Originally posted on mPatient Myeloma Radio
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Dr. James (Jay) Bradner, MD
Dana Farber Cancer Institute
Interview Date: August 30, 2014
Dr. Jay Bradner describes how Myc works as the master regulator of cell growth in myeloma and other cancers. Because all roads lead to Myc, it is an attractive target that begs inhibitors. He discusses this Myc problem in detail and shares how the therapeutics technologies we have today are not suitable to drug Myc. He describes three ways to target Myc 1) Find out what turns Myc on 2) Target Myc collaborators and 3) Create new technologies to drug Myc. He describes the exciting detail behind the creation of JQ1, a Bromodomain inhibitor (BRD4) by Jun Qi and how they used a rare open source platform to help develop the molecule. BRD4 is a Myc collaborator and targeting it has shown success in a mouse model. He shares that discovering a new molecule is easier and faster than turning it into a real drug that can be used in-clinic, but this new BRD4 inhibitor (now called TEN-010) is being used in Phase I clinical trials. He notes importantly, “Time is our enemy. We must be as creative with our scientific strategies as we are with our science.”
The live mPatient Myeloma Radio podcast with Dr. Jay Bradner, MD
Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. If you like to receive a weekly email about past and upcoming interviews, you can subscribe to our newsletter on the homepage of mpatient.org or follow us there on Facebook or Twitter and please share these interviews with your myeloma friends.
For today’s show, we are very excited to have with us and fortunate to have one of the top myeloma researchers, Dr. James Bradner with us. So welcome, Dr. Bradner.
Dr. Bradner: Hello, Jenny. Thanks for the invitation to join you.
Jenny: Well, I will give a short introduction –it’s hard to keep this one short but I will try — about you.
Dr. James Bradner is a Staff Physician in the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, as well as an Associate Professor in Medicine at Harvard Medical School. He is also Associate Director in the Center for the Sciences of Therapeutics at The Broad Institute. Dr. Bradner is Scientific founder of Tensha Therapeutics and Syros Pharmaceuticals, is on a lengthy number of Harvard, Dana Farber and Brigham and Women’s committees and is on the National Board of Directors for the LLS and additional Leukemia & Lymphoma Society committees.
He is the Development Committee Chair for ASH and is on review boards for the MMRF, the Samuel Waxman Research Foundation, the Leukemia Research Foundation, the LLS and the Doris Duke Charitable Foundation. He is an ad-hoc reviewer for over 15 major hematology publications and has received numerous awards including the ASH Scholar Award, Damon Runyon Cancer Research Foundation Innovation Award, and the Nakada Award from the University of Pittsburgh, just to name a few. Dr. Bradner leads the very large Bradner Lab which studies gene regulatory pathways using the newer discipline of chemical biology.
So with that, which is amazing, let’s get started with our show today. And one of the reasons that I wanted to talk to you is the important reason that Dr. Bergsagel mentioned Myc as THE most common myeloma translocation. And then he mentioned your work to target that translocation.
So can you give us a little bit of background about Myc, why you chose Myc as a target, the importance of Myc and maybe give us a little refresher about Myc in myeloma?
Dr. Bradner: Absolutely. And Jenny, thanks for that introduction which is just hysterical. You’ve clearly been talking to my mother.
I will tell you that I’m sort of an accidental chemist or discovery chemist, I trained as you said, as a Hematologist and taking care of myeloma patients on the wards, training with Ken Anderson and Paul Richardson and colleagues, I really became very frustrated that the medicines that we had access to — this is now 1998-1999 — for the treatment of myeloma were all hand-me-downs. They were medicines that, it’s fair to say, weren’t developed or discovered with the disease myeloma in mind. They were hand-me-downs from other successful or unsuccessful drug discovery efforts.
Now these medicines were very simplistic — melphalan and prednisone and autologous transplantation — but very helpful to patients. There were meaningful responses to these drugs and life was extended with these drugs.
But I will tell you that the drugs that were developed for myeloma in the 1950s, ’60s, ’70s, all the way through to around the year 2000, they weren’t directed at the disease itself. They were medicines that could kill myeloma cells at doses that would not kill patients, so crude early substances. And this was frustrating because of the work of Dr. Bergsagel, Dr. Anderson, and so many other in our field, we knew quite a lot about the disease and yet there weren’t companies set up to study just myeloma, at least at that time.
And so I retrained in chemistry at Harvard with the idea that possessing this new understanding, molecular and genetic understanding of this disease — still incurable — that we might make our own drugs for myeloma. And when you take all of the things that a myeloma cell does that are toxic and all of the mutations that a myeloma cell possesses and all of the rearrangements of the chromosomes that can happen to lead to myeloma, one target rises to the top and that’s this gene that you spoke of called Myc.
Myc is the master regulator of cell growth. It’s a gene that normally lives and exists in your body; everybody’s born with two copies of Myc. And this gene exists so that during development, one cell can become two and then a fetus and then a child and then an adult. There’s so much cell growth in the body and Myc is the master regulator of cell growth; if you make a mouse that has only one copy of Myc, well it’s smaller.
What happens in cancer and this is true really of almost all, if not all, human cancers is that the cell finds a way to keep Myc on, it fails to turn it off. It isn’t necessarily that there’s more Myc, it’s just that it’s lost the natural regulation of Myc. If, God forbid, you cut your arm and you lost a lot of blood, your bone marrow will turn Myc on so that you could make more blood, but then it would turn it off when there was enough blood made.
What happens in cancer is that genetic events occur as in myeloma especially and the culmination of these genetic events is that Myc never shuts off. So it can be no surprise then that nowadays when cancers are genotyped and cancer genome sequencing has occurred on a grand scale, especially in myeloma, that we find as Dr. Bergsagel apparently reported to you, that the number one most commonly activated gene in cancer and in myeloma is Myc. This is because Myc can be kept on by upstream pathways that signal to it; or the cancer cells can just short circuit, short step the whole process and activate Myc directly. How does this occur?
Well, it can occur in myeloma as Dr. Kuehl and Dr. Bergsagel have studied over many years, by taking a gene that’s normally ripping on in a myeloma cell, the gene that would make immunoglobulins, and it will hook it up to Myc. Literally, the chromosomes will break apart one at the immunoglobulin or antibody site in the genome and the other in the Myc site in the genome and then they will fuse back together.
