Dr. Jonathan Licht, MD on high-risk 4;14 myeloma and MMSET’s function and future targets

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Originally posted on mPatient Myeloma Radio

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Dr. Jonathan Licht, MD
Northwestern University
Robert H. Lurie Comprehensive Cancer Center

Interview date: April 11, 2014

Summary

Dr. Licht shares a deep dive into high risk myeloma with an emphasis on the 4;14 mutation that triggers the overproliferation of the MMSET gene. Dr. Licht describes how MMSET affects the cells and his work to screen 100,000 compounds against that gene to find targets that impact MMSET effectively. He describes the relationship between the MMSET and MYC genes and how MMSET promotes MYC growth. He shares how cell signaling pathway treatments, like MEK inhibitors and BRAF inhibitors are being studied to change the signaling for cancer growth for high risk and normal risk myeloma as well. 

 

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Full Transcript

Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. If we learn more about today’s myeloma research and are willing to participate in clinical studies, we can help advance the collective knowledge to find better therapies for ourselves. I can’t stress enough the importance of our participation. We are one of the important keys in finding a cure.

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We have a new site called myelomacrowd.org that’s the first, all-inclusive site for myeloma. You can take a look at the information on the site. If you dig deeper than just the homepage, you can find a myeloma doctor, learn who to follow on social media for myeloma, and learn more about diagnostics, as well as many other things.

Today we are very fortunate to have with us Dr. Jonathan Licht. Dr. Licht is the Johanna Professor of Medicine and Chief of the Division of Hematology/Oncology and Associate Director for Clinical Sciences of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Dr. Licht received his medical degree from Columbia University and trained in Oncology and Molecular Biology at Dana-Farber, and served on the faculty at the Mount Sinai School of Medicine in the Department of Medicine and Molecular Biology.

Dr. Licht’s laboratory studies are on transcriptional repression as a cause of hematological malignancies including leukemia, myeloma, and lymphoma, and he’s exploring many strategies to reverse these repressions. Dr. Licht was a former Leukemia Society Scholar and recipient of a Burroughs Wellcome Clinical Scientist Award in Translational Research and is currently the principal investigator of a Leukemia and Lymphoma Society Specialized Center of Excellence grant setting mechanisms in hematological malignancy.

He’s a senior editor of Clinical Cancer Research and serves on the editorial boards of Cancer Research and Oncogene. He’s also served as a councilor of the American Society for Clinical Investigation and a member of the Association of American Physicians.

Dr. Licht, welcome to the program.

Dr. Licht: Well, I’m so pleased to be here with you. Thank you for inviting me on to your show.

Jenny: Well, I know that several patients have requested actually that I interview you. They are high-risk myeloma patients. I know you spent quite a bit of time, decades of studying high-risk myeloma. Can you first explain in general how you have approached the study of high-risk myeloma?

Dr. Licht: Well, I could say how did we even know there’s high-risk myeloma? There have always been clinical features that might say a patient has a larger body burden of disease by the time they come to medical attention. That can be if someone has a lot of bone disease, if their kidney function is compromised. There are certain blood markers such as the level of immunoglobulin, the beta-2 microglobulin, which can all portent a more guarded prognosis.

But what happened in the late 1990s was the discovery of abnormal chromosome sets in the cells of patients with myeloma, meaning these malignant plasma cells or mature B cells that are specialized to make antibodies had within their DNA a sort of rearrangement of the chromosomes.

People like Mike Kuehl, who I think you are interviewing soon, and Dr. Leif Bergsagel, who you’ve interviewed before, help characterize these chromosomal rearrangements. Once you have that as another marker, you could cut across patients who had different levels of disease burden as measured by the parameters I said before and say, well, if this person has one type of chromosomal swap or another, does that have a different prognosis?

Now, the answer was indeed yes, that these chromosomal abnormalities did correlate with prognosis and the reason for that is that these chromosomal rearrangements lead to the abnormal switching on of proteins that have a normal function of the cell to regulate whether or not a cell divides or not, or whether or not a cell should turn on particular genes or they shouldn’t, but when these genes are rearranged, they’re expressed at a very, very high level and then havoc can be wrecked. The normal regulation of the cell cycle, the normal decision pathways of whether or not a cell should live or die will be changed.

We think that these so-called cytogenetic abnormalities where genes are rearranged are actually what we call driver events, things that actually alter the biology of the plasma cell and contribute to how aggressive a case of multiple myeloma might be. So high-risk includes the t(4;14) translocation that we study. Another high-risk, for example, is the deletion of Chromosome 13 where a whole number of genes that are involved in the normal governance of cell behavior are deleted in the cancer cell and therefore, that cell may have a greater tendency to grow and to cause harm.

The first approach was to define these groups and I think those groups are continuing to be defined by even more fine genetic analysis more recently, sequencing every single letter of the genetic code in the patient’s cells with multiple myeloma. That work is ongoing.

Jenny: You had some slides online about the MMSET. Can you explain in layman’s terms for us all what does MMSET do? What did you find to be the initiating event in the t(4;14) translocation? Maybe we’ll start talking about that one first.

Dr. Licht: Sure. The t(4;14) translocation, what does t(4;14) mean? It means that we have 23 chromosomes and we have two copies of each. We have two of each chromosomes, one inherited from your mother, one from your father, and t(4;14) means that a portion of Chromosome 4 has broken off that chromosome and has appeared on Chromosome 14 and vice versa, so there’s a switch of genetic material. They’re in the wrong place.

