Chapter 04: Pioneering Research on Antibodies and Thoughts on the Future of Treating and Preventing Cancer
Files
Identifier
MendelsohnJ_01_20050103_C04
Publication Date
1-3-2005
City
Houston, Texas
Interview Session
John Mendelsohn, MD, Oral History Interview, January 03, 2005
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Collaborations; Discovery, Creativity and Innovation; Discovery and Success; Professional Practice; The Professional at Work; Overview; Definitions, Explanations, Translations; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Technology and R&D; Patients; Patients, Treatment, Survivors
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
James Olson:
: OK. We’re – when the papers were first published, do you remember what kind of attention they got or was there a momentum that kind of starts to build?
John Mendelsohn, MD:
: There were three papers. One showed that cells growing in culture were inhibited by the antibody. We had two antibodies that we were following. We had another paper about cells growing in mice – tumors were inhibited. And a third paper, in collaboration with Gordon Gill who knew a lot about (inaudible) showed that not only were we blocking the binding of EGF we were actually inhibiting the (inaudible) activity, which was the hypothesis of course. And yeah, there was a lot of interest. I don’t think it was world-shaking interest, but this was the first demonstration that interfering with a signaling pathways, and interfering with (inaudible), and interfering with a growth factor could modify cell growth. A whole lot of people are in that field today, and whether they were thinking about it in parallel and our original publications proved it could work or whether we gave them the idea, I don’t know. Because I think it was a pretty – it was apparent to us that this was the right way to go in science. And I’m sure other people were thinking about it. But soon after that, Genentech developed its antibody inceptor against a related inceptor and they got it out faster because I didn’t have a company behind me at first anyway. But the original work on Herceptin actually --an antibody against HER2-- the original work was from Bob [Weinberg] and his laboratory published two years after our publication showing that the antibody they had raised could block the production of HER2. And then Genentech came out with their antibody soon afterward, and then a lot of drug companies had been working with things, [tironfostins?] chemicals that might inhibit (inaudible). They geared up and started developing molecules that would block the ATP binding site and most of the large drug companies have projects about how to block EGF receptor. So I think our work contributed proof of concept that this was a worthwhile field to go into. But I’m sure many scientists in this country were interested in the EGF receptor. We picked an easier way to block it maybe with an antibody initially.
James Olson:
: But it’s certainly not an exaggeration to say that you’re a pioneer?
John Mendelsohn, MD:
: Yeah. I mean, I think, the Bristol Meyers Prize that I got and the Karnofsky Award I got from the American Society of Clinical Oncology and the [Birchenem] Award I got from the American Association for Cancer Research all were based on the fact that we had pioneered – that I and we initially as a group but I carried it forward for 15 years – that this was pioneering work in blocking a growth factor of stimulated of cell proliferation and in blocking the (inaudible)’s function and the signal function of the (inaudible), that this was the first example of it.
James Olson:
: If you were going to sort of close your eyes and look down the road 20 years, where do you think this science and this technology will be in terms of cancer?
John Mendelsohn, MD:
: Well, there’s Gleevec. CML. There’s one (inaudible) that’s the abnormal molecule and by blocking that, some patients, many patients, have been put in complete remission. Some of them have been cured, but the word cure is a hard word, because you have to wait time. And many of them have recurred, but with the addition of molecules – because of changes in the genetic changes in the (inaudible) itself and you’re playing games with cancer the way you do with tuberculosis. The tumor develops a resistance to one drug. And you get another drug that will kill it. And we’re doing the same thing with BCRA and CML. Not we, but people here. Dr. [Hagop] Kantarjian and Dr. Arlinghaus [oral history interview] are major contributors in that area. But I think what most of us feel, and I certainly feel, is that in the common cancers, there are probably half a dozen pathways that are abnormal. Not just the one. And I don’t see evidence that most cancers are caused when there is a change in the EGF receptor function. Rather, I think there is a group of mutations or abnormal functioning steps in genes that coalesce and fortunately in most cases the cell gets messed up and dies. But occasionally a cell has the right combination of changes so it becomes a super cell and it stimulates its own proliferation and it avoids signals that it should stop proliferating. A number of papers have been written, the characteristics of a cancer cell. A paper came out on the cell in 2000 by Hanahan and Weinberg that lists six characteristics that cancer cells develop. Those are all genetically driven. The first characteristic was self-stimulated growth and our original work attacked that premise. I forgot to mention, one of the things we knew in 1980 --work that had been by George Todaro and then built upon by a man named Michael Sporn-- is that cancer cells make their own TGF alpha and