And now the Myc gene is taken out of its context where normally the body would say, “Well, we have enough plasma cells, please stop making them” but now that gene is hooked up to a faucet that never shuts off in that cell, the antibody faucet.
And so learning this about myeloma, it seemed that how are we really going to cure this disease if we don’t take care of what we call in my lab the “Myc problem”. The Myc problem is that all roads in cancer, and in blood cancers like myeloma especially, lead to Myc. The drugs that we use, the targeted drugs, acts upstream of Myc. Drugs like Revlimid, we’ve recently reported with Bill Kaelin here, function to turn off a gene called Icarus which modulates a gene called IRAS4 which eventually shuts off– guess what — Myc.
So these incredibly effective drugs like even glucocorticoids that can turn the Myc faucet down a little bit, eventually the myeloma cells figures how to turn Myc back on. We have a Myc problem in cancer. The responses commonly occur from shutting off an input to Myc but then cancer finds a way to turn Myc back on. It’s so clear then what we need. We need Myc inhibitors.
Jenny: And it sounds like you need to target Myc earlier in the process.
Dr. Bradner: I think so.
I was just at Cold Spring Harbor, New York last week for this unbelievable conference on the mechanisms and modeling of cancer and heard Gerard Evan from University of Cambridge speak, a world-leading expert on Myc, and he presented something quite remarkable. He showed that you can take another cancer-causing gene called KRas which is just one of the most active genes in the cell. And you can turn it on in a cell that’s not yet a cancer and it has a hard time making a cancer. But if you add just a whiff of Myc, you get a cancer out the other end.
And so your question gets to if Myc is so important for established cancers, could targeting Myc prevent cancers from happening at all? And I think this is a really exciting idea but we would need medicines that target Myc. And so far, we have not yet one drug that can directly bind to and impair the function of the Myc gene. Myc is, in the parlance of the field of drug discovery, a term I hate, called “undruggable”. Undruggable just means that there’s no drug yet for a given protein target and Myc is the prototypical example.
There’s no drug for Myc and I tell you it’s not for lack of trying. People have been trying to drug Myc since 1984-85 when it was discovered and characterized in the context of cancer.
The problem with Myc is sort of like, I think the best analogy I can come up with, is the problem of breaking through a wall with a locksmith. If you call the locksmith and you say, “Look, I’m having trouble getting into my car”, they say, “Oh, no problem.” They have tools to access the lock on a car and they can get you in. But if you call a locksmith over to a brick wall and you say, “Look, I’m having trouble getting through this brick wall”, they show up with their pins and needles and screwdrivers and they say, “I don’t have the tools needed to get through a wall. I make small keyholes function.”
You see, Myc lacks keyholes. As best we can tell, the Myc protein is a long noodle that winds up when it finds its partner to switch on all the growth genes in the cell. And when they get together, it’s like watching two helices converge, like two dance partners connect, and there’s no pocket, there’s no open pore or hole where chemists like those in my lab, could imagine where to put the molecule. There’s no keyhole to make the small molecule key or drug.
So what it means then is if we’re going to drug Myc and we’re going to go down swinging trying in labs like mine and others is we’re going to have to create new therapeutic technologies that lead to perhaps a better way of studying Myc, perhaps a better way of studying other types of Myc’s functions, new types of chemistry that can engage long noodly proteins like Myc.
I’m just not convinced that the therapeutic technologies we have today are suitable for drugging Myc. Maybe we have no drugs then because our drug discovery technologies are imperfect. And recognizing this as the doomsday scenario, that we can make all the drugs in the world but if we don’t solve the Myc problem, it will be hard to cure cancer, definitively cure cancers.
I set up this lab at Dana-Farber, of all places, an academic center that has no drug discovery capability, with the idea that we wouldn’t make drugs but that we would study Myc in its completeness to try to find pathways that signal to Myc, to try to find ways of disabling Myc, ways of destabilizing Myc, ways of targeting the collaborators of Myc, ways of finding new collaborators for Myc and targeting them, thinking that maybe Myc doesn’t act alone.
And so I suppose you could say that a central theme of the researchers in my lab, these are chemists and biologists and biochemists and computer scientists who’ve come together not to make drugs, we’re not a commercial operation but to make ideas, to make technologies that would — either here or in somebody else’s lab, that would be fine, too — to make first therapeutics that work to turn Myc off.
Jenny: And now we’re dying to know what you’ve learned so far. If they started in 1984 trying to target Myc, what have you learned about Myc in your lab?
Dr. Bradner: We’re very respectful for the science of the last three decades and we read it like the Holy Bible trying to find insights or approaches that were learned or how to most effectively deploy new technologies.
There are three ways that we’re thinking about drugging Myc and I’ll give you a progress report on all three and we could get together in ten years for the next one. My lab’s only been open six years so please regard this as a work in progress, which it very much is.
Let’s take three different approaches to Myc. One I’ll call upstream. What are the factors that could turn Myc on and could you target those factors such that you more effectively disable the faucet that is driving Myc?
Second, let’s target the collaborators of Myc. If Myc doesn’t work alone, if it’s the godfather of the cancer mafia, let’s execute the family. What are all of the proteins that Myc needs to work with and let’s one-by-one develop chemical strategies for them.
And then third, we don’t accept that Myc is undruggable. We think that with new types of chemistry, new types of therapeutic approaches, new drug discovery technologies that maybe we can in 2014 do something that was impossible in 1984. Can we deploy new therapeutic technologies to directly target Myc though it has been and we’re very respectful of this Holy Grail in drug discovery for decades.
So we have scientists organized around each of these three approaches — the upstream targeting of Myc, the collaborators of Myc, and directly targeting Myc. I’ll tell you the most progress we’ve made in the lab so far has been the collaborators. It is possible now with modern proteomic science to find all of the binding partners of Myc and we did that experiment right when I opened the lab and we found a lot of insights of what types of proteins Myc might require to execute its cancerous functions.
Number 2 is I hit the literature looking for ideas or insights. Are there things that Myc does to cells, to the circuitry that would point to new potential targets, things that didn’t have a big literature about Myc but just made good sense?
In this vein, I came up with an idea to target a protein called BRD4 and I believe this must be the project that Dr. Bergsagel referred to. BRD doesn’t stand for Bradner — I wish it did — BRD4 stands for bromodomain protein 4. More on that in a second.