The t(4;14) leads to the linkage of the MMSET gene to sequences of the antibody producing gene, the immunoglobulin gene, and realize that plasma cells, so-called B lymphocyte cells, they’re specialized to make a lot of immunoglobulin. They make the antibodies to protect us from bacteria. So what’s happened in the t(4;14) is that the drive to make a large level of a gene is swapped from the antibody-producing gene to MMSET.

As a result, the MMSET is produced at a very high level of the cell. We think at least ten times more of it in the myeloma cell than in a normal cell. So we think that the first driver here is that the MMSET gene is put under abnormal regulation. It’s switched on to very high levels that are not normally seen in any cell in the body.

Jenny: And is the t(4;14) translocation performing that or is the MMSET the initiating event? I guess I get confused about that.

Dr. Licht: Right. The t(4;14) is the initiating event. What happens is, as you might recall, when we get a vaccination, we usually get more than one shot. You’ll get initial vaccination and then you’ll get a booster shot. What actually happens when you get booster shots is remarkably the genome, the actually DNA within a normal lymphocyte that makes antibodies, shifts around and breaks apart and rejoins in an organized way and causes the antibody production to become more specialized.

Now, what’s happened in a multiple myeloma patient with t(4;14) is that normal breakage and rejoining of the antibody producing genes goes awry and instead of the antibody genes just rearranging a little bit to become more specialized, the antibody gene gets linked accidentally to the MMSET gene. This is a normal process that it’s kind of remarkable. It was unbelievable when it was first discovered two decades ago. We used to think that the DNA in your cell just stayed as one big linear piece and never moved, never shuffled, but in immune cells, it normally shuffles around in a controlled way.

When it goes wrong like in the t(4;14), the antibody gene gets linked to MMSET gene. The MMSET gene is normally in vanishingly small quantities in a cell, and when it gets abnormally linked to the antibody gene, you make a lot of it. So it’s the t(4;14) that comes first and that generates the high level expression of MMSET.

Jenny: Okay. When I was interviewing Dr. Fonseca, I asked if you could reshuffle it back to the way it was, and he said no, it doesn’t really work that way.

Dr. Licht:  I think these DNA rearrangements, first of all, they’re in every one of the cells. If you could do it, you’d have to reshuffle it back in billions and billions of cells at 100% efficiency and that’s just something we can’t do, so it is kind of a forever thing. Once it happens, it can’t be undone.

What’s interesting is that some patients with MGUS, the pre-symptomatic phase of myeloma where someone may present to a doctor with no symptoms and maybe on a routine blood test is found to have a high blood protein level and a little bit of the so-called M spike, the immunoglobulin or antibody spike in the bloodstream or high quantity, they may be otherwise asymptomatic and some of these patients have the t(4;14) translocation.

So it seems that it can be a very early event in myeloma and we believe that there are second genetic events, some kind of mutation that collaborates with a mutation, a shuffling of genes like the t(4;14) to then create full symptomatic myeloma. Those patients who have the t(4;14) tend to have a more guarded prognosis than other patients, but the MMSET is one of the drivers of the disease, but there must be others as well.

Jenny: Do you see the same thing where you see an increase of it from MGUS to smoldering, from smoldering to active? Is it consistent across those patient types?

Dr. Licht: Well, if a patient had a t(4;14) translocation as MGUS, they will almost always keep it as they might move to smoldering and to full symptomatic myeloma. That genetic change, once it happens, it happens. What may happen is that as the patient moves along, and may get more progressive disease, they may accumulate other mutations.

What mutations those are exactly is under study with a big project from the Multiple Myeloma Research Foundation called the CoMMpass Project where patients are getting their cancer genomes assessed at diagnosis upon progression after treatment. And if someone relapses, they would get sampled again. So the idea is to get snapshots across a patient across time to see what genetic abnormalities might be correlating with the different phases of disease.

I think those data are still being accumulated. We do have snapshots on what kinds of mutations are found in patients at diagnosis. There have been a few limited studies of checking the cancer genome and the sequence of all these genes at relapse, but I’d say it’s too early to make broad conclusions about what happens during the progression of disease. In general, most cancers are complicated in that they may have a signature genetic event like the t(4;14) or some of the other translocations, but likely their disease has other lesions as well that contribute.

Jenny:  I know a lot of study has been done about the detail behind that. I interviewed Dr. Lohr about that and his findings were that myeloma is all over the place in some instances. Can you describe what MMSET does and how it works maybe in the most simple terms possible?

Dr. Licht: Sure. Genes in our cells are under very controlled regulation. A gene is a piece of DNA that’s deoxyribonucleic acid which is, if you would like, the hard drive of the instructions to make every part of our body, and those instructions will get translated into what we call RNA, which you might think as maybe being the cable from your hard drive to your computer. That will then, let’s say, give a picture on the screen, let’s say, just to use that analogy.

Your hard drive, you’re going to access different information at a different time, and these genes need to be turned on and off in a precise manner. It turns out that one of the ways you turn genes on and off is by causing a chemical modification of the DNA and the protein immediately surrounding the DNA.

DNA is a negatively charged molecule. It’s an acid. Acids are always negatively charged. The DNA is wrapped around a positively charged set of proteins and this helps stabilize the whole structure. That structure is called chromatin. The combination of DNA and these positively charged proteins are called chromatin.

