Chapter 06: Shifting Focus to Lung Cancer
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Description
In this chapter, Dr. Dmitrovsky talks about how he built on his studies of retinoids and leukemia treatment and began to investigate treatments for lung cancer. He decided to focus on retinoic acid's role in causing the destruction of a cancer-causing protein. He explains why he selected lung cancer and why it was important to him that lung cancer affects both men and women. Dr. Dmitrovsky says that his initial question was, Can we use retinoic acid to prevent lung cancer? He explains his first experiment, which showed that after treatment with retinoic acid, immortalized cells did not become malignant when exposed to tobacco carcinogens. He talks about studies that revealed the molecular pathways involved in this process, challenges that arose in creating a targeted approach (because of a silencing of β-receptor for Retin-A), and how these obstacles were overcome over a ten year period, enabling him to eventually discover a survival advantage. Dr. Dmitrovsky explains that he found activity in a very resistant form of lung cancer for which survival without treatment is 4 " 6 months and with retinoid treatment, 1 " 4 years. Dr. Dmitrovsky then says that he compared his results with those obtained by colleagues at MD Anderson who were involved in the BATTLE trial. They had similar results. He says he hopes to find an even better retinoid.
Identifier
DmitrovskyE_01_20150303_C06
Publication Date
3-3-2015
City
Houston, Texas
Interview Session
Topics Covered
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
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
Ethan Dmitrovsky, MD:
So we asked the question in my group, "Is there something we could learn from this experience, that we could move into a more common cancer that was a very challenging problem?The same idea that when we started this differentiation project and it turned out that in patients with APL, the cells actually matured as they did in the laboratory, so it validated this idea of differentiation-based therapy. And what we found is that when we treated APL cells with retinoic acid, something quite unexpected occurred. So it turns out that retinoic acid causes the destruction of this translocation product, this protein that is called PML/RAR alpha for the fusion product in chromosomes 15 and 17. It was really surprising. So retinoic acid was destroying the cancer-causing protein, PML/RAR alpha, and I thought that that was something that we could move forward not that it destroyed this protein that maybe the drug, retinoic acid, was causing a more general protein destruction program to be produced. Am I explaining that clearly?
Tacey A. Rosolowski, PhD:
Mm-hmm, yes. It's very clear, thank you.
Ethan Dmitrovsky, MD:
So we had, sort of, two ideas. One was: what could we take from the work that we had done on APL, and then what could we study? So I had a colleague who encouraged me to move into lung cancer because it's the most common cancer for cause of cancer death for both men and women. And I was drawn to the fact that this was not only a mens' health issue, but a women's health issue, and it wasn't appreciated at that time that actually, it disproportionately causes the death of women with lung cancer more than any other cancer that affects women. More women are diagnosed with breast cancer, but far more, sadly, pass away from lung cancer. So I thought that if we were going to have an effect on lung cancer, the greatest opportunity was in the earliest forms of lung cancer. So the idea was that we could maybe use this drug, retinoic acid, to prevent the lung cancers from forming in the first place, and that was a big idea that has not stood the test of time for a variety of reasons that I'll come to in a minute. So we did a very simple experiment that turned out to be highly informative, and it was a paper that we published in the Proceedings of the National Academy of Sciences. We took human lung epithelial cells that had been immortalized with it's called the T-antigen. So they were not malignant, but they could proliferate in culture. And we actually applied to those cells the very carcinogens that cause lung cancer, so we applied cigarette smoke condensate, or the particular carcinogen from tobacco called nitrosamines. Independently, we did this. And we found that when we applied this carcinogen, we could take these immortalized cells and make them malignant. And how it made them malignant was the question we were asking, but they acquired the ability to form tumors in recipient mice. They grow in this anchorage-independent manner. They would grow unattached to tissue culture plates what's called soft agar growth. These are, in the laboratory definitions, requirements for the malignant state. But we then pre-treated with the drug, retinoic acid, and we actually could prevent this malignant conversion. So we asked, "Is there a mechanism that we could find?And we actually found one that we published in the journal PNAS. We found that retinoic acid was causing the destruction of another protein, so it was actually causing a destruction of the very cell cycle proteins that regulated the G1 phase of the cell cycle. These are cyclin E and cyclin D. And it was doing so through a similar protein destruction pathway as we found in APL, called the proteasome degradation pathway. Over a decade, we studied in great detail the mechanisms involved. We found there was a proteasome degradation path that was involved, and we found an alternative degradation pathway that was involved. And because I'm a physician-scientist, and my lab is about moving work from the bench into the bedside, I felt very quickly that this was a to use the vernacular a druggable target. So now, here's where the story becomes very interesting. I wasn't alone in this thought, and in fact, there were very large clinical trials that were underway, of which I wrote the accompanying editorials. And they