Well, Myc lives in the nucleus of the cells. This is the middle of the cell where the DNA lives. And what Myc does is it’s the light switch that turns on the 5% to 15% of genes in the cell that are involved in growth. There are 25,000 genes and about 2,500 of them are involved in cellular growth and Myc is the master switch that turns them on. When Myc is on, the cell grows. When Myc is off, the cell can’t grow.
And though this is simplistic, and there are exceptions, it turns out to be generally true. So Myc helps the cell accomplish a metabolism that can make more building blocks to build a second cell right next door. Myc helps to expand the ribosomes where proteins are made to allow more cellular functions that are needed for cells to grow and Myc also influences the proteins that control the checkpoints that keep cells from growing or not. Myc is the master conductor of the growth orchestra.
And the way it does it is it sits down on DNA, not on genes per se, but next to genes at places that are called enhancers. Enhancers enhance the expression of a gene. These are the switches that turn genes on and off, and Myc is an on switch. When Myc sits down at these enhancers next to genes, it flips the switch and the gene turns on. How does it do that? How does Myc turn genes on and how does a cancer cell, when it goes through cell division and it makes two cells, how does it remember to turn the genes back on, how does it remember that it’s cancer?
Well, I’ll summarize a lot of really complicated science, and we can go into it as much depth as you want, but Myc requires the function of post-it notes to remind it where to go. Myc sits on the DNA and then it forms this assembly, it really brings an orchestra together to turn the gene on and it tends to go to these places where there are post-it notes, little reminder notes that say, “Hey, Myc, you were just here in that last cell and now we’re trying to make another cancer cell again so get back over here and turn this gene on.”
And these post-it notes are chemistry. There are chemical changes to the DNA and to the proteins that the DNA is wrapped around that though they don’t change the sequence of the DNA, the G, A, Cs, and Ts, the genetics of the DNA, they change the protein that the DNA is wrapped around the epigenetics of the genome. And when these chemical marks are placed, it’s like Hansel and Gretel and their bread crumbs. Now the cell can remember what genes to go back to to turn on. Cells can remember that they’re cancer.
One of these marks is called acetylation. And acetylation, I won’t go too deeply into it, is an on switch mark. It goes wherever Myc goes, like bread crumbs, these acetylation marks are placed behind Bromodomains bind acetyl marks. And so the bromodomains are little bundles of protein that stick to, like a post-it note, to these chemical marks.
So to rehash, Myc causes cancer, number 1. Myc functions by switching on growth genes, number 2. Myc remembers where to go and thus cancer cells remember that they’re cancer through epigenetic changes to the genome, one of which, the master of which, is called acetylation and bromodomains bind acetylation marks and thus are the post-it notes that remind cells that they’re cancer.
So I got to wondering. Among these 42 bromodomain proteins, are there any of them that Myc might just utterly require as a collaborator and we found this protein called BRD4. And it turns out that for Myc to function in myeloma, it really needs this BRD4 protein to be nearby like a drinking buddy to function.
And so chemists in my lab and biochemists in my lab organized around the challenge of making a first inhibitor of BRD4 to test in myeloma to see if it could turn off the Myc switches. Okay?
Jenny: Okay. Makes sense.
Dr. Bradner: Are we doing okay, Jenny? Are you following this okay?
Jenny: Yes, I am. And I’m taking notes.
Dr. Bradner: Good. And so this was a highly-collaborative effort and we got a lot of insights from the published literature. We got some insights from the patent literature. We got a lot of insights from collaborators such as Stefan Knapp, a brilliant crystallographer at Oxford University and we would communicate on Skype and use Dropbox. And Jun Qi, a chemist in my lab, made a very first inhibitor for BRD4 called JQ1, which he vainly named for himself — Jun Qi, JQ1 — and using this compound, we were able to show in myeloma that the Myc gene turns off.
Now this isn’t a drug-targeting Myc. This is a drug that targets Myc’s collaborator. And so we wanted to test this compound in models of myeloma that might predict whether it’s just a research experiment, was just a chemical tool, or where there was a real therapeutic opportunity, a translational opportunity to go from bench-to-bedside. And we are very lucky to be here in Boston because we have arguably, the world’s leader in this kind of research, Ken Anderson and his lieutenants, who are now many of them on faculty here. And one of them, Constantine Mitsiades, a brilliant Greek genius of myeloma biology, is here as well and a very good friend.
And so Constantine and I teamed up our labs to study the JQ1 molecule in myeloma and lo and behold, this drug turned the Myc gene off. And when it did that, the myeloma cells forgot they were myeloma and they went to sleep, something we call cellular senescence, and they died.
It’s around the time in science you start to get really excited because what was this kind of basic science project, can we turn off Myc with a drug that targets BRD4? And you’ve got to understand that this time there weren’t a lot of labs that even could spell bromodomain. Not a lot of people that cared about bromodomain proteins and we were just trying them on for size. All of a sudden, Constantine says, “Look, this is really something special. Have you ever thought about making a drug out of this JQ1?”
So this is around the time in science you get excited about treating some mice because unlike a Petri dish, a mouse has a brain and a heart and a liver and lungs and you can learn whether what you have here is just dish soap, something that would be great to kill cells but you could never tolerate it as an ingestible product, or whether it really had like drug-like properties.
And it turns out that Leif Bergsagel has developed, what is in my opinion, the most predictive mouse model of myeloma and I hope he talked to you about this, it’s actually very exciting work. It’s a model that’s driven by Myc where the mice get a disease that looks just like myeloma, and Leif and his wife Marta Chesi, bothered to do the experiment that most scientists don’t do. He took all the drugs that have ever been tested in myeloma in the clinic that he could get his hands on and one-by-one, he put them through his model.
And he said, “Do the drugs that work in humans work in the model?” Yes or no. And “Do the drugs that don’t work in the model work in humans?” And it actually correlated really well, that by-and-large, the drugs that would provoke responses in the mouse were the drugs that worked in the humans — drugs like Velcade, drugs like carfilzomib, drugs like histone deacetylase inhibitors, melphalan, prednisone, doxorubicin — things that work in humans work in the mouse. That’s called positive predictive value.
Jenny: That’s a great correlation.
Dr. Bradner: Yes, and moreover, drugs that did not work in his mouse tended not to work in humans.
And there was one exception, Revlimid, but we understand that better now and that’s more for another time.
