
Chapter 12: From Adriamycin to Molecularly Designed Drugs
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Description
Dr. Hortobagyi explains that he was the first to introduce Adriamycin into adjuvant therapy, responding to the fact that many patients were referred to the breast service after surgery (though MD Anderson surgeons were not referring patients to them). Adriamycin was combined with the FAC therapy and accepted as a standard of care by the 1990s. MD Anderson was also the first institution to report that Taxol was just as effective as Adriamycin when used in the FAC regimen and it was accepted as a new standard. His group then worked with Taxotere, which was demonstrated effective. Research in the eighties was frustrating and his group tested about forty drugs, with little to show for it. He talks about the process of drug development and notes that the community ran out of ideas for a time.
During this same period there was a move to more molecularly designed chemicals as well as the discovery of oncogenes, tumor suppressor genes, and a burst of enthusiasm for the human genome project. This fertile scenario led to the development of the major targeting agents such as Herceptin.
Identifier
HortobagyiGN_02_20130107_C12
Publication Date
1-7-2013
Publisher
The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center
City
Houston, Texas
Interview Session
Gabriel Hortobagyi, MD, Oral History Interview, January 07, 2013
Topics Covered
The Interview Subject's Story - The Researcher The Researcher Discovery and Success Devices, Drugs, Procedures Discovery, Creativity and Innovation Professional Practice The Professional at Work On Research and Researchers The History of Cancer Research and Care
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
Gabriel Hortobagyi, MD:
Okay, so that was locally advanced breast cancer. That was multidisciplinary planning and implementation of therapy. Now I already mentioned that Adriamycin was introduced by us into the management of metastatic breast cancer and then neoadjuvant chemotherapy. But we also were the first to introduce Adriamycin into the adjuvant treatment of breast cancer. In the early ’70s—again, I'm talking about 1974 or so—we got a number of patients referred to us from the outside by surgeons who had already operated on them. They didn’t go to our surgical department. They came directly to us because our own surgeons were not referring patients to us for adjuvant chemotherapy. They didn’t believe that that would work. We said, “Well, this regimen FAC works so well on metastatic disease and locally advanced breast cancer it should work in these high-risk patients with many positive lymph nodes.” So we put together a protocol for that, and we were the first to report on the results of adjuvant chemotherapy with FAC or with an Adriamycin-containing regimen. That continued to be our standard, and eventually it was accepted by the world, probably in the mid-1990s, as being better than all other regimens.
By the 1990s, we were the first institution to report that Taxol was every bit as effective as Adriamycin and therefore a force to contend with. And then soon thereafter, we introduced it into adjuvant chemotherapy in sequence with our FAC regimen, at first compared directly to FAC and secondly in sequence with FAC. That turned out to be the next standard. There are multiple ways of doing that, and some centers and some groups give Adriamycin and Cytoxan before followed by Taxol. We have always done it the other way around. There is actually some scientific evidence that suggests that if you do Taxol before and Adriamycin second you get a better result than if you do the reverse sequence. The reason is not completely understood, but clinical trials have shown that. Then shortly thereafter we started to work with Taxotere, which is a first cousin of Taxol, and again demonstrated Taxotere was a substantially effective drug, that it was not the exact same drug as Taxol, and some tumors that were resistant to Taxol responded to Taxotere and vice versa.
Then we also showed that the weekly administration of Taxol was better than giving the drug every three weeks, so small incremental steps there. But all of that was going on, and during much of the 1980s I focused—along with my colleagues—with the early development of new drugs. And over the decade of the 1980s, for instance, we must have tested no less than forty different new drugs in phase I and phase II studies, and at the end of that we had very little to show for it. It was a very frustrating decade of very hard work and very little in terms of returns. By then we had done the Adriamycin part. We had done the development of FAC, the development of multidisciplinary therapies for locally advanced and early breast cancer, so we were sort of at the top of the world in that. But then we came to a screeching halt.
Tacey Ann Rosolowski, PhD:
What do you think the reason was for that lull?
Gabriel Hortobagyi, MD:
Well, it was to a large extent the fact that new drug development in oncology in the early years was a process of finding natural substances that seemed to kill cells and then trying to develop them into drugs. When you start with that, then you find the low-hanging fruit, the alkylating agent, the antifolates, the fluoropyridines, the anthracyclines, and the vinca alkaloids in the platinums. And then I think the community sort of ran out of ideas at that time, and everything else was sort of slightly better but not a whole lot. And then we started to look at analogs—just minor chemical permutations on the same molecule—and it takes years and years to figure out whether something is better or not than a previous one, especially if the difference is minor. Most of the drugs that we tested were just not terribly good. During that time, there was already an evolution towards a more molecularly designed group of chemicals, because technology and science had advanced to this stage to understand that these drugs were not just killing cells at random but that they had a specific effect.
Then people started to work on that and work backwards. So, if this group of drugs does this to a cell’s mechanism, how can we enhance that effect by developing a better molecule? That was an entirely conceptual approach, very different. Then the discovery of oncogenes came and the discovery of tumor suppressor genes and then the enthusiasm for developing the Human Genome Project to understand how our cells were structured. Then gradually as we started to understand that process, then first the newer drugs like the taxanes and gemcitabine and vinorelbine and other drugs came about, and then came the major targeted agents—Herceptin, Rituxan, Tykerb, Avastin, and a number of others. But those were already based on very firm scientific hypothesis in structure, function, interactions, and that was a watershed event. What we are doing today to develop new drugs, while not a whole lot more efficient in terms of numbers, it is I think a much more scientifically valid approach to do it. And actually, over the past year, more oncology drugs were approved than for any other discipline by the FDA. I think we are doing better. We still need some technological improvements to improve the efficiency of the process. We still start out with 100 drugs or candidate drugs and come up with one or two out of that. It’s a very inefficient process. But at least some of the drugs we are developing are clearly superb drugs. The Gleevecs and the Herceptins are a clear example of that.
Recommended Citation
Hortobagyi, Gabriel N. MD and Rosolowski, Tacey A. PhD, "Chapter 12: From Adriamycin to Molecularly Designed Drugs" (2013). Interview Chapters. 1117.
https://openworks.mdanderson.org/mchv_interviewchapters/1117
Conditions Governing Access
Open
