Chapter 09: A History of Translational Research at MD Anderson

Chapter 09: A History of Translational Research at MD Anderson

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Description

Dr. Keating sketches the history of translational research at MD Anderson beginning with the “pioneers” Dr. Emil Frei, III and Dr. Emil J Freireich.

He begins with context: NCI support of research into the biology of cancer and the role of drugs in treatment and their impact on DNA. He explains Dr. Freireich’s understanding of cancer, what led him to study the phenomenon of hemorrhage in leukemic patients and platelet transfusion. He lists other lines of research that evolved to sketch the areas of knowledge converging at MD Anderson. He notes that he found it “stunning” to come to the institution and find people who “knew diseases back to front.”

Dr. Keating then compares translational research in these early days with today’s push toward targeted therapy focused on genetic changes in all of the cancers.

Dr. Keating next talks about MD Anderson patients and their willingness to try almost anything in the hands of experienced clinicians who are creating new knowledge. He praises the Texas State Legislature for creating the institution. He notes that MD Anderson has made an enormous impact by training physicians who carry their knowledge out into Texas and the world.

Identifier

KeatingM_02_20140520_C09

Publication Date

5-20-2014

City

Houston, Texas

Topics Covered

The University of Texas MD Anderson Cancer Center - Overview; Overview; MD Anderson History; Building/Transforming the Institution; Controversy; Ethics; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; MD Anderson Impact; MD Anderson and Government

Transcript

Tacey Ann Rosolowski, PhD:

All right, and now we are recording. All right. The time is 2:28, and this is Tacey Ann Rosolowski, and today I’m in the Department of Leukemia in the Faculty Center interviewing Dr. Michael Keating for our second interview session together. So thank you very much—

Michael Keating, MD:

Pleasure to be here.

Tacey Ann Rosolowski, PhD:

—for making time.

Tacey Ann Rosolowski, PhD:

I wanted to focus today on your research, but before we get started on the specifics of that, I wanted to ask you to tell me a bit about the history of translational research at MD Anderson and even how the idea of doing translational research evolved since the early seventies. Is that when it began?

Michael Keating, MD:

Probably even earlier than that. I think that the people that pioneered the translational research at MD Anderson was Drs. Emil Frei and Dr. Emil Freireich [Oral History Interview], and they both came from the National Cancer Institute. I think that one of the features there was that the NCI, rather than being the massive structure it is at the present time, was rebuilding so that they could establish people that were interested in the biology of cancer, interested in how drugs metabolized and the impact of the drugs on DNA, which was just emerging as a feature at that time, and the building blocks that were used to manufacture the DNA, so that there was this concept of the whole process of how are cells manufactured, how do they differ from normal cells. Dr. Freireich has used the term that the reason that oncology is so fascinating is that it’s fundamentally a disturbance of growth, normal growth, and if we learn things from oncology, we may be able to apply it to the general process of growth and differentiation, how cells develop, how organs develop, etc. So that there was a sense then not only of the translational research from a cell point of view and a drug point of view and a treatment point of view, but also the impact that it had on the normal host. In those days, a lot of the research that was undertaken was trying to establish why people died of cancer, because it hadn’t been well documented. They just said that they died of cancer, but many of them died of infection as a consequence of it. Some had organ dysfunction as the tumors took over those organs, and, in particular, the hematologic malignancies, the leukemias, lymphomas, there was a sense of the failure of production of normal blood elements, which led to infections and also to hemorrhage. There was a lot of debate to what the hemorrhage was all due to, and Dr. Freireich, in particular, found an association with the platelet count, and you could separate out the platelets from the rest of the blood and count them, and this was done in a chamber. So he decided to see if he could collect platelets from blood that was donated to the Blood Bank and if he could potentially transfuse them, and this led to the first concept that platelet transfusions could alter the likelihood of people dying of hemorrhage. And it was not met with very much grace, because no one really knew what platelets did very much, and this led to the whole concept of the platelets were very important in plugging the first holes that occurred in blood vessels, and that as time went by, we understood that clotting factors were more important in the continuing of this process going. It was around about this time that they began to note the association of infections with a low neutrophil count, and that has been supplanted at the present time by the use of granulocyte-stimulating factors to boost the neutrophil count and prevent infections from occurring. There was also the concept of developing isolation technique, so the protected environments, which were initially just plastic bubbles around the beds of patients and subsequently into laminar air-flow rooms, were being developed. And it was around about that time that two things happened, that there was a lot of interest in the development of assays of drug levels and the correlation between the drug levels and the side-effect profile and also the likelihood of patients responding to different treatments. There was a lot of collaboration that was established with the Southern Research Institute at that time, with Drs. Skipper, Howard Skipper, and Frank Schabel, S-c-h-a-b-e-l. They were looking at the kinetics of mouse leukemias and finding that if they were rapidly dividing, you had to give agents that would catch the cells in cell cycle, and if they were not rapidly dividing, that wasn’t quite so important. And many of the early principles of translational research measuring the levels and correlating it with clinical outcomes were developed at that time. Subsequently, there was a lot of interest in the immune system, so that in the very late sixties and early seventies, there was the concept that the immune system didn’t work very well in pretty much all cancers, but, again, most probably likely to be dysfunctional were in the blood malignancies, the leukemias and lymphomas, and this was where many of the early studies were done. There was the development of agents such as Colleys, C-o-o-l-e-y-s, toxins, which were bacterial cell-wall products, and they’re reemerging now as stimulators of the innate immune system. There was the observation that some patients’ tumors went into spontaneous remissions, and these tended to occur in diseases such as renal cell cancer and malignant melanoma, so that these ended up being targets for new initiatives in the development of ways to stimulate the immune system. It was in these days that there was just the early evaluation of the lymphocytes being B-lymphocytes, the title coming from the bursa of Fabricius in birds, which was near the appendix, and this was where the B-cells were most prominent, and then the T-lymphocytes, which were in the thymus. So that all of these things were beginning to come together at, oh, probably the early 1970s, and I arrived here in 1974, and this is when MD Anderson was bringing all those concepts together. So it was stunning to me when I arrived that there were people there who knew the diseases back to front. They had tremendous experience with it. There were developments more and more of the laminar air-flow technology and the use of antibiotics to prevent infections in people that had a prolonged depression of their blood counts. There was the immunology group that were concentrating on solid tumors, and in particular they were looking at malignant melanoma by the use of these very nonspecific stimulants such as BCG, and this would stimulate the immune system. Some patients got responses in melanoma and some in other conditions, so that the whole process was looking at what’s happening to the host in this circumstance, so what was the production of normal blood counts and normal immune function, how were the organs working and how did dysfunction of the organs affect the metabolism of different drugs, and how did that affect the toxicity and likelihood of response. So that Dr. TiLi Loo, T-i-L-I L-o-o, was doing the pharmacology, and Drs. Hirsch and Gutterman were looking at the immune system. Dr. Bodey was looking at the protected environment and antibiotics to prevent infection. Dr. McCredie was developing the cell-separator technology so that you could collect white cells and stem cells. And then the coming together of many of these things was the introduction of stem cell transplant to the MD Anderson, which really only occurred around about 1975, ’76, when Dr. Carl Dicke, D-i-c-k-e, came over from the Netherlands and set it up together with Dr. McCredie. So they were the major players there. There were a number of people that were looking at solid tumors, Dr. Livingston in lung cancer, and everyone had their own special little area. Dr. Jeff Gottlieb, who, unfortunately, died on, oh, I think, July the 1st, 1975, of cancer, was a brilliant young man, and he was leading the development of new drug evaluations in a variety of cancers, integrating many of these issues.

Tacey Ann Rosolowski, PhD:

Can I ask you, because you’ve listed a real long list of people here, what was the percentage of people at MD Anderson involved in translational research? Was it accepted? Was it controversial? I mean, it seems like a new paradigm for putting together research.