So I emailed Leif to ask if he could be interested to try this molecule in his model. We have this theory that maybe it turns off Myc, your model is driven by Myc. And I’m always excited when experiments work in my lab but I’m actually a little more excited when they work in somebody else’s lab because we don’t want to make the drugs that only work in Boston. We want to make the drugs that work in Scottsdale, Arizona and Boston and wherever anybody tries this, right? The reproducibility issue in science is a big deal right now. And Leif and Marta were lovely. And Jun sent them some compound and they injected it into their mice. And we’ve gotten sort of used to, in cancer, drugs that will delay the progression of disease in a mouse or make the mouse live longer, which is no small feat, but it doesn’t make the cancer go away.
What was exciting to us in Leif’s model is that some of these mice had near-complete remissions with a week or two weeks of the drug. And Leif’s excitement and Constantine’s excitement and Ken Anderson’s excitement really got our lab excited. Because these guys have been living in this myeloma world for 20 years and they know. They just know what demands testing in humans.
But Jenny, now there’s a problem. This JQ1 molecule from our lab is not a drug. This molecule is not super-soluble. It’s a molecule that we use in the lab like a prototype.
Also, Dana-Farber is not a drug company. We don’t have manufacturing facilities. And their enthusiasm caused us to think differently about the project and that we would need to make a drug-like version of JQ1 and that’s what we did next.
Jenny: That’s amazing. So what is the next step after you determined that it does work in mice? You work it in the lab, you work it in mice, and then?
Dr. Bradner: Well, the next experiment is to try it in humans. Now in order to get it into humans, we needed to find a version of our molecule that has properties that normally we don’t care about in academia, drug-like properties — is it soluble, is it bioavailable, does it have a long half-life, does it escape metabolism by the liver?
Intellectual properties — it turns out to be really expensive to bring a molecule out of an academic lab and into humans. You know what I’ve learned so far in science is that discovering drugs is pretty cheap and easy; developing drugs is very expensive and very hard. And there are no grants for this type of work. There is no grant to take a molecule out of my lab and make it into pills or injectable vials, and then carry it into the clinic. And so we need to be more creative to find partners, people who are as expert at developing drugs as a lab like mine is at discovering drugs. And the very best people in this type of work, believe it or not, are not in academia, they’re drug companies.
And so we did two things at this point that I would love to tell you more about.
The first thing is that we’re not a drug company and so we have this one thing that we have an easier time doing than drug companies do because they’re well-resourced and they do such exceptional science, and that is share. This is ordinarily the time in drug discovery where you go quiet, where you know you have something really cool or maybe really cool and you don’t want competition and maybe you file a patent or something, maybe you keep it a secret until you have the drug of interest. And we’re not a drug company. Dana-Farber is a charity and our lab really believes in an open-source philosophy.
The availability and access to computer code has just transformed the information technology in software arena but drug discovery is famously very secretive. And so we got to wondering what if we did a social experiment? What if we were to take this transformative strategy from computer science open-source and apply it to the most secretive science in the history of the world — drug discovery.
And Jun and the lab were excited about this idea. And so we synthesized 100 grams of the JQ1 molecule and we said we would make it freely available to any scientist worldwide and provide them with the molecule immediately and for free and without restriction on the quantity. Meaning that if they wanted to do an animal experiment if they were studying psychiatric disease and the only good experiment was in a mouse, then we’ll give them a gram if that’s what they would want, and then it would be free and immediately available.
And you might think if you’re not a scientist, like my older sister is a philosopher, she’ asks “Well, isn’t that how it is? Isn’t that how science is? Don’t you always get your science in the hands of other people?” And the truth is, in chemistry, it’s just really hard to get drug molecules for open and unrestricted study. They are governed by very restrictive material transfer agreements. So we thought we would experiment with this open-source strategy.
And it’s with this strategy that we were able to get the molecule in the hands of Leif Bergsagel and that he was able to test it. And that drug companies were able to get the compound and validate this science and show that not only does it work in myeloma, it works in lymphoma as well. It’s how we were able to get the drug to Cold Spring Harbor Laboratories, to Chris Vakoc and Scott Lowe, and they were able to say, “Well, gosh. This drug works really well in acute leukemia”, something we’ve been studying in our lab as well.
Through this strategy, we learned that the drug might work to reactivate HIV, something that you wouldn’t think is a good idea, but it turns out the drugs are really effective in HIV but the virus is hiding and that this drug, much to our surprise, teases the virus out of hiding. We even learned that the molecule behaved as, of all things, a male birth control pill but that’s for another time.
Back to myeloma. So the open-source strategy, which grew out of my lab, was able to point new directions where people with bromodomain drug molecules might take the molecules to benefit humans. And this research activity, I believe, telescoped what might have been 20 years of research down to a one-to two-year period where there was just an explosion in publications, and I guess for lack of a better word, just knowledge about the potential of BRD4 inhibition.
But we learned early on through our work with Constantine of the promise in myeloma how to get a drug version of JQ1 to myeloma patients. And so Jun Qi, in the lab, and I worked to develop a drug-like version of JQ1, something that had the drug-like properties and I suppose the intellectual properties needed to recruit the commitment, expertise, investment, and organization of this biopharmaceutical world around the idea and opportunity to bring this Myc-directed therapy to patients with myeloma.
And it took about two years but we made a molecule called TEN-010 that is about maybe ten times maybe more potent than JQ1. It lasts about ten times longer in the blood stream than JQ1 and maybe that’s how it got its name. Ten, ten, ten, ten, ten..
But we’re not a drug company here and so we tried to find collaborators, experts, in drug development who could help us. And we teamed up with two guys, Doug Onsi, a business person, and Steve Landau, just the most brilliant drug developer I know who could take this drug into humans. And over about 18 months, they did. And now this technology, this molecule sits at a company called Tensha Therapeutics that Dana-Farber and I and these two fellows started to try to bring this molecule to patients.
The update there is that about, I suppose six or eight months ago, the molecule was first used in phase 1 clinical trials to establish the dose that’s safe in humans. It’s not a foregone conclusion that a new drug will be tolerated by humans and I believe two or three phase 1 clinical trials will be performed with this molecule in both solid and liquid tumors.