auto stimulate their own proliferation, so that the lock and key – the key isn’t normally available to the cell. It comes from the environment. If you have a wound, TGF alpha is released and it stimulates the EGF receptor. You’re aware that TGF alpha and EGF are the two main stimulators of the EGF receptor. And the cell releases this TGF alpha and it binds to the receptor on the surface of the cell and activates it. So that’s this chewing gum mechanism. It was very much – that paper came out in 1980 summarizing that work. So when we began this work, we not only knew (inaudible) and that cancer cells produced high levels of EGF receptors and there seemed to be an important growth factor but that cancer cells made their own stimulant. It’s like lymphocytes made their own fatty gluton and would stimulate themselves to proliferate. Well, getting back to what we think is happening in cancer, we think there is – this paper summarized the six different qualities a cancer cell develops, and the first of them is autostimultion of their own proliferation. It turns out when you stimulate the EGF receptor, you activate all six of those that are summarized in – we didn’t know this in 1980. This is 20 years later when Hanahan and Weinberg wrote this. And when you block the receptor, you block all six of those functions. So serendipitously, we had picked a target which seems to be very relevant to a cancer cell acting in a malignant fashion. Now, there are probably five or six other – because I said there are about half a dozen abnormalities in the cell, but if you block one of those six, you may perturb the cell or you may hurt it, but we – I think it’s a general given in the medical oncology in the cancer community now that we’re going to have to have a cocktail of treatments that block more than one of these six functions, and that we will eventually work to eliminate the cancer. So that’s what I would predict in the future. The future – the approach we took blocking one cellular oncogene function. It was fun. When I came home, in 1984, when the papers came out showing that it was a cellular oncogene, I walked into the house and said, ‘hey, guess what, Anne’. We’ve got an antibody that blocks an oncogene. We didn’t know that when we started but that was exciting. I think we’re going to have to have products that affect some suppressor genes and oncogenes and maybe some other molecules turned on in cells and it will take a cocktail. That’s what I would predict for the future. But when I talk about this, I point out that when my father was born, the most common causes of death were pneumonia and tuberculosis. In the United States. And right around that time, the pathogenesis of those diseases were being worked out by Pasteur and (inaudible) and people were beginning to synthesize chemotherapy. It’s a form of antibiotics, but it’s chemotherapy, to treat those diseases. And today, if you have a very complicated infection, we have laboratories that will ferret out which are the likely antibodies to work against that infection and you open a few drawers and pull out the right antibiotics and 36 hours later you put the patient on the right antibody and we’re never going to get rid of pneumonia and tuberculosis, but they are no longer the two main causes of death. And we hope the same thing will happen with cancer. It will be complicated. We may need a pharmacy with 500 drawers in it, with either a replacement gene or a RNA molecule or an antibody or a low molecular weight compound that will affect that abnormal gene function, and that will take a tumor and we’ll type what are the five or six or maybe more abnormalities in that tumor and we’ll open five or six drawers and we’ll get the right antibodies out and we’ll treat the patient. That’s the dream.
James Olson:
: And these six factors will cross different solid tumor types then?
John Mendelsohn, MD:
: So the type of tumor depends on the stem cell. If it’s a stem cell producing breast or – this isn’t embryonic stem cell – or a stem cell producing colon or a stem cell producing blood, that gives certain characteristics you can pick up with a microscope. But the gene causing the abnormality might be present – the same gene might be causing an abnormality in each of those. And we’ll be causing the gene causing the abnormalities rather than the tissue in which it occurred.
James Olson:
: Otherwise, the number of iterations you’d have to have would be huge.
John Mendelsohn, MD:
: But still it’s estimated that probably there are 30,000 genes in the genome – it’s estimated that only 400 or 500 are relevant to cancer. And at least 50 or 100 are very relevant to cancer. There’s P53, and there’s a commonality in many cancers that there is an abnormality in the P53 pathway, but it may be – there may be four or five ways to make P53 function abnormally using different molecules in the cell. So it’s going to be multi factorial.
James Olson:
: Now the breast cancer, is that BCR –
John Mendelsohn, MD:
: BRCA1 and 2.
James Olson:
: In Jewish populations.
John Mendelsohn, MD:
: Right. Especially in Jewish –
James Olson:
: Any thoughts about your own family?
John Mendelsohn, MD:
: Oh, this is – it’s more common in Jews. My wife’s family of course isn’t Jewish. They’re Episcopalian Quaker, but it’s not come up in our family, and it’s more common in Jewish families, but it isn’t a question that all Jewish families should get screened for this. If you’re in a Jewish family, or if you are in any family, and you’ve got a two direct blood relatives who have had breast cancer – let’s say a mother or a sister or a mother and an aunt on the same side of the family – you should get screened.