When a gene turns on in a cell, it’s not turned on from a naked piece of DNA, a double helix. It’s actually turned on from the DNA wrapped around these histone proteins. It turns out that those histone proteins tend to shut genes off when the DNA is tightly wrapped around them, so you actually have to actively change those histone proteins to chromatin. You have to chemically modify them. You have to move them out of the way and then let the double helix kind of melt in a controlled way.

An enzyme comes in that then moves along the DNA and converts it into the RNA, and the RNA is sort of the currency upon which the instructions are delivered to the cytoplasm of the cell to tell you to make a certain protein, let’s say making an antibody protein. So the DNA encodes the antibody protein, the RNA is sort of the messenger in between, and then protein factories in your cell will make the antibody protein.

What MMSET does, it’s one of a set of about 50 or 60 enzymes that actually make a specific chemical modification on those histones and this tends to open up the chromatin, help the process of moving the chromatin out of the way, and helps let genes get activated. So it’s not a permanent modification. There are other enzymes that can remove this chemical modification so you can oscillate or switch between a gene being on and a gene being off.

So MMSET is normally present in very limiting quantities in the cell and it’s only supposed to be at some places and not others. ThereIt’s not much of it in a cell. What happens in the t(4;14), what our research has shown is there’s a huge increase in the MMSET protein and it causes the chemical modification of the chromatin, of the histones almost everywhere in the genome whereas normally it only works at a few spots here and there, so it makes a big chemical change in the chromatin.

We think this does several things. We think it changes the physical state of the chromatin. We find that it’s easier to — the chromatin, when we do experiments in a lab, we can actually probe it with little molecular scissors. We find it’s easier to cut the chromatin. It might be a little more easily damaged and that might be a bad thing. It might associate with accumulation of mutations. We find that genes that are normally shut off in the cell are abnormally turned on because of this chemical modification, and we find paradoxically there are some genes that are normally on that are shut off.

So in our studies, when we look at cells from a t(4;14) patient where we’ve artificially removed the MMSET protein, that’s something you could do in the laboratory. We can’t do it reliably for patients, but if we do it in the laboratory, we see thousands of genes change in their levels of expression and we see that the cells tend to slow down and stop growing.

Jenny: So it’s impacting the entire environment?

Dr. Licht: It impacts the entire genome. Our genome is a billion letters of DNA wrapped up in such a way that there’s something on the order of 20,000 to 25,000 genes, and thousands of these genes may be affected by the high levels of chemical modification of chromatin that occur in response to MMSET, so it’s really very, very abnormal. A lot of times, we look at how normal cells develop, normal organisms develop, and this gives us a paradigm or a model for how genes should work.

As I tell my colleagues in the laboratory, MMSET, we have to break that idea. This is very abnormal. We have to try to understand this abnormal state of affairs and try to find which genes are being turned on, how they’re being turned on, and can those genes be somehow turned back off. Can we reverse the process? That’s one thing that we’re very interested in. Can we reverse the chemical modification that MMSET is doing across the entire genome?

Jenny: That would be amazing if you can figure that out. I’m glad you’re looking at it in a different way. I’ve heard about HDAC inhibitors. We talked a little bit about those on the show because they affect histones, from what I understand. Do those relate at all to MMSET or no?

Dr. Licht: Well, we do have some evidence that MMSET can bind to some of the histone deacetylases and they may collaborate in some of their aspects of regulating genes. Histone deacetylase inhibitors are approved for the treatment of Cutaneous T-cell lymphoma and they’ve been used in clinical trials in lymphoma and myeloma. There seems to be a biological — what we call “signal” that some patients have quite a nice response to them, but most patients do not and we don’t yet understand why that is.

Histone deacetylase inhibitors lead to another type of global chromatin change or global change of these histones. What I mean by global is if you surveyed across the genome, you’d find histones would be increased in this chemical modification called acetylation all across the genome. If we could lay out the human genome in just a long thread, we’d find all along that there’d be increased acetylation.

That actually has been shown to really make the genome much more fragile and more easily broken. So in a way, like radiation and chemotherapy, histone deacetylase inhibitors may work in part by causing damage to the DNA, which some cancer cells have problems repairing and this could lead to cancer cell death. Another way histone deacetylase inhibitors work is by turning on a whole lot of genes that are abnormally silenced in cancers and pushing the cells along a path of programmed obsolescence.

A third way histone deacetylase inhibitors work is they actually work not only on histones, but on proteins outside of the nucleus of the cell. Remember, the nucleus is the brains of the cell. The cytoplasm is the workstations of the cell. The histone deacetylase inhibitors can lead to increased modification of proteins outside the nucleus that are involved in how we make sure proteins are of high quality in the cell.

Cells have a quality control mechanism. You might make a protein that’s supposed to be the antibody to fight the disease and it’s just a little bent out of shape. The cell has the quality control mechanism to destroy those proteins. And what’s been shown is that these histone deacetylase inhibitors interfere with that quality control mechanism and can cause enough problems, enough faulty proteins to show up in the cell that the cell eventually realizes it and can sort of commit suicide rather than be gooped up with all these faulty proteins.

So histone deacetylase inhibitors are complicated. We think they have several different effects. Which effect is most important for a therapeutic situation may vary in different types of cancer cells.

Jenny: So it sounds like the jury is still out on that one.

Dr. Licht: Well, the jury is still out on how they work and how well they work, but they are very interesting drugs.