Michael Keating, MD:

There were conventional groups. There was a Department of Medicine that concentrated on lymphomas and Hodgkin’s disease as some of the blood malignancies, but the whole concept of developing chemotherapy drugs in solid tumors was really at its infancy. It was at that time predominantly a surgical and radiation therapy-based institution. But it was obvious that the patients that were dying were not so much dying of local recurrence as they were from metastatic disease, so that there had to be some systemic therapy that was developed at that time. Systemic therapies were stimulating the immune system generally, killing off the cancer cells, developing hormone strategies in breast cancer and prostate cancer. And there was always an attitude of trying something different because it was known that the natural history of a lot of the patients that had various types of cancers in various stages of the disease was dreadful, so that it was worth trying something different. There were some people that found that treating people with investigation drugs with the side effects of ulceration of the mouth and bleeding and hair loss and a variety of other side effects like damage to the nerves was almost inhumane, and there was a lot of discussion that went on as to the ethics of experimenting on people. It was not until there was a number of dramatic changes that occurred at around about the same time that there was an increase in the likelihood of adults with acute leukemia going from desperation to the point where perhaps 15 to 20 percent of them were ending up being cured of the disease, and this was predominantly due to one drug, cytosine arabinoside, or ara-C, and also the anthracyclines, the red drugs, that Daunorubicin was one of those in acute leukemia, and Adriamycin or Doxorubicin was the lymphoma drug and the breast cancer drug and the sarcoma drug, and it was broadly effective in solid tumors. So suddenly people were seeing very dramatic responses considering the time, but it was still the situation where there was most interest in treating the earlier forms of cancer definitively with surgery and radiation, and then when it came back and there was nothing else that you could do, they were then referred to what was called developmental therapeutics. That was not just drug development, but development of different ways of administering the drugs, by intravenous, continuous intravenous therapy, intra-arterial therapy. There was a thought that you could then begin to deliver high concentrations in the artery to the limbs of patients that had sarcomas and see if you could kill off the tumor by having very high concentrations. All of these were very new strategies to deal with the failures of the local therapy, the surgery and the radiation therapy concept.

Tacey Ann Rosolowski, PhD:

Now, let me ask you, because it sounds as though this attitude, trying something different, I mean, that’s kind of what happens at the beginning of any new paradigm or when there’s a new idea, how has the model of translational research changed since that time? I mean, comparing now with then, what does it look like now as an approach, as a model, how you set up a translational study?

Michael Keating, MD:

I think that there are two major elements to it. One is to know the cancer, so that as MD Anderson got more mature, there were databases that were set up that identified all the patients that would be coming into the particular diagnosis, a sense of what the characteristics were that were associated with a bad and a less bad outcome rather than a good outcome oftentimes, and so that we got to know the tumor better. The second element was the concept of what drugs worked for this and what drugs worked for that. There was then the whole concept of the process of metastasis, and that was then something that was developed by Josh Fidler [Oral History Interview]. And everyone knew about many of the things, but he had some elegant mouse models that were looking at that, so that a lot of the biologic processes of cancers were being developed. We then had the situation where with relatively crude genetics and relatively crude measures of estrogen receptors in breast cancer and progesterone receptors as well gave us predictions as to how patients would respond to hormonal therapy, so that as we discovered more cases that responded to different things, it was possible to develop the whole concept at that time of therapeutic dissection of disease. So you gave patients with a particular tumor a treatment, and some of them responded and some of them didn’t, and you developed the concept of why is that happening, and it was trying to correlate the levels, etc. There was not very much information, particularly in solid tumors, of the genetics, that most of the staining, most of the analysis of the cells was done by staining of proteins, staining of some surface molecules, and trying to get some grading of the aggressiveness of the disease. The thing that’s happened now is that the big push is to understand and catalog the genetic changes that occur in all of the cancers if we can, and then identify some of the potential ways that we could target these abnormalities. And it’s got away from the concept of treatment of a particular treatment. For example, the development of inhibitors of what they call BRAF, B-R-A-F, in melanoma, where there’s commonly a mutation, gave dramatic response in some people because it would specifically inhibit the abnormal protein that was generated from the mutation. In chronic myelogenous leukemia, the Philadelphia chromosome led to the development of a unique new protein enzyme, BCR-ABL. So that the concept then, it was okay to have a specific abnormality, you have an enzyme, you have a specific inhibitor. But now we know that these mutations are not restricted to just one type of disease, so that the inhibitors that were developed for chronic myelogenous leukemia, for example, are also very active in a subset of patients that have acute lymphocytic leukemia and in patients that have the gastrointestinal stromal tumor, because you find that there are abnormalities, and you can look at the drugs that were developed, for one, and see if they inhibit the proteins in other situations. It’s fascinating at the moment that the rare blood malignancies, for example, hairy cell leukemia, is one where the BRAF mutation described in melanoma is present in almost all of the typical cases of hairy cell leukemia, and they are very, very different diseases. But the inhibitor that’s being developed in melanoma gets remissions in almost all of the patients with hairy cell leukemia, so it’s a crossover. So it’s not so much the morphology of the tumor, where they arise, but the genetic change which leads to an abnormal protein which can be inhibited by a drug wherever that mutation abnormal protein exists. So the question of targeted therapy has come along in that direction. The other area, however, which is really burgeoning at the present time, and it’s based on the powerful impact of monoclonal antibodies in the management of, initially, lymphoma, there is a drug called Rituximab, which would bind to a surface protein called CD-20, and when it attached to it, it uses the body’s own immune system, both proteins in the circulation such as c____ and T-lymphocytes to punch holes in the membrane of the tumor cells. And it did it also to the normal B-lymphocytes, but the B-lymphocytes recovered a lot quicker than the tumor did. And then it was found that when you weakened the cell by this interaction with the monoclonal antibody, all of the chemotherapy worked very much better, so that there was this finding. Some of the dramatic changes in immunology at the present time in immunotherapeutics has come from the discovery by Dr. Jim Allison that you can have antibodies against proteins on the surface of the cancer cells or the immune cells and break this tenacious stranglehold that existed between the immune cell and the cancer cell. Once you broke that open, the immune cells could work. So that this is another application of an antibody. The other is utilizing the surface proteins so that the antibodies could attach to them. The cancer cells would then suck the antibody in, and if you had attached a payload of a killing drug or some other chemical, this was then delivered fairly selectively to the cancer cell and didn’t involve other tumors.

Tacey Ann Rosolowski, PhD:

All of those approaches must probably would have sounded like science fiction back in the seventies, you know, dreams. (laughs)

Michael Keating, MD:

It did. In fact, the first time that Dr. [Jordan] Gutterman [Oral History Interview] did grand rounds with interferon, there was a comic with Flash Gordon, and there was someone talking about the only thing that would save a particular person in this comic book was interferon. And he was going along and showing, well, this is what happens now, and there was [unclear] that this was tremendously active again in this rare leukemia, hairy cell leukemia, and that led to the development of the first biologic agent that worked against cancer. So that one of the great things about working at Anderson is that, (a), we have a lot of patients that are willing to try pretty much anything because they’re being told by a number of people that their particular disease has no accepted treatment, and without a response, they’re going to die, and so that they’re willing to do that. But even more important, there are very, very experienced cancer doctors who will notice that something different has happened outside of their experience. One patient leaves you excited and two patients intrigue you, and if you have three that responded, there’s a real hypothesis, so that there’s tremendous acceleration. We have so many patients, particularly in the solid tumor area and some of the blood malignancies, that are difficult to handle, where there’s nothing happening and there’s a lot less interest in clinical trials because the likelihood of getting something positive is very low. But as soon as you see one, two, three responses that are out of the norm, there is a tremendous acceleration of accrual. So that one of the great features of MD Anderson is the ability to amplify the findings in a small number of patients, and that’s, again, because the patients are willing to try it and the doctors are willing to do it, and they’re experienced in how to manage them. Again, I hearken back to I think what we talked about last week, the tremendous wisdom of the state legislature to get a central Cancer Center, and it’s functioned as the spoke-and-wheels-type thing, that the MD Anderson’s near the axle and everything spreads out from there. There’s been tremendous training of physicians in cancer that spread right through Texas and really right throughout the world now from this one institution.

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Chapter 09: A History of Translational Research at MD Anderson

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