Now this is all their story to tell, but a myeloma study is planned and I’d encourage you to talk, if you’re interested, to Steve Landau and Doug Onsi at Tensha Therapeutics more about this program. It wouldn’t be right for me as an inventor of this molecule to also be the prescriber of this molecule and I now sit on the sidelines cheering and hoping that this can work in just the only relevant experiment in myeloma and that is the care of patients with myeloma.
Jenny: Well, I think it is completely amazing and I love how you used the open-source strategy. So did you get a lot of takers when you did that? I would hope so.
Dr. Bradner: Yeah, we did. We’re just writing a story about this and the only restriction on the drug is you can’t eat it. We got a lot of emails, very moving emails from people in tough situations who felt like they’re running out of options, who read the paper, and who wanted to try even the prototype drug JQ1. And it’s heartbreaking because this isn’t a drug molecule. There are steps needed to bring a technology like this to the bedside and by the way, it is still very uncertain whether this can work in humans as well as it does in Leif’s mice.
We got a lot of interest from the community. To date, Jun is now on the third 100 gram synthesis of this drug and every week we mail out samples to researchers around the world and I think more than 400 labs now have received the sample of JQ1 for study in just a broad number of disease areas and biological questions to understand Myc and other master regulators in more detail. I have lost count of how many publications now feature the JQ1 molecule but for us it’s been really exciting because you hope as a chemist that people will be fascinated by your molecule and if you get a couple of emails even that someone is willing to test it in this that or the other thing, it’s very exciting. And to hear 400 labs become interested in the drug has, for Jun, been I think the experience of a lifetime.
Jenny: Oh, absolutely! And it seems that this is a model that the founder of carfilzomib (Craig Crews) used when I interviewed him very early on in the series. And he mentioned this valley of death that happens between you as a researcher coming up with the solution and this new molecule and then actually getting it to the point where a drug company can develop it with drug companies sometimes not wanting to take a lot of risk, but it is possible to cross that valley of death to get it over. So congratulations to you for starting this process.
Dr. Bradner: Well, I appreciate your congratulations but I want to be the first to say and I want you to hear me loud and clear. We have done nothing. This is just now getting to the point where we can learn if this science can help people. I’m not being modest, this is the God-honest truth that we live in an era where it’s possible with science to have a measurable impact on patients, on a disease, and working in this environment in Dana-Farber around guys like Ken Anderson and Rich Stone, Dan DeAngelo, my heroes, who have brought science to bear on a problem in the clinic.
With all respect, Jenny, and I know it comes from a good place, it’s just too early for congratulations. But with that said, yes, I think that academic centers can play more of a role and are playing more of a role in addressing the shortcoming of modern therapeutics. We ought to not behave like drug companies and get ahead of ourselves but if there is a group or a department with a real area of expertise like my colleague, Nathanael Gray here, the world leader on the study of kinases. He’s been doing nothing but kinases for 15 years and the level of sophistication and creativity that he brings to bare on this pathway now is really something to watch. And his science helps address this gap that exists between basic fundamental knowledge of cancer and our ability to act on that information. So hopefully, from our lab, more stories like this will arise.
We’re not a drug company, we’re not trying to act like one and I don’t even call what we do in my lab “drug discovery”. We like to think that if we study a pathway with chemistry and if we make molecules that can answer questions about pathways in the cell and if we share openly and effectively with colleagues who deeply understand disease, that connections will be made of therapeutic relevance and that drugs will then emanate from these efforts.
And sure enough, over the first six years of the lab, three times now, therapeutics have transitioned into the clinic. We have, you might know, another molecule in phase 2 for myeloma now at a company called Acetylon, inhibitor of HDAC6 that’s being studied in combination with both proteasome-inhibitors and separately with IMIDs.
So like Craig Crews, the founder of Proteolix, I do think that there is a big opportunity for pathway biologists to catalyze the development of breakthrough therapeutics.
Jenny: Well, it seems like creating this transitional infrastructure, I guess you could say, like he did with Proteolix, is effective. It worked for him.
Dr. Bradner: Oh, yes, for sure. Proteolix is an amazing story.
In the case of Proteolix and the carfilzomib molecule, an inhibitor of the proteasome, it was guided of course by the development of bortezomib, the first proteasome-inhibitor in the clinic and that was guided by a drug called MG132. This was a chemical tool like JQ1 that was available for scientists to study the principal garbage disposal system of the cell. And Ken Anderson and the other colleagues in the myeloma area use these tools to establish that the proteasome was a great target for myeloma cells.
So carfilzomib owes a debt of gratitude to bortezomib, which owes a debt of gratitude to these chemical tools that help to guide drug discovery. And so I’m a big believer, as you can tell, in open-access to chemical tools because it helps clinical scientists learn how to deploy these powerful targeted new therapeutic weapons.
Jenny: Well, it seems the greatest advantage is speed when you talk about the open access.
Dr. Bradner: It is. And you know, I’m still doctoring and this week, I’m on the stem cell transplant service at Brigham and Women’s Hospital and it’s very orienting these weeks on the wards with patients in impossible situations.
There’s an aspect of speed that is scientific strategy. How can we move our science as a field as far as fast as possible but this time with patients is so orienting because you realize how vital time really is. And it’s frustrating to me that drug development moves so slowly relative to the urgency of need in the clinic. And I know that my colleagues in clinical drug development are working as hard as we are in drug discovery to identify efficiencies of pace and how breakthrough drugs can be accessed more easily.
I regret I’m not an expert in that area but time is our enemy and we must be as creative with our scientific strategies as we are with our science.
Jenny: Well, I love what you’re doing. Thank you for trying something new and seeing where it will take you.
I have a backup question, if you don’t mind, on the HDAC inhibitors.
Dr. Bradner: Sure.
Jenny: I saw that you are doing work with the ACY-1215 and wondered if it relates to Myc or if it’s completely separate.
Dr. Bradner: Well, it’s a little bit of both, as it turns out.
So ACY-1215 is an investigational drug molecule that targets a histone deacetylase. Now interestingly, HDAC — which is what it’s short for — are a group of enzymes that remove the post-it notes. They erase the mark, this acetyl mark, they pull it off.
And so one way of thinking in our field is if you remove the mark, maybe Myc forgets what to do, right? I mean, if here we’re making the reader of the mark blind with JQ1, what if you remove the mark? That would mean inhibiting the hat, the acetyltransferase.
Another way to go might be what if you block the removal of the mark? You know what happens? The mark starts showing up all over the place. You lose control of the mark and the cell gets confused, like a smokescreen, and some cancer cells will die if the mark starts to appear in an unregulated way.