Jenny: I saw that you were doing some research on HMT inhibitors for MMSET. Do you want to talk about what you found to be particularly most effective for the t(4:14) translocation or what you’re learning?

Dr. Licht: Absolutely. This is a great segue into this. As I said, the over-expression of MMSET in a myeloma cell drives a major change in chemical modification of chromatin. In the laboratory, we use a technique where we can knock down or almost knock out the MMSET protein, decrease the level of protein to 5% of the levels normally in a myeloma cell. And if we do that, those chemical modifications in the chromatin go away and the cells stop growing.

As I said, that’s not a practical thing to do in patients. What’s more practical to do is to find a small chemical that will inhibit the ability of MMSET to chemically modify chromatin. What the chemical modification MMSET does is to put a small carbon link to three hydrogens called the methyl group onto one particular site of chromatin, 1 particular site of the histone molecule.

So we and I think others in the field are searching for specific chemical inhibitors of MMSET. We think that if we could inhibit MMSET, we would stop myeloma cell growth. And in a modeling experiment, which I think will soon be published, we found that if we depleted the cell of MMSET and gave chemotherapy — actually, the chemotherapy that’s used in stem cell transplant, melphalan — we could have a major impact on the longevity of mice injected with a myeloma cell line.

So we think that if we could inhibit MMSET activity using a chemical, we might sensitize those cells to chemotherapy effects. The idea now is can we find that small molecule inhibitor? You may have a follow-up question. I can come back to this. Go ahead.

Jenny: Oh, no, no, go ahead.

Dr. Licht: Okay. So to look for inhibitors of these proteins, we have to make these proteins in the test tube. We make ours in a bacteria, so we take the human MMSET gene and we put it into bacteria and we make large quantities of a portion of the MMSET protein, the portion that actually works as a histone methyltransferase. We have an assay in which we take a small fragment of the histone protein of the chromatin. We put it into a test tube with MMSET and we actually can monitor the transfer of a carbon atom to this small fragment of chromatin.

We could do this by actually directly measuring how heavy that little fragment of protein becomes. If you add a methyl group on to a protein fragment, it gets 14 units heavier. And with my colleague, Dr. Milan Mrksich at Northwestern, we are using a screening facility which can actually measure that 14-unit shift in methylation.

Currently, we’re starting — it’s actually starting this week or next or actually probably Monday — a screen for 100,000 compounds against this enzymatic activity. “Enzymatic” means the ability to mediate a chemical reaction. So we’re trying to see if we can find chemicals that will block the ability of MMSET to make that transfer of a carbon group onto histones.

We have a few other candidates that seem to work in the test tube, but haven’t yet worked in the cells. So it’s one thing to take a test tube full of MMSET and full of proteins and it all works together. Some of the chemicals that come out of that screen may be just very toxic to every type of enzyme. We can screen and rule that out.

Some of them may be not very soluble in water, so they might be hard to administer to animals or people. Some of them may work in the test tube, but have a hard time getting into a living cell. So job one is to set up an assay, a test tube-based assay where we mix the chemical components together. We see the chemical reaction occur and we look for the inhibition.

That’s where we’re going now and screening 100,000 more compounds. We suspect that from 100,000 compounds, we might get several dozen of what we call hits, things that work in the test tube. What we will then do is use a second form of an assay, which we’ve developed with colleagues at Dana-Farber and the Broad Institute in Boston. That’s Dr. Jay Bradner’s lab and we’ve agreed that anything we find, we’ll test in his assay, which is a different type of assay that uses an antibody that actually recognizes that methylation or that chemical group.

We’ll screen ours against his assay and if he finds something, he’ll screen against ours, so we have a nice collaboration there. If we validate these chemicals with two different types of test tube-based assays, then we will go and put these on to myeloma cells and see if they have biological effects of inhibiting this methylation in the cells. We can monitor that. We have various ways to monitor that and we can see if that would correlate with any inhibition of cellular growth.

This paradigm has worked already for lymphoma, and the paradigm meaning finding an inhibitor of an overactive histone methyltransferase, put it on a cell, reverse that chemical modification and to stop cellular growth. This is already working in a form of lymphoma and we’re hoping to now make this idea work for myeloma.

Jenny: How long does that screening process take when you go through those various steps?

Dr. Licht: Well, I think we probably could get some — using Dr. Mrksich’s machinery, we can probably screen, I think, 10,000 compounds a day, something like that. So in a week or two, we can get through the 100,000 compounds. That’s my understanding.

Jenny: That’s fast.

Dr. Licht: There are these amazing machines where they actually will pipette 1,500 little reactions from one plate to another. Imagine you’re sitting with a little pipette in chemistry lab and doing it 1,500 times. You’d go insane. That’s why we have robots to do that. Everything is computerized and each one of these reactions is then put into a machine to measure the weight one by one. It’s sort of an assembly line, so you could do thousands of compounds per day. So in a couple of weeks, we hope we’ll have a list of these hits.

Then we have to do some validation, so actually, what happens — it’s interesting technically; we have 100,000 compounds sitting in tiny little dishes and occasionally, one of them gets misplaced. We think it’s in Row 2 Column G of a grid. You go back to that grid, pull out the compound and test it again. Occasionally, the compounds got misplaced, so you want to be sure you have the right compound.

And then what you might even do is order a fresh batch of the compound from a chemical supply company to re-verify that your so-called hits are the real thing. Do you see what I’m saying? So there’s certainly quality control that goes in here. You could easily do this badly.

