JQ1, the Bradner-Harvard team molecule…

October 27 2011 post (oldest post first). A team of Harvard researchers led by Jay Bradner has discovered a molecule, JQ1, that makes cancer cells become NORMAL cells. And this, my friends and family, INCLUDES MULTIPLE MYELOMA CELLS. Thus far the molecule has been tested in mice (wait until you see this with your own eyes), but human clinical trials are planned (I tried looking for this molecule on the Clinical Trial website, but I couldn’t find it…I will search some more when I get home from work tomorrow).

Here’s the link to one of the most promising things I’ve heard/read about since I began my journey with myeloma: http://goo.gl/CQiYk

May the information no longer be a secret! Open source FOREVER!!! Thank you, Jay!!!!!!

UPDATE: A friend in the UK notified me just a little while ago (it’s 8:30 PM in Italy now) that the link didn’t work for him. I tried to access the video in different ways, even looking up Jay Bradner on the TED website, but no, nothing worked. I get taken to a “Page Not Found” on the TED website. I hope the problem is only temporary (perhaps too many people linked to the video, and the system crashed?)…Anyway, it is a problem on their end. Bummer! Has anyone else had the same trouble? Well, it’s getting late here in Florence…I have to get off the computer now. Hope it’s up and in proper working order by the time I get up tomorrow morning, before I take off for work. Anyway, I’m on this story like a dog with a steak bone. So exciting…And yes, I’ve already written to Dr. Bradner… :)

UPDATE OF THE UPDATE!!! Okay, thanks to Mary, you can view it here: http://goo.gl/p3Qem Until TED gets it up again, this will have to do…

October 29 2011 post. As I mentioned yesterday, my feet are back on the ground. It has taken me almost two days (well, let’s see, yesterday afternoon, after I got home from work and before I went out; then, this morning/part of this afternoon) to go through the full myeloma-JQ1 study, which was published in the September 16 2011 issue of “Cell.” See http://goo.gl/llsuY

To be honest, the title alone almost made me want to crawl under my covers and take a verrrry long nap: “BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc.” Mamma mia! But really, it’s not that bad. Especially since I’m going to (try to) boil down all this scientific jargon into something more comprehensible…turning it into into a sort of silly action movie :) …So sit back and relax. This is going to take some time…but in the end, I think/hope you will agree that you didn’t waste your time…

Let’s introduce Margaret’s, er, “movie” script:

  1. The treatment target is called MYC, = one of the padrinos of myeloma progression who keeps instructing the dumbbell myeloma cells surrounding him to grow and divide and go about doing their evil deeds…
  2. Our superhero is instead called JQ1, a bromodomain inhibitor.

Hmmm, now for a quick digression. Bromodomain. What’s that? For the scientifically-inclined, bromodomains are protein domains that bind and recognize histone acetylation. Yeah, I know, I know. My sentiments, exactly. Let’s see if we can