And so we’re kind of excited, as you can tell, easily, but we’re excited about anything related to these acetylation marks, anything related to these epigenetic marks, we think that there needs to be a molecule for that. And so HDACs, the enzymes that remove the marks, turn out to be very druggable. And so my lab remains active in trying to make a chemical toolbox for the study of the 18 enzymes that remove these marks — 18 and counting.
And early on, when I was at The Broad Institute and training in Harvard Chemistry with Stuart Schreiber, we teamed up with Ken Anderson to make first inhibitors of an HDAC called HDAC6. And I won’t bore you with the details but the theory is that HDAC6 is involved in the handling of proteins. And as you know, myeloma cells make more protein than they can stand and it spills over into the blood and that’s often how we measure the burden of disease in myeloma. And so drugs like the proteasome-inhibitors that gum up the protein-handling system are active in myeloma, uniquely active in myeloma. Could inhibition of HDAC6 work the same way?
And so, with Stuart Schreiber, in chemistry, I developed and importantly one of my very best friend since science, Ralph Mazitschek, a brilliant synthetic chemist now at MGH but we shared an office at The Broad. We developed prototype inhibitors of HDAC6 and then Ken Anderson tested these compounds with Teru Hideshima in his lab and lo and behold, they were highly-synergistic with proteasome inhibitors like bortezomib and carfilzomib.
And so what’s interesting is that these drugs do not do anything by themselves. They don’t do anything to myeloma cells when used alone. They turn out to be great partners for other drugs.
So Jenny, here’s something really interesting – we always use cancer drugs in myeloma most effectively in combination yet nobody makes drugs that only work in combination. I mean by-and-large, companies want to make drugs that work on their own, they can stand on their own two feet, that they can sell without having to worry about some other drug. That means we’re missing a whole class of drugs — synergizers, facilitators, drugs that would work when combined.
And so we thought that’s a good academic project. So Ralph and Stuart and Ken and Teru and I teamed up to try to make drugs in the HDAC class that would be, well, great partners for other drugs like thalidomide, Revlimid, or like bortezomib, carfilzomib.
In any event, Ken and Teru’s studies show that these HDAC6 inhibitors were great partners. But by the way, HDAC3 inhibitors were good partners, too. And so we took this toolbox of HDAC inhibitors and said to Ken, “It doesn’t really matter to us what the winner is, just what’s the winner?” And it was a compound called 161.
161 was a lot like JQ1. It wasn’t a drug, it was a tool, but when we put in the mice, the mice did great. And so we got excited about making a drug-like version of 161 so we teamed up with a real expert named John van Duzer to make a drug version of 161 and that drug is called ACY-1215. And like Tensha, that technology sits in its own company called Acetylon. And in a collaboration with Celgene, that drug is now being tested in a large number of clinical trials at the company, Acetylon.
Now I should tell you, these molecules are like children of mine off to college. We have everything invested in this technology. The idea, the molecules are molecules that I co-invented with these friends. Dana-Farber, my lab and myself, have stock in these companies and I want to explain to you the conflict of interest that exist there. But the experiment that we establish whether or not these molecules matter at all will be performed by other people and is being performed with our patients and leaders in the myeloma field.
So the HDAC work connects to Myc. It wasn’t the rationale for using those drugs but I think Myc needs HDACs, too, like collaborators for Myc. And we should learn in the next year to two years, how bromodomain inhibitors work in myeloma alone or in combination and how HDAC inhibitors work alone or in combination. And it would be great and exciting from a science standpoint if it were the drugs from my lab that carry the day but Jenny, we deeply don’t care. We just want the answer. Can these two classes of drugs help patients with myeloma?
Jenny: So my final question will be, because it’s such exciting work, is what are your next steps and how can we help you? And then I’ll open up for a couple of caller questions.
Dr. Bradner: Sure.
Well, the next steps for us is, we roll back up our sleeves and get back to work trying to find the next generation of myeloma drugs. We’re very interested in the MMSET protein which is a common and a poor prognosis partner in the 4;14 fusion in myeloma. We need drugs for that target; my guys are really working hard on that. We need to make these direct Myc inhibitors and we’re going to go down swinging. This project is our Higgs boson. This project may run 10, 20 years. It’s not easy to get that funded but it’s a critically-important science project and we’re not trying to own it. We’ll collaborate with anybody that wants to work on that big challenge.
And so if you walk through my lab right now, the lights are on, everybody’s here and they’re trying to drug Myc. They’re trying to drug the Myc partner. They’re trying to drug the MMSET. They’re trying to create the next generation of prototypes from which the pros in the pharmaceutical industry can make the next generation of breakthrough therapeutics.
How can you guys help? It’s a team effort and my lab and I are genuinely honored by your interest. I get these emails from people that are so uplifting and we put them right up on the bulletin board to make sure these young chemists and biochemists, who aren’t doctors and don’t spend time with patients, know how much this community supports their science. So thank you for that. It means quite a lot to us.
And if you walk with the Dana-Farber or bike in the PMC or jog with the MMRF or in the team-in-training or Light The Night with the Leukemia & Lymphoma Society, one thing is true is that this country and this Boston community in particular, does so much to help support science that, ours and others, it matters quite a lot. This philanthropic support and the foundation support that we get for these ambitious high-risk, high-reward projects is just our most vital source of support. So for all the listeners to this program do to support blood cancer research, let me say thanks.
Jenny: Well, we so appreciate what you’re doing, so I think that’s the minimum that we can do.
I’d like to open it up for our caller questions so if you have a question for Dr. Bradner, you can call 347-637-2631.
Caller: Hi, Dr. Bradner. Thank you so much for thinking out of the box. I’m a smoldering patient. My name is [Caller] and I truly, just sitting here listening, try to capture a great deal of it, most of it was very well-explained, and I thank you for breaking it down into terms where the layperson and a lay-patient could really try to follow along so thank you for that.
I have a few questions. I understand that the Myc gene activation can occur through chromosome translocations but it can also be deregulated through amplification. Could you take a minute to explain the difference between a translocation cause or an amplification cause? I know they are two different situations, am I correct?
Dr. Bradner: That is a really sophisticated question.
Caller: Oh, is it? Oh, no!
Dr. Bradner: It is and I’m happy to answer it and no, I’m thankful for it. I’m going to give you the scientific answer first.