Jenny: You have to test it for accuracy.

Dr. Licht: You have to test for accuracy, right. It sounds great, but the devil is everything is in the details, so we’re trying to dot our I’s and so forth to be sure that anything that comes out of this screen is real. We have money from NIH to do this. We have moneys from the MMRF and The Leukemia Society, and we know how hard the community works to try to support scientists. We are taking our data integrity very seriously.

Jenny: When I was talking with Dr. Bergsagel, he went into some discussion about MYC. I know MYC and MEK can get confusing because I’m going to ask you about both, but you had done some research about MMSET and MYC. I don’t want to interrupt if you had other things to talk about with the validation process, but I’m curious about that as well.

Dr. Licht: Absolutely. I’ll just say one last thing about the validation and then I’ll move on to that. If we get a chemical that works in these test tube assays and then works in cells, the next thing to do would be to see if it can be safely given to an experimental animal. We would do this with grafts of the myeloma cells into a special animal and we can monitor the growth of these tumor cells in animals and we would give the animals these drugs, and we can monitor if these would limit or reverse the growth of the myeloma cells.

If that all goes well, then you start to get into the realm of trying to develop a clinical product. At that point, if we were successful at that point, we’d have to try to license this work with a larger corporation because the scale of monies you need to take something from your own laboratory and academic institution to try to get all the data together, to try clinical trial patients is many tens of times, tens or hundreds of times more money and there we need industrial partners. So if it all worked well, that’s what we’d hope.

Now, turning to MYC, MYC is an essential gene. It’s a gene that’s found in lower organisms like the fruit fly. It’s found in people. Current ideas are that MYC is sort of like the volume control on your amplifier. If any of you remember the movie “This is Spinal Tap” where the guitar amplifier went to 11 instead of 10, the band was so loud. When MYC gets reshuffled in many diseases, it’s like turning the volume control to 11.

A whole lot of genes get turned on in a very abnormal way and cell growth is really pushed very fast. We have some cell lines in our lab which have MYC rearrangements that seem to divide two or three times a day like twice as fast as most typical cells. So MYC, it turns out as the more myeloma — there’s actually a fundamental — let me back up. There’s a fundamental paradox about myeloma.

The normal specialized lymphocyte that makes antibodies called the plasma cell has a very low level of MYC. In fact, MYC levels drop as you go from a more immature lymphocyte to a fully mature plasma cell. MYC levels drop, but the myeloma patient has the paradox that they have this very specialized cell that makes lots of antibodies and the antibodies can cause many of the symptoms of myeloma, the abnormal levels of antibodies in the bloodstream, but at the same time, that plasma cell has high levels of MYC and is always dividing. This is really a fundamental paradox and a problem we have to solve.

What we found was that high levels of MMSET increase levels of MYC in the myeloma cell. And if we deplete MMSET from the myeloma cells, MYC levels drop. This happened in a complicated way. It’s not that MMSET actually turns the MYC gene on or off directly. It actually regulates the levels of the MYC protein through an intermediary, a very small piece of RNA that is suppressed by MMSET. MMSET suppresses this small piece of RNA.

That small piece of RNA called a micro RNA normally limits MYC levels in the cell. It does this by destroying the MYC RNA, basically sequestering and destroying it. Let me say that again. MYC is normally under tight control including control by small RNAs called micro RNAs that bind to the MYC RNA and destroy it. When MMSET levels are very high, at least one of those micro RNAs go down and then MYC levels go up. That’s a little complicated, I understand, but the major point is that MMSET, like many other of the genetic abnormalities in myeloma, tends to increase MYC levels. MYC therefore is a therapeutic target of myeloma as well.

Jenny: I still have so many questions I want to ask. I don’t want to inhibit the other questions that I have from getting asked that people have emailed me or people might have online, so one final question about MMSET, is there anything that myeloma can discover from MMSET in other cancers like ALL or prostate cancer or leukemias or lymphomas?

Dr. Licht: What we’ve discovered this past year is the MMSET protein is mutated in a very specific region and it hyperactivates the protein in acute lymphocytic leukemia of children. It seems to be doing the same thing in that disease, very similar things that it’s doing in myeloma. But in this case, the gene has not gotten scrambled and turned on to a higher level. It’s just that the protein is more active and it’s doing that chemical modification at a very high rate. This also happens in certain cases of mantle cell lymphoma.

So what we’re learning about MMSET in myeloma may translate into other types of blood cancers. Lastly, MMSET levels have been found to be very high in particularly advanced prostate cancer. We think that again, it may be doing something similar in perhaps turning on MYC, in stimulating cell growth. So we think if we had an inhibitor of MMSET, it might be useful for several different diseases.

Jenny: And you’re just at the point now where you’re screening for those and trying to find what’s going to be the most effective.

Dr. Licht: That’s correct.

Jenny: It still sounds early. Well, I wanted you to also cover — I know you had done some other research also in MEK, in other translocations like t(4;16) and maybe in t(14;20) or the MAF translocations. And so, while we have you, I’d like to ask about those as well.

Dr. Licht: Well, the idea of MYC and MEK in myeloma, there was one thing we actually thought about here, is that MEK is a different piece beast from what we’re talking about MMSET. MEK is a protein that is involved in transmitting a growth signal from the surface of a cell into the interior and eventually into the nucleus to tell cells to just go on and off.

