surgeon from Harvard who came up with the idea that cancers needed to grow their own blood supply in order to survive and grow. Then many investigators contributed to that field, including several from our institution, including Dr. [Michael] O’Reilly from radiotherapy, Josh [Isaiah. J.] Fidler, Lee Ellis, Mien-Chie Hung, and many others. One of the first realizations was that, again like for apoptosis, there were a number of proteins. There was this very large family of proteins that had either angiogenesis stimulating effects or angiogenesis inhibiting effects and that it was the balance of these various pro-angiogenesis and anti-angiogenesis proteins that eventually determined whether in a particular tissue a particular group of cells was able to or unable to elicit the formation of new blood vessels. One of the early anti-angiogenesis substances that was identified was something called endostatin. As the name suggests, it is something that inhibits the development of endothelial cells—endostatin. Endostatin was actually taken to the clinic. Someone purified it or synthesized it—I don’t recall—and we did some Phase 1 and Phase 2 trials. It was a bust. It was a bust to a large extent because the half-life of endostatin once you inject is so short that it just doesn’t stay around. Within just a few minutes it is gone.

Tacey Ann Rosolowski, PhD:

Just like in a comparative sense, what’s kind of a time frame for the creation of a blood supply to a growing tumor? Or is that hard to characterize in a general way?

Gabriel Hortobagyi, MD:

No. So the concept is that when a cell that has developed the ability to grow to a certain extent uncontrolled by the surrounding control mechanisms and suppose it has metastasized to the liver, lung, or what not. It can divide and grow its little colony of cells, and it can absorb from the extracellular environment nutrients and can sort of dump the residues of that. But it cannot do that beyond—after reaching a certain size because there’s just—the cell itself, from the outside of this collection, will be an obstacle for those on the inside to obtain nutrients and get rid of their debris. So once it reaches that size—and very arbitrarily we’ve been talking about one cubic millimeter, and one cubic millimeter, of course, takes a whole lot of cells. We are talking about probably a million cells or more. So once it reaches that size, this colony becomes sort of stationary. It cannot grow any further because even though the cells on the outside can divide because they have direct access to the extracellular fluid around them, those on the inside die because they have no way to eat, drink, or prosper. So it’s at that time when they—it is thought that they start to release in increasing amounts these proangiogenic substances that then disseminate through the extracellular area and start to attract endothelial cells. The process must be fairly quick—measured probably in days or just a very few weeks—because otherwise cancer wouldn’t happen the way it happens. But I don’t know that anyone has actually determined in a human model what the timeline is. It is a very difficult experiment to design.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

In fact, I know that there are experiments in animal models. But animal models are so artificial and so idiosyncratic—depending on what animal and what cancer and where you put it—it’s not terribly reliable. But if you inject a proangiogenic substance, like VGF for instance, I’m sure that within hours you will start to see some effects of that. Now how long will it take for an endothelial cell to leave an existing blood vessel and sort of move to where the cancer cells are? And do they actually move or do they just start building buds and the buds get longer? That part is less well understood. So endostatin was one of the first ones. There was another one called angiostatin. That was a bust, too. Those sort of went—

Tacey Ann Rosolowski, PhD:

For the same reason?

Gabriel Hortobagyi, MD:

Yes. So there was some disappointment, and then those sort of disappeared. Then the field of angiogenesis didn’t revive until Genentech came out with what is called Avastin today— bevacizumab—which is a monoclonal antibody that binds to the vascular endothelial growth factor or the EGF. Being the monoclonal antibody it is, it has a very long half-life measured in weeks. For the first time there was some measurable effect in human tumors. There were some objective regressions of breast cancer and colon cancer and brain tumors and so on. Then the entire field sort of got very enthusiastic. But very early on it became apparent that bevacizumab, while it had some therapeutic effects, it also had some side effects and toxicities that were not desirable.

Tacey Ann Rosolowski, PhD:

I’m sorry. I missed the name of that drug.

Gabriel Hortobagyi, MD:

Bevacizumab or Avastin.