Dr. Bradner: They’re the same. The scientific answer is that translocation and amplification are basically the same biological event. DNA is broken and it gets stitched back together. Now let me tell you the differences as regards to Myc because you asked about Myc.
Myc needs to get turned on, it needs to be activated and one way is it gets hooked up to a way bigger switch than it ever needed. Normally, Myc has this little dimmer switch next to it that gives you just the amount of Myc you need. But when a translocation happens and the Myc chromosome breaks and it reconnects to another chromosome like the antibody chromosome that has a huge switch on it, you start making way more Myc than you ever wanted. So a Myc translocation can happen where Myc hooks up to a new chromosome.
In amplification, all happens on the Myc chromosome where all of a sudden, because of breakage and rejoining events, the number of Myc genes next to each other is 2 or 3 or 8 or 20. So what you get or you get 20 copies of the gene where you used to only have one.
Caller: But it doesn’t actually break off and find another partner?
Dr. Bradner: Well, it does break. That’s what I was trying to explain is that it breaks but then it reconnects right next door on the same chromosome.
Caller: Oh, okay.
Dr. Bradner: There’s a scientist here at Harvard called Fred Alt, Frederick Alt. we just wrote a paper together on this phenomenon that he’s been studying his whole career in B-cells that talks about the way that chromosomes break and rejoin. And it turns out that amplifications and translocations, especially in B-cells use the same machinery but if the gene hooks up to a new chromosome, we call it a translocation. If the gene hooks up to the same chromosome with now a new copy of that gene right next to it, it’s called an amplification.
Caller: Okay. And typically, which translocation occurs in multiple myelomas? Is it the 8;14?
Dr. Bradner: Well, myeloma features a whole bunch of different translocations. The Kuehl lab will tell you just the whole list of them. Translocations of chromosomes 13 in myeloma are quite common as are translocations of Myc but there’s just a goodly number of myeloma translocations, too long a list to even enumerate.
Caller: Oh, no, right. I know the common ones. The 11;14, 4;14, et cetera, et cetera. But I wasn’t aware which chromosome is the c-Myc gene found on?
Dr. Bradner: Well, it depends if we’re talking about mice or in humans. Chromosome 8 is the location of the Myc oncogene in human cells.
Caller: Okay, okay. Because that’s not a routinely-tested for translocation on FISH panels, from what I’ve gathered because I know I’ve never had it.
Dr. Bradner: It would depend on the lab that’s trying to do that.
So Myc is on what’s called the long arm of chromosome 8 and it commonly is translocated into the immunoglobulin heavy chain locus. In fact, the human immunoglobulin locus has a number of partners that it can go to, Myc just being one of them. In myelomas you’ll find Cyclin D1 on chromosome 11, MAF on chromosome 20, FGFR3 and MMSET translocations occur short arm on chromosome 4. I mean there’s a bunch of them, there’s just a bunch of them.
Caller: Right. The reason why I ask is when Jenny interviewed Dr. Kuehl, I had given him a little bit of information about my own biology and he was the one that brought up and planted the seed of the c-Myc gene possibly in my case.
Again, I’m smoldering, I have to really establish where I’m at. I haven’t had a bone marrow biopsy in two years so I think it’s time for that. But for me and my case, I’m actually Cyclin D1-positive in my bone marrow through immunohistochemistry on a core biopsy sample but my FISH panel was actually negative for 11;14. So I understand that in theory, I should have that translocation in 11;14.
But I also had a plasma cell labeling index performed on those cells and using that technique, the result was zero. So I didn’t have any turnover for proliferation, I guess, of the cells but the pathologist who did it said, “Well, your cells are expressing Cyclin D1 like crazy” and he was actually very surprised that FISH did not pick up the 11;14.
So I was wondering, could I have a Myc translocation that they didn’t discover or an amplification that could possibly be behind the Cyclin D1 deregulation?
Dr. Bradner: Well, it’s easiest to answer your question in the broadest sense, not as much about your disease, which will be impossible to do by telephone.
What I can tell you is that from what it sounds like, you’ve had all the appropriate clinical testing. With that said, modern genetic testing five years from now will probably look very different. We are, only in the last five years, able to completely sequence the whole human and thus cancer genome with the efficiency needed to look at a patient’s genome. And our current technologies are only so good for capturing translocations. They’re great for point mutations; they’re just okay for translocations.
So my instinct is that in the fullness of time when cancer genome sequence — and this, by the way could be ten years from now — but my instinct is that in the fullness of time, cancer genome sequencing will capture amplification, translocation, point mutation, alteration, and coding genes alterations and noncoding genes but at the current moment, the gap between the measurements that you’re asking about, alterations and amplifications and translocations of Myc are specialized studies that are often not necessary in the smoldering myeloma circumstance.
Caller: Okay. Okay, great.
Dr. Bradner: But about Cyclin D1, you can get a gene very highly-expressed through translocation, through amplification, or by just direct gene expression. We’ve been studying genes in my lab now that are highly-activated by things we call super-enhancers. It just sounds so crazy. It’s — interestingly enough — often not a genetic event. It’s an epigenetic event that we have been studying with Rick Young at the Whitehead Institute, a leader in gene regulation biology. And some genes will make a lot of a protein just because there’s a huge switch next to it. And it didn’t move there through a genetic event, it was built by the cell’s program, or a gene regulatory program.
So this is my way of saying there’s any number of ways of having a lot of Cyclin D1.
Caller: Okay. Is c-Myc typically a secondary event in myeloma or could it be also primary?
Dr. Bradner: I’d be shocked if Myc wasn’t involved even in the earliest pathogenesis of myeloma the disease. But it is true from the Bergsagel and Kuehl labs that as the disease progresses and especially after lines of therapy, rearrangements, activation, and the abundance of Myc only grows so I think it’s probably involved in initiation and progression.
Caller: Well, I thank you for enlightening me and educating me. It’s really been such a pleasure listening to the show today. And again, thank you for all you do and for your staff that are so passionate about it.
Dr. Bradner: Oh, thank you. This has been a fantastic experience.
Caller: Thank you again.
Jenny: Thank you, Dana.
We have one final caller so please go ahead and ask your question.
Caller: Hey, Jenny and Dr. Bradner. Thanks for taking the call.
Dr. Bradner: Sure.