all did not work. They did not work because the clinical trialists, when the work began, didn't know that the receptor for retinoic acid that controls the effects of retinoic acid working in everything that I described you, the receptors were intact. But when it became a malignant lung cancer, the very receptor that the drug, retinoic acid, works through was the second retinoic receptor, not RAR-α, but RAR-β beta for the second was silenced in lung cancers. And it wouldn't possibly work to give the drug, retinoic acid, because the receptor was silenced. And in my mind, it's such a critical pathway. The cancer cells become cancerous because they silence the pathway. But this protein, retinoic acid receptor beta, forms what's called a heterodimer with a related protein called the retinoid X receptors. And the retinoid X receptors and the RAR receptors sit together, and they sit they complex, and they sit on DNA. So if you silence one partner, you could still activate the other. And after these studies again, this is a series of serendipitous events showed that there wasn't activity, at the same time, a receptor for the retinoid X a drug for the retinoid X receptor pathway became discovered. And we had the idea we could bypass the block by giving the retinoid X receptor drug, and we showed in the lab it would actually destroy the same cell cycle proteins. And at that point, I was convinced that we should conduct clinical trials to show where that works. Over ten years, I published five clinical trials testing this idea, beginning in what's called phase 0 trials, that is to ask those in the perioperative setting, we would treat patients before and immediately after. Ten days before surgery, we would give them this rexinoid RXR agonist. And we showed, within ten days, that the very pathway that we had found caused the destruction in cells in the lab caused the destruction of the same destruction of the cell cycle proteins in the lab also did the same in patients' tumors. And then, we found a separate pathway involving the epidermal growth factor receptor, and we had inhibitors to that pathway, small molecule inhibitors that would also repress reduce the expression of these proteins, but through a different pathway. So the first pathway that we found destroyed the proteins through this proteasome degradation pathway, and then we found a second one that repressed the same proteins through a different pathway, and our idea was to combine these two drugs together. So over ten years, we methodically went through and showed, first, the pathways worked alone with two drugs, just as we expected, in the post-treatment versus pre-treatment tumors. Then, we ran those were phase 0 trials. We ran a phase 1 study combining these two drugs together and published that in the Journal of Clinical Oncology, and all this work were separate publications. And we found, actually, in heavily pretreated patients in a phase 1 study, that there was a survival advantage for the patients. We then launched a phase 2 study and what's called the phase 0 trial, where we looked at pre- versus post-treatments, looking at the effects of these two drugs, the EGFR tyrosine kinase inhibitors EGFR TKI and the rexinoid. And then, in a large pha ten patients who were treated in this window of opportunity phase 0 trial, and then we did a phase 2 trial at the same point, and we found a survival advantage. We actually found activity in a form of lung cancer that is highly resistant to current therapy, those that harbored what's called RAS mutations. So we had heavily pretreated patients. All of these patients were, by their very nature had sadly had other therapies fail them, and the median survival, from historical experience, would have been about six four to six sorry, about four months. And we actually had people who survived one, two, three, and four years. So we shared those data I was still at Dar sorry, at that point, I had moved from Sloan Kettering to Dartmouth, to become chair of the pharmacology department. And I was invited by the president of Dartmouth to do a term as the interim dean of the medical school, so I did that while I was at Dartmouth. So this work began at Sloan Kettering, and all the clinical work was done at Dartmouth. So I shared these data with colleagues at MD Anderson, because they were actually running the same trial, based on our work. And the BATTLE trial, which is very well known what's less well known is that the most active arm in the BATTLE trial was the trial that we developed.
Tacey A. Rosolowski, PhD:
How interesting, yeah.
Ethan Dmitrovsky, MD:
And so I shared these results, before publication, with the BATTLE trial team, and they had the same results. So here's an example of moving from the lab to the clinic, and then having and we published our papers in two different journals, but within a few weeks of each other. So what we're hoping to do now is to find an even better rexinoid that has even better pharmacologic properties and to see if we can develop this as a treatment for a non-small cell lung cancer patients. In my lab, we have an iterative approach, so we're always moving from the bench to the bedside and back again. And along the way, I thought that one of the key experiments that we need to do was to see whether, if we deregulated these cell cycle proteins by causing them to be abnormally expressed in a lung in a way that prevented their destruction or in their wild-type state, I wondered whether we could cause the lung cancers to form in mice. So actually, we did that experiment, and that's what we found, and we published that in the Proceedings of the National Academy of Sciences. So we make these models available to any investigator who might want to work with them.
Recommended Citation
Dmitrovsky, Ethan MD and Rosolowski, Tacey A. PhD, "Chapter 06: Shifting Focus to Lung Cancer" (2015). Interview Chapters. 641.
https://openworks.mdanderson.org/mchv_interviewchapters/641
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