This kind of growth factor rearrangement actually even occurs in the t(4;14) translocation because in many of those patients, they have an overexpression of the fibroblast growth factor receptor. So part of the problem in the t(4;14) might be that this receptor that signals into the interior of the cell is hyperactivated and overactive.

MEK is a protein in a sort of chain reaction starting with — imagine a growth factor binds to a receptor on the cell surface. This sets off chemical reactions that go in a chain from protein to protein, each protein being chemically modified. That protein gets activated and it modifies the next protein and it amplifies a signal into the cell.

So MEK is one focal point in this signaling cascade and there’s evidence that if you gave inhibitors to MEK, you could actually inhibit these chemical signals and inhibit myeloma cell growth, so that’s one current type of research going on in myeloma.

Jenny: Is that just for the MAF or is that for MMSET, too, or is that for everybody?

Dr. Licht: There’s been some interplay with MMSET and MEK, so there is some idea that the MMSET tumors might be particularly dependent on MEK, but I don’t think that’s been completely clarified. I would say that this type of inhibition of signaling approach is one that should be continued to be explored in many forms of myeloma.

Along that line, there are mutations in these signaling pathways and one that’s been of interest has been in a protein called BRAF. This has mutated in about 5% of patients with myeloma. This causes hyperactivation of RAF and you could possibly treat those patients with RAF inhibitors, chemicals against RAF, or possibly MEK inhibitors. I believe clinical trials are underway to try this, but the drug would only be thought to work in a small set of patients with these activating mutations in the signaling pathway.

In summary, what I’d say is that in addition to changing gene expression programs through these chemical modifications or chromatin, changing signaling pathways from the surface of the cell where cell gets this signal to grow or not to grow through chemicals that inhibit the chemical reactions that convey those signals is another very viable potential therapeutic approach for myeloma.

Jenny: And when you look at the MAF translocations, is there an approach that you think works better than others?

Dr. Licht: I have not done anything really on MAF myself, but what I think is going to happen in the case of the MAF is it’s going to turn on certain pathways. What we actually find is that with the MMSET rearrangement and the MAF rearrangement, it could be that it turns on certain gene pathways that then makes the cells more susceptible to inhibition by MEK.

So I think when you have a MAF rearrangement, you can actually potentially change how the cell depends on other pathways. And as such, you might sensitize the cell to inhibitors of signaling such as MEK. So I actually think more work needs to be done on MAF to understand the identity of all these other pathways that might complement the MAF rearrangement to support the growth of the myeloma cell.

Jenny: That makes a lot of sense. I know there’s been some discussion and recently there was a video on Managing Myeloma where several of the doctors got together to talk about the updates on cure versus control. When you look at those who are being potentially cured, I want to say, are those patients with no translocations at all or are those others?

Dr. Licht: Well, I think that that’s still a little early to understand that. I think we only now have the technology to understand the patient who has been treated and has had no relapse for 10 or 15 years, so you know there are ever more of those patients. I think that some of this will have to do with what set of chromosomes they had. Not every t(4;14) patient will do poorly. We know that bortezomib works well as an initial therapy for t(4;14) patients.

And so, if we get better drugs and we have better drugs all the time with all the IMiDs coming out and getting ever better and all of the next versions of bortezomib coming out, so we’re getting better drugs all the time. Eventually, we’d like to have patients with every chromosomal abnormality, every mutation, have an equally good prognosis. We’re hoping for that time, but we do find that there are some patients who have extraordinary responses to drugs and very often, these so-called single patient experiments are very informative.

It’s been found if you sequence the genome of the cancer cell of the patient who has an extraordinary response, you find that they had an extraordinary mutation and it helps explain the response. I think things like the CoMMpass trial where we have a snapshot of the genome of patients before therapy and following them all the way for years and years, we may be able to backtrack and say, “Here are the people who have lived 20 years or never had their myeloma come back.” What was particularly special about the set of genes that they had in that cancer cell to start?

Is it due to a special set of cancer genes? I suspect it will be, but I don’t know what that set will be at. I do think not having chromosome 13 deletion, not having some of the worst translocations, it will be amongst those patients, I think, but there may be other genetic mutations that they specifically might have or not have that might help correlate with how well they did.

Jenny: All right. I have two more questions for you and then I’m going to open it up for callers. The first is when you’re talking about the CoMMpass Study that the MMRF is putting together, I think that’s an easy, easy study for patients to participate in and I think we need more of that. So when you look at disease registries like Celgene’s or the MMRF CoMMpass Study, they’re existing to find patterns big enough to find populations so you can start seeing these patterns, but are there other ways that that data can — I don’t know how the data is shared, but could that be provided to lots of different providers so everyone can kind of pitch in what they’re thinking? Or is that how it’s done currently?

Dr. Licht: I think there needs to be some safeguards on genetic data in the sense that when you sequence the genomes of the cancer cell, you’re also sequencing the DNA of the normal part of the patient. It’s very hard to let out all this data without discerning identities. It turns out there’s enough genetic data deposited in websites like 23andMe, which is shut down now, but others like it, so it’s very easy to link people to identify who that person was.

So we would release this data if it was anonymous, but it’s hard to keep raw, genetic data from these studies anonymous because there are computational ways to figure out who that person was. It’s really quite remarkable. So I think these types of genetic studies — if you simply say, “Patients 1 through 10 who had a mutation in MAF and patients 2 through 20 had MMSET and here’s their prognosis, ” that’s the kind of stuff you could release.