Tacey Ann Rosolowski, PhD:

Oh. Okay. Yeah. That is the name—

Gabriel Hortobagyi, MD:

Bevacizumab is sort of the generic name and Avastin is the commercial name. So then Mien-Chie and I started to think about, well, this drug is good but at the same time it can have some nasty effects. It can drive your blood pressure through the roof. It can make you bleed. It can make you have clots. So all kinds of problems with it. We said, “Well what can we do with endostatin so as to make it more of a functional drug?” At that time, Mien-Chie came up with a construct where you could use endostatin bound to something else—not to use it as a drug but to use it as a taxi, as a vehicle because there are receptors for endostatin in endothelial cells. So then we said, “Well, then we would use that just as a guide, but we still have to kill the cells with something else.” Then from that eventually emerged this very clever construct in which we took an enzyme that—we took a prodrug. A prodrug is a chemical substance that has no activity on its own because it has to be processed by an enzyme to remove some of the inactivator parts. So we said, “Let’s take this prodrug and link it to the endostatin. The endostatin will take it to the area where the tumor cells and the tumor vasculature is. Then independently we will administer an enzyme that will go to the same place and affect the activation of the prodrug.” So that sounds very complicated but it works beautifully—at least in the test tube. There are actually precedents for it in other areas where you put together this package that targets the organ system or tissue where you want it to go, and then you administer this activating enzyme and that accomplishes two things. Virtually all of the therapeutic activity you are looking for happens at the target—

Tacey Ann Rosolowski, PhD:

Right there.

Gabriel Hortobagyi, MD:

—tissue and nowhere else, and by not happening anywhere else you prevent all of the side effects—the non-target effects of that treatment. So this became the Endo-CD project with which we are still working. CD stands for cytosine deaminase, and cytosine is a purine that it is related to 5-Fluorouacil, and 5-Fluorouracil is one of the cytotoxic drugs we use for breast and colon and many other cancers. Cytosine is not known to be a therapeutic agent, but with the process of this enzyme that can activate, we hope it will become so. That is one of the latest projects that the BCRF is funding us with. Again, this is not strictly speaking gene therapy. It is very high-profile molecular biology in which you are modifying a molecule in vivo—in the live patient—and not in the laboratory, not in the pharmacy. So those are sort of the projects we have been working on with BCRF’s support and in collaboration with Dr. Hung’s lab. This has been happening while at the same time we were conducting clinical trials with Avastin. So I was on both sides of that discovery part. Unfortunately, Avastin didn’t quite live up to expectations. While it is an active agent, it is not the magic bullet. It is not as effective as we were hoping for. So it does produce shrinkage of breast cancers in maybe one in ten, one in fifteen patients. When added to chemotherapy, it increases the tumor shrinking ability of chemotherapy substantially by about fifty percent. It prolongs the duration of control of the disease but at the end of the day doesn’t make most patients live any longer. The problem, of course, is that it has the toxicities that I mentioned and that a lot of people not used to this drug are unaccustomed to and afraid to. We think today that while it is effective, it is effective only for a relatively small subset of patients with breast cancer or colon cancer and other cancers. The problem is that despite trying very hard over the past ten, fifteen years, nobody has been able to come up with a biomarker that can actually identify those patients who benefit and those patients who do not benefit. Something that complicated matters with Avastin is that the company that produces it decided that this was a great cash cow. So they priced it at something like—if a patient were to receive it for a full year that would be roughly $100,000 before administration costs and before any other additional costs to the patient or her insurance would have to cover. So that became a political football and eventually the FDA withdrew—the breast cancer withdrew the breast cancer indication for Avastin. It is still on the market for many other cancers. I think it works for breast cancers, but it has some issues.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

So we were working on that. The more Avastin got into trouble, the more we got interested in our Endo-CD project because it seems like it has some possibilities that Avastin will not have any time soon.

Tacey Ann Rosolowski, PhD:

As you kind of look ahead to the next step, where do you see the interesting intellectual points coalescing to suggest what is the next project you are going to try to be working on?

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Chapter 18: Therapy to Block Angiogenesis

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