James Olson:
: I’m sorry. I got confused. Did you say your wife’s mother or aunt had died of breast cancer? Or had breast cancer?
John Mendelsohn, MD:
: My wife’s mother did have breast cancer, but she isn’t of Jewish – so you weren’t confused. You have it right.
James Olson:
: OK. Are you optimistic?
John Mendelsohn, MD:
: I am optimistic, because when I was born, the five-year disease free certifiable rate that the American Cancer Society quotes was in the 30s. And now it’s in the 60 percent range. So a lot has happened in my lifetime, and a lot of it was come upon empirically but today we – we will take empirical help anytime we can, but now there is rational and targeted approached which I think are going to add power and tools, so that I believe we will continue to improve the treatment of cancer. But the other thing is the prevention of cancer, it’s been estimated that if everybody did what we know could prevent cancer, we’d get rid of 50 percent of cancer deaths without doing more research. I talk about that a lot. If everybody quit smoking and we had colonoscopies starting at age 50 --which it’s estimated that you’d reduce colon cancer by 50 percent if you took the polyp out, because you’d take out the polyp that’s going to become cancer --and women would get mammograms and there would be follow up, and people had PSA tests and prostate exams and things like that. You can argue about the fine points, but in general, I think there’s a pretty good argument that half the cancer deaths would go away, either preventing or detecting early. And we’re learning more and more about this. And I think one of the big challenges for a place like MD Anderson is to educate the public because people will spend a lot of money checking their car every year, making sure their brakes and steering wheel and clutch all work, but they hesitate. And the car you turn in. Some after three years. Some after 10 years or more. And your body you’re stuck with. And we’ve got to educate people that there is as much you can do checking your body now, which wasn’t true a number of years ago, as checking your car. You ought to take in your body and get a good check on it.
James Olson:
: If you were going to break down, Dr. Mendelsohn, the idea of cancer prevention, including chemo prevention and such things, and there are critics of critics of chemo prevention, what do you think of their criticisms?
John Mendelsohn, MD:
: The critics, of course, are going to have even a stronger basis because the unknown side effects of giving chemicals to people for years are going to come to the forefront now that we know that the COX-2 inhibitors, which are some of the main agents being studied in chemo prevention, here and elsewhere, can cause cardiac incidents. There’s no free lunches. And what we’ve got to step back and figure out is what are the benefits and liabilities. The example I give all the time is DDT. Now, before DDT, there were lots of people dying from infections. Malaria. Yellow fever. Things like that. And now we have the problem that DDT in our food caused problems in health and we don’t use DDT in this country. But in the underdeveloped world, they trade off those risks in order to get rid of the most common cause of death on the planet, which as I understand it, is malaria. So you have to weigh it. That’s an example of weighing risks and benefits, and we don’t use DDT in this country anymore. Chemo prevention is going to be the same thing. We have to weigh the risks and benefits of tamoxifen. We know that if you have a high risk of breast cancer, you take tamoxifen for five years, you’re going to cut the risks by 50 percent. There was a very nice study, but we know some of those patients got phlebitis, and had clots in their lungs, and a higher incidence of uterine cancer. You have to screen for that. So you have to weigh the benefits and risks. Otherwise, we’d put tamoxifen in the drinking water. So I think that’s going to come up. And then the idea – people still challenge the idea that we’re ever going to understand cancer well enough to do chemo prevention. I believe we will, but I believe it’s not going to be hyped. It’s something that will take a long time, and the COX-2 story shows you why. COX-2, incidentally, does reduce colon polyps and probably would be an effective way to reduce cancer. Now what we have to do is think carefully about what is the real increase in cardiac risk versus the reduced incidence of cancer and step back and maybe they will be reintroduced. Maybe somebody will device a COX-2 inhibitor that does the same thing against cancer but reduces cardiac toxicities. That will be a challenge for the drug companies. It’s a slow – the learning process always gives you surprises, so I won’t prognosticate and I don’t say it’s going to be quick. But over 100 years, let’s say in 1900, the most common causes of death were pneumonia and tuberculosis. And in the year 2000, it was cardiovascular disease and cancer. In the year 2100, I don’t think cardiovascular disease or cancer will be the top two killers. Alzheimer’s and brain disease and something we haven’t even thought of will be the top 2. Over the next decades, I believe we will be making progress. Optimism.
Recommended Citation
Mendelsohn, John MD, "Chapter 04: Pioneering Research on Antibodies and Thoughts on the Future of Treating and Preventing Cancer" (2005). Interview Chapters. 1446.
https://openworks.mdanderson.org/mchv_interviewchapters/1446
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