Chapter 05: A Faculty Position and a New Laboratory to Study the Role of Retinoids in Leukemic Differentiation
Dr. Dmitrovsky begins this chapter by noting that his successful study of DMSO and the c-Myk oncogene enabled him to secure his first faculty position at Memorial Sloan-Kettering Cancer Center in the Division of Hematology/Oncology. He then talks about the evolution of his research, beginning by sketching academic medicine's conventional research path. Dr. Dmitrovsky then explains that the next step in his research would build on his work with DMSO and leukemia, so he posed the question, Can you cause cancer cells to mature? He explains why DMSO was not a viable treatment option for this process in humans, and so he built his "nascent lab" around studies of retinoic acid. He cites another example of serendipidity: within a few months, receptors for retinoic acid were discovered, giving credence to his hypothesis. He began to study how retinoids could cause germ cells to mature and become tumors. Dr. Dmitrovsky then says that he heard about a Chinese study of the use of all-transretinoic acid to treat acute promyelocytic leukemia. He embarked on the first American clinical trial that showed success in using retinoids to treat APL, and then collaborated with Dr. Ron Evans to clone the Retin-A receptor. Dr. Dmitrovsky then explains that the APL's molecular and genetic mechanisms became widely studies, and so he decided to change his research focus.
The Interview Subject's Story - The Researcher; Overview; Definitions, Explanations, Translations; The Researcher; Discovery and Success; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care
Ethan Dmitrovsky, MD:
But the result was big enough as a result that I got my first faculty position because of it, at Sloan Kettering, where I had trained. So I joined the faculty there. And the tradition at that point which is a different tradition today was that you should stop everything that you are doing as a post-doctoral fellow. Obviously, I had published other papers during my fellowship, but this was the major observation that I made. The tradition was to stop everything that you were doing and to move into a completely different project that you would take on as your career-beginning project, so I subscribed to that tradition. So I end up staying at the NIH for about the National Cancer Institute for roughly four years, received three years of in-depth laboratory training, and then joined the faculty at Sloan Kettering. And because of this drug, DMSO, having this extraordinary ability to cause cancer cells to mature, that was the idea that I wanted to begin my career on: could you cause cancer cells to mature? And as they mature, they die, because they lose the unregulated capacity to grow. As you go from the white pellet to a red, the white cells have continuous ability to replicate, but the red cells, because they're specialized, have limited ability. In a sense, differentiation is repressing reducing the ability of these malignant cells to be malignant. So this was a big idea when I began my laboratory, but DMSO was a drug. It could be given to people and can be given to people, but it is its effects are seen at what's called millimolar concentrations, and I had a feeling that would never be practical in patients. And there was a drug that had been identified a "drugbecause it was a natural product. It was a vitamin A derivative called retinoic acid. Retinoic acid, unlike DMSO, worked at a thousandfold lower level, so it what's called "micromolarconcentrations. And I set out to build my nascent laboratory around studying retinoic acid for two reasons. One is I felt that a natural product, a vitamin a vitamin A derivative, that's what retinoids are it's a class of molecules that share a structure with vitamin A would be able, because it is a natural product, to be given to patients and to be tolerable. And secondly, I felt, because it was working at micromolar levels, that there must a receptor. So just as I was opening up my laboratory, within a couple of months is my memory just within a few months, serendipity struck, and the very receptors for this drug, retinoic acid, were discovered and were published in back-to-back papers in the journal Nature by a French group led by Pierre Chambon C-H-A-M-B-O-N and an American group run by Ron Evans, one at the Pasteur Institute, and the other at the Salk Institute. And that was validating, because the idea seemed to have some value. So I began studying how retinoids could cause germ cell tumors testicular cancers in culture to mature. And they do cause these cells to mature. And these the reason I studied this model was because human testicular cancer has a spontaneous ability to mature in patients, and it's called teratoma formation T-E-R-A-T-O-M-A. So embryonal cancers E-M-B-R-Y-O-N-A-L, I think, Y-O-A-N-A-L can spontaneously cause differentiation to a structure, a histologic structure called teratoma that has all three germ layers of tissues present. So you can find teeth in teratomas. You can find brain. You can find muscle. And I felt that if you could just give the right signal, you could cause these cells to mature in people. At the same time, serendipity struck, and we heard about a study in China showing that the very drug I was studying called all-trans-retinoic acid could cause complete remission in a rare leukemia. Remember, I was studying leukemia at the National Cancer Institute. So we set out to move this work into the clinic in the area of this rare leukemia called acute promyelocytic P-R-O-M-Y-E-L-O-C-Y-T-I-C leukemia, APL. So we lead the first American trial that actually showed that this drug worked, and I was the last author on that paper that we published in the New England Journal of Medicine. And unbelievably, we found and reported in the study that every patient who responded to this drug expressed an abnormal protein for the very receptor that Ron Evans and Pierre Chambon had found called the retinoic acid alpha receptor. Then, I got a call one day from Ron Evans, to ask if we could collaborate in cloning this, and we actually cloned the receptor and published that in Cell.
Tacey A. Rosolowski, PhD:
Ethan Dmitrovsky, MD:
And unbelievably, if you have this receptor, you always respond to the drug, retinoic acid. A minority of patients were cured of APL with chemotherapy, but when you combine retinoic-acid-based therapy with chemotherapy, the vast majority of patients are cured. So we cloned the receptor, and then my lab developed and patented the genetic test for this abnormal receptor that's now widely used to diagnose this canc this leukemia and to monitor treatment response. So when you're in remission, you can't detect the receptor anymore, because all the cancer cells are gone. And then, we published the first transgenic model in mice that expressed this abnormal protein. So here, the story becomes quite extraordinary to tell because of this serendipitous nature. So APL has a diagnostic chromosomal translocation, and extraordinarily, that translocation is exactly breaks up the retinoic acid receptor alpha gene. So here, you have a genetic lesion that's also a target of therapy, and so this is one of the early examples of targeted therapy. So when we cloned this translocation product from chromosome 15 and 17, we uncovered a new gene product that we called PML. And after several years of study, I did a literature search, cueing in the word "retinoic acidand the word "APL,and there are just a bit under 2,000 cases a year in the United States. Remember, I said from a minority, now, to a majority of patients are cured, and there are other drugs that are now combined with retinoic acid, like arsenic trioxide. So this therapy has even moved into the oral therapy of both retinoic acid and arsenic trioxide, or orally active agents. So I cued in the word "APLand the word "retinoic acid.I found that there were more papers published on this subject than there were annual cases in the United States. So when I did this experiment if you will I thought it was time for me to broaden my reach, because I was sure that any discoveries that would be made, there were enough people studying it. I wouldn't have to worry.
Dmitrovsky, Ethan MD and Rosolowski, Tacey A. PhD, "Chapter 05: A Faculty Position and a New Laboratory to Study the Role of Retinoids in Leukemic Differentiation" (2015). Interview Chapters. 640.
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