Caller: So Dr. Bradner, I think you’re modest in your response when you say nothing to congratulate me on yet. But I think the congratulations that Jenny was talking about is appropriate, not for the success you’ve had in the lab, but for the open and collaborative approach you’re taking. I thank you for hitting the accelerator on getting research into the field and getting faster, independent validation. I think that’s where the collaboration and your open-mindedness in your approach is actually well-deserved.
Dr. Bradner: Well, I appreciate it. It has to kind of make you sad in a way that an open strategy to science could be, even by your comments, celebrated.
I mean more and more in this field… I start to think of science with a service mindset. In the clinic, you’re providing a service, a perspective, a recommendation, a type of training that help people make better decisions. Science isn’t all that different. The folks in my lab have a specialized training set that really on its own is not that unique but together is very powerful that interdisciplinary or team science that there are labs like — many of the labs by the way are capable of — and they want to have an impact.
I’ll tell you something. When I was training as a scientist over the last 20 years, it was a different era. You think about what are you going to be known for, or what is your big discovery, or what would your Nobel Prize say? Ridiculous!
The current young scientists with — and I’m not being just light about this — Facebook and Twitter and Tinder and all these other problems they shouldn’t probably be doing while they’re at work, they want to be connected to people. They don’t understand waiting. They don’t understand getting up and changing the television channel. Science for them needs to be as immediate, as social, as connected, I think, as everything else in their lives.
And so what seemed like a new idea for me and for Jun when we started discussing it with the group, was immediately accepted by them because they thought it was awesome that they could, in their position as young scientists, connect to Harold Varmus, a Nobel Prize winner at the NIH, that they might share an email with him would be exciting for them.
So on the one hand, I really appreciate what you’re saying because it felt innovative at the time that we started doing it but I think this next generation of science will just be culturally influenced in the most positive way by the move of this young generation of scientists in their daily lives to a highly-collaborative, spirited, efficient, impatient way of life and it would be great for patients.
Caller: mPatient is the name of the radio show, it’s mPatient and that’s really probably the main focus and core for Jenny is doing is to hit the accelerator. So this has been a very appropriate show.
I think the misalignment of incentives has thwarted much of the progress that could have been made today. And I just want to highlight this moment and say thank you and it hasn’t gone unnoticed.
Dr. Bradner: I really appreciate it.
Caller: I only wish I was a mouse, maybe then I could get faster access to healthcare.
Dr. Bradner: That sounds like a bumper sticker I’d put on the car.
Caller: Okay. So my last comment is what else can I do as a patient to accelerate healthcare and have delivery of these opportunities? So let’s talk specifics about something maybe we could help out with.
And one of the things we can do as patients is funding. So if you want a strange collaboration with the patients to another level, could we do crowdsourcing or funding for these initiatives? I mean we can’t spend the money when we’re gone so maybe we can spend it in advance and put money towards projects that have promise but that may be underfunded and chief financing so they accelerate it. So if that’s something that can be helpful, then we’re raising our hands saying where do we donate? We have donated to the different organizations, to the Moore Foundation. We donated to MMRF, we donated to the one on the East Coast, Suzy’s organization —
Caller: IMF, yes. But in terms of just really, I guess this valley of death that Jenny talked about, what can we do to help fill that valley of death with promising targets and what else is out there?
Dr. Bradner: So that’s also a really generous question. I’ll say this.
I had a chance to watch the MMRF very closely and being on the Board of Directors now of the Leukemia & Lymphoma Society and the American Society of Hematology, to watch all three of these charitable organizations very, very closely and I can tell you without any hesitation that the job that they do to steward the allocation of these precious resources from philanthropic activities like you’re describing is beyond reproach. They are experts; they care deeply about the mission, all three organizations that are just the three I’m most familiar with, by the way, there are surely others. They are putting the money to use in the most efficient and explosive, ambitious way possible. They are responsible stewards of that investment.
With that said, I think it’s also quite an experience if you have occasion to connect with an idea, a scientist, a lab, a group of scientists and institution, to join forces beyond the checkbook. I think that there are opportunities. I have a member of my lab, I consider him — I got an email from a fellow who said, “My dad is sick with cancer. I commute every day to my high-powered computer science job. I love your idea of open source. I’m not going to move, I don’t know anything about cancer biology, but I am a whiz with a computer. What can I do to help?” And we put him right to work.
Our computer software that we write is good. It’s not Google-good, it’s not Oracle-good, and this fellow takes this software and turns it into something so special and he’s doing it on the train commuting in every day. It is openness in science taken to the next level.
Now on that case, that’s a family member of a patient but it has been a powerful experience for us both. I know that here at Dana-Farber, we have a group of visiting committee of people whose lives has been affected or businesses or they themselves are suffering from myeloma and all of its various stages. And I’ve no doubt they make contributions to the organization or individual labs here but they assemble at least once, if not twice, a year and the scientists and me among them, present to them our update, assurances that we have our foot on the accelerator firmly depressed.
So these organizations are wonderful if not the best way of putting the vital community resource of philanthropic giving to work in the most effective way possible. But if there is a lab or an idea that really resonates with you either philanthropically or personally, I think there are ways to connect to it that are very special life experiences.
Caller: Thank you for being open to that. That’s fun that you were creative enough to just accept the guy who wanted to code for you on the way to work. But it’s that spirit of “Well, Let’s try it, what the heck.”
Dr. Bradner: Unbelievable and it cracks me up because we can never afford him.
Caller: Thanks for taking the call.
Dr. Bradner: You bet. Thank you.
Jenny: Dr. Bradner, thank you so much for joining us today. It has been completely enlightening and very inspiring and encouraging. It’s work like yours that will continue to drive really exciting discoveries in myeloma. We’re so thankful you’re working on these targets and we look forward to your updates.
Dr. Bradner: Absolutely. And I mean it when I said this is a really unique experience. I’ve never been on an internet radio program before, never had the chance to connect with this community in this way. Anyway, I hope I left you with the clear message that we’re working just as hard as we can to eradicate this horrible disease.
Jenny: Well, thank you so much for all you’re doing. It was so helpful and so well-explained.
Dr. Bradner: All right. Well, thank you, Jenny.
Jenny: Thank you for listening to another episode of innovation myeloma. Join us for our next mPatient radio interview as we learn more about how we, as patients, can help drive to a cure for myeloma by joining clinical trials.