If you want to get all of the raw data released, that takes privacy in collaboration agreements and other safeguards, but a lot of the more somewhat digested data can be shared and re-analyzed. I don’t think the CoMMpass data is — it’s early days for that, but there are other databases where there are genetic information, databases where you could go and see, “Does the RAF mutation in colon cancer, do those patients have a bad or good prognosis?” You could do some explorations of these types of data.

And so, I think this will be shared and I do encourage your listeners to participate in clinical trials that do include genetic information. I assure you that this has been very, very heavily thought through and that genetic information will be safeguarded and will be kept private, and would only be used in such a way that only good would come from it, but I think it’s going to go on.

Jenny: I highly encourage it because as a patient, this is what I want to see. I want to see all patients with my genetic mutation and then I want to see comparative work to say what therapy did they receive and what’s the best outcome for that mutation type. That doesn’t exist for me as a patient today. When I’m coming in newly diagnosed and I have to make a quick decision about what kind of therapy I’m going to receive, that’s something I want to know.

Dr. Licht: I understand that. I think that information wants to be free and I think we as physicians want to do that, but we want to be sure we’d do it in a very collaborative way, in a way that the information can be properly interpreted. A little bit of Google searching and you can get all kinds of the wrong ideas about things, so I agree with you.

Jenny: Well, I think what you’re doing is amazing and wonderful and we hope you keep going. I’d like to open it up for caller questions, so if you have a question for Dr. Licht, please call 347-637-2631 and press 1 on your keypad. We’ll start with our first caller.

Caller: Hi, Dr. Licht.

Dr. Licht: Hello! How are you?

Caller: Good, thank you. Thanks for sharing your work. I wanted to ask you what are your suggestions for patients with the addition of Chromosome 1?

Jenny: I guess as a high-risk marker, maybe.

Dr. Licht: Right. I think that the issue here in these types of high-risk things is that we’re currently annotating those. If I had a patient at our clinics here, patients and physicians want to know what the prognosis may be. These types of markers can be an aid. What they might militate towards in some cases is most patients now are starting on multi-agent therapy that will include IMiD, that will include a proteasome inhibitor.

I think when you have these markers of a more guarded prognosis, you as the physician or patient might opt for stem cell transplant a little sooner. You might have a guarded level of monitoring to try to be sure therapy is working. We’re always doing that anyway, but it’s a matter of heightening consciousness.

If it was a matter of after giving initial induction therapy, there are some debate in the field on how much maintenance therapy there should be after you’ve gotten an initial excellent response, should you continue IMiDs, indefinitely, how often. I would say that the patients with the higher risk would be the patients who might get more maintenance, who might get transplantation sooner rather than later who are going to be watched very carefully.

But right now, it’s not been the practice at our institution nor people in the field to change the initial therapy a great deal. Of course, there might be some who disagree with that, but I think it’s a matter of just having a heightened state of vigilance, and again, that collaboration between physician and patient.

Caller: Okay. Thank you. Thanks for your recommendations. I was here making some notes, but thank you.

Dr. Licht: Okay.

Jenny: All right. Our next caller please go ahead.

Caller: Hi! Good afternoon, Dr. Licht. Thank you so very much for being able to understand this very complex disease on our behalf. I’m a smolderer. My name is Dana and I have a question in general for smoldering patients. How important is it for smoldering patients to know their FISH and/or gene expression profile? Do we need that level of testing? Will it determine and help us understand our risk progression or is it more significant and helpful for just treatment plans?

Dr. Licht: Well, currently gene expression profiling is not in our practice at Northwestern and in many other places. It’s not part of standard care. It has been part of the Arkansas group. That’s part of their thing and I think that it may be at one time. So I’d say that if we were to do it at our place, we’d consider that a research study and something to still understand.

One thing about these gene expression profiles is that the devices of so-called platforms upon which are being are changing as well. Now, we have other technologies to look at, the gene expression profile that are even more sensitive than the gene tests used in the past. I think that’s a bit of a moving target.

In terms of looking at FISH profiles and chromosomal rearrangements, I’d say for someone smoldering, I think it would be sort of a bit of a peek at the future, but I suspect that additionally that many times, if a patient goes from a smoldering state and then unfortunately progresses, many physicians would consider getting those chromosomes again and see what was different. That might actually be very important as well in terms of looking at that.

So my general feeling about these chromosomal markers is that they are an adjunct to good clinical judgment by your physician. You don’t want to start therapy too soon on someone who really has minimal M spike and no bony lesions and everything is just — it’s just kind of smoldering. It sounds good. So sometimes, you have to do a watchful waiting and collaboration between the patient primarily and the physician, and be sure we use good judgment when to  move forward.

Caller: Thank you, Dr. Licht.

Dr. Licht: You’re very welcome. Go ahead.

Caller: Just a follow-up question to that. What diagnostic testing would be then the most critical for someone with smoldering to have and to make certain that we are indeed getting on either a regular basis whether it’s quarterly, semiannually, annually, to make certain that we truly are being followed in the best way?

Dr. Licht: Right. I think initially, my approach would be to sort of get a sense of the case of the patient themselves. The way I would probably start is probably with some kind of quarterly measurement of the immunoglobulin spike, the beta-2 microglobulin, being sure that the creatinine is fine. Listen to the patient very carefully. Be sure of how they’re feeling symptomatically. I think once you get a sense of how the patient is progressing or not progressing, you might space that out a little bit longer.

