Full Transcript
Blake Morrison (Interviewer): Good afternoon. We are here at Ash, and I have Dr. Rafael Fonseca with me from the Mayo Clinic in Scottsdale, Arizona, where he is the Chief of Internal Medicine. Dr. Fonseca has some interesting discussions to present today in terms of mechanism of action and how that is being looked at in the application of multiple myeloma and treatment.
Dr. Rafael Fonseca: Sure. Well, thank you. Thank you for the opportunity, first of all. At this Ash meeting, I had the opportunity of chairing the Scientific Subcommittee on Plasma Cell and Neoplasias, you know, long way of saying multiple myeloma science. We had two speakers, Dr. Larry Boise from Emory University and then Dr. Florian Bassermann from Munich, Germany.
We called our session “The Yin and the Yang of Multiple Myeloma.” What we mean by that is that, you know, you can go about treating cancer in a couple ways. You could target the genomics of cancer. So the canonical example of this is CML. Beautiful treatment, beautiful story. You have imatinib. The patients do very well. Period. Now, let’s call that the yin.
The yang would be a different way of treating cancer, in which you try to capitalize on some vulnerabilities that cells will have, that they have acquired as a consequence of their differentiation. So what I mean by that is you have a happy B cell, and the B cell evolves, and, you know, a normal B cell wants to become a normal plasma cell. In the process of doing that, you know, it goes through certain steps of differentiation and maturation that will optimize it for what it’s supposed to be, a protein factory, professional protein-producing cell of immunoglobulins.
So it needs to become what I call aerodynamic for that purpose. But in doing so, it generates some vulnerabilities that could be used against it. In fact, I would argue that has been the reason why we saw so much progress, starting in the late 1990s and 2000, in the treatment about multiple myeloma, because that was what was capitalized on. I can’t say that that was a before thought. It’s a little bit of we’re learning afterwards.
Blake Morrison (Interviewer): Sure.
Dr. Rafael Fonseca: But, you know, the proteasome inhibitor makes sense, and proteasome inhibitors, you know…You have cells that produce proteins, and if there’s mis-folded proteins, there’s problems with the trafficking or the metabolism. The cells will get stressed, and the cells will die very quickly.
What’s somewhat new is IMiDs. So IMiDs actually appear to work through the same mechanism. Dr. Bassermann presented some of his work, where he has shown an important chaperone function for cereblon which is the target protein where IMiDs bind MCT-1 and CD-147, which are essential components of the plasma cell and metabolism. It turns out one of them is a lactate supporter. So, it does change a little bit of what happens in the intra-cellular milieu. Very, very interesting results, and he has this in a Nature Medicine paper. [Nat Med. 2016 Jul;22(7):735-43. doi: 10.1038/nm.4128. Epub 2016 Jun 13.]
Dr. Bassermann has shown an important chaperone function for cereblon which is the target protein where IMiDs bind MCT-1 and CD-147, which are essential components of the plasma cell and metabolism.
Now he also cited some work from our lab, where one of my fellows, Santo Sebastian actually did some experiments, and he found that if you look at normal plasma cells…This gets really to be very interesting. You look at normal plasma cells. Every time they produce a protein, the protein folds. There’s need of a di-sulfide bond. That releases a tiny amount of hydrogen peroxide. But there’s so many proteins, that every cell produces somewhere between 100,000 and a million molecules-per-second of hydrogen peroxide. So if the cell doesn’t have a good mechanism to dispose of that, it’s gonna poison itself. Right?
So this is done through an enzyme called thyrodoxin which is ubiquitous. All of our body has that, but it’s particularly important there. But for thyrodoxin to work, it needs to be kept whole by thyrodoxin reductase. It needs to be reduced. What thyrodoxin does is it processes very quickly this hydrogen peroxide into water and oxygen. What was found was that IMiDs actually inhibit thryrodoxin reductase. So pretty much, it’s like tricking the plasma cells. So they produce hydrogen peroxide. They self-poison, they signal CR stress (Chromium (VI)-induced oxidative stress), and cells die.
What was found was that IMiDs actually inhibit thryrodoxin reductase.
This has a lot of implications because both the work of Dr. Bassermann, as well as ours, would suggest that there’s mechanisms for IMiD action that are different from what has been published in the science papers. It’s what, you know, the scientists would call ubiquitin-independent.
Blake Morrison (Interviewer): Right.
Dr. Rafael Fonseca: I think it’s a better explanation why these drugs work better with proteasome inhibitors. You know, it raises a lot of interesting questions. That same complex of thyrodoxin, thyrodoxin reductase is also the target of steroids. That’s why steroids work. Actually, steroids induce a protein that’s called TXNIP, which blocks that. So steroids also make plasma cells self-poison. For that matter, I think that’s why they work in lymphoma as well, too, at least a big part of it. That’s how they signal for apoptosis. But then there’s other drugs that can block that pathway, that are independent of cereblon and potentially could be used as therapeutics for myeloma. So again, the ramifications are multiple.
I think the point of our session was just to say that, you know, you have a cell that’s really good at something. You know, it’s like a tank will be really good at power, but not at speed.
Blake Morrison (Interviewer): Right.
Dr. Fonseca: That’s what happens with plasma cells. What we would like to suggest is that…if you look across the board at other cancers, these principles would apply. They already do. You know, breast cancer and prostate cancer, they depend on hormones. So for some time, they can work. Hormonal inactivation can work, right? But one has to think about the cell of origin of multiple cancers because I am sure there’s a catalog of vulnerabilities that we’re not thinking about yet.
I am sure there’s a catalog of vulnerabilities that we’re not thinking about yet.
Blake Morrison (Interviewer): Yeah. That’s very interesting, you know, those…the two classes of agents you’re talking about have been around for almost 20 years.
Dr. Rafael Fonseca: Sure. Sure.
Blake Morrison (Interviewer): And we’re only, now, really understanding how they work. We know they work, and they work well, and they’ve been exploited for that benefit. But to understand precision, precisely how they work, you know, at the molecular level is very interesting.
Dr. Rafael Fonseca: Yeah. No. I think we’re very, you know, very excited, and I should have…I was pretty selfish. I think the yang includes many other things, you know, micro environment, amino therapy, and all sorts of other things. But it’s just to say that I think the one cancer is multi-pronged. We should keep going for the target that approaches position medicine, but let’s look at other pathways at the same time.
Blake Morrison (Interviewer): Thanks for sharing. Appreciate the lecture. That was a good one.
Dr. Rafael Fonseca: My pleasure. Thank you.