Many physicians might do cytogenetics initially, but that’s only done sort of at diagnosis and that’s done by the bone marrow biopsy, so you don’t do those over and over again. So basically, you have to monitor the blood count, make sure that all the red cells, the white blood cells, the normal white blood cells, the granulocytes that fight infections and platelets, they’re all fine, what do the blood chemistries look like, how large is the M spike, the abnormal antibody spike, and get a sense of the pace. That’s the way I would approach it.

Caller: And the Free Light Chain ratios for smolderers, how important are they? If we have abnormal ratios, what does that signify to us? Does that mean that we have a disease that’s more likely to progress? Is it more unstable?

Dr. Licht: That one is a little bit outside of my expertise. I’m going to be honest about that, so that’s one that I have not done much work on the study myself, so I would have to defer to that. Actually, there are some good sites for that for patients. The International Myeloma Foundation has things about that as well, but I’m going to have to defer on that one. I apologize.

Caller: All right. No, that’s fine. Thank you so very much for your time. It’s much appreciated.

Dr. Licht: You’re very welcome.

Jenny: Okay. Thanks, Dana, for your question. I have two more quick questions and I need to ask them because people requested it.

Carol said, “Do you think the IMF consensus group will or should redefine active myeloma to include high risk smolderers with a del(17p)?” She says, “It matters because clinical trial availability is affected by the definition as well as early access to standard myeloma treatment.” She says she participated at the NIH CRd trial and she’s currently MRD negative and on maintenance Revlimid. She says, “I’m in no hurry to start another regimen, but would like to know it’s there if needed. Do you have an opinion on that?

Dr. Licht: Well, personally, I know there have been a number of studies of treating smoldering myeloma now with IMiDs. I think it remains a little bit controversial. The thing about that is that I think these are good questions to ask and I think that these studies should go forward and we need to continue to follow how these patients with smoldering myeloma, if we intervene early, will we make a real long-term difference.

It should be noted that maintenance IMiDs are not without side effects as well, so I think we have to carefully balance that. I think that I’d have to defer to my colleagues who are much more involved in the clinical trials, friends like Paul Richardson at Dana-Farber, Ken Anderson, Nikhil Munshi, people like that, so I really would defer to them.

Jenny: Larry’s last question, he says, “I wrote a post on The Myeloma Beacon about high-risk patients that can go on to clinical trials until they’ve relapsed,” so it’s kind of the in-between stage. So he asked, “Isn’t this counterproductive for the high-risk patient who may need to be doing some proactive therapy? And I don’t know what you found for t(4;14) patients or others with those types of situations.”

Dr. Licht: So the issue here is the patient is high-risk, but has very good response, has had minimal residual disease, but the caller or the emailer would like to know — “Shouldn’t I do more therapy now?” is that the question?

Jenny: Yeah, or “could I possibly” because most clinical trials, you can’t join them unless you have active disease. So is there anything that might have less impact like an IMiD or a proteasome inhibitor and maybe like a monoclonal antibody or vaccine that might kick you in to a longer term remission especially if you have a higher-risk feature? I think that’s the question.

Dr. Licht: Right. So you’ve had a high-risk disease. You’ve gotten very intensive therapy. You’ve gotten dexamethasone. You’ve gotten bortezomib. You’ve gotten IMiDs. You’ve got a very good response, but you’re still in the high-risk and you really want to do something before relapsing. I think that would be an excellent place for something like a vaccine trial to come in because in that time period, you don’t want to add too much more toxicity, but you might want to try something that might be efficacious.

I think that would be a reasonable time to try something like a vaccine trial. I think that adding a potentially toxic first-in-human drug in someone who’s in a relatively asymptomatic and has minimal disease, that has problems with potential safety issues and additionally realize that we’d need to have an ability to objectively understand disease response.

Now, what I’m saying is if you have a new drug and it’s the fifth generation bortezomib and you want to know does it work at all, one of the ways that drug will get eventually proved is to show that it works in someone who’s relapsed from bortezomib or has been refractory to bortezomib. So there’s sort of a clinical strategy. For the pharmaceutical industries, it’s a bit of a business strategy of where will they take this new resource, which is limiting. These drugs are expensive to manufacture. They want to be sure that they’re going to apply it to patients who really need it and in a safe way and a way where we can make an actual judgment about whether or not it works.

Taking a very new agent and giving it to a patient who has very little disease is not a reliable way to actually show that the drug works. So that’s where we need your collaboration and understanding that these are experiments that you as the patient — we have your benefit number one in mind. Clinical trials, we encourage them. We think they give the paradigm for the best care, but it may not be always for everyone and we understand that, but we would like to collaborate with you and take a leap into the unknown together to try to make this disease — get it to a very curable state.

Jenny: Well, thank you so much for your work. Thank you for your dedication to myeloma and especially for high-risk myeloma, for those of us who share those features. You’ve been very, very enlightening today. We’ve taken lots of your time, but we’re so grateful you made the time for us. It’s really comforting to know that you are looking out for us and we’re very grateful for your really amazing work.

Dr. Licht: Well, thank you for this opportunity and I’m delighted to be introduced to your community and to our community. I’m looking forward to working with you together to try to eliminate this disease. I wish you all the best.

Jenny: Thank you so very much.

Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn how we as patients can help drive cure for myeloma by joining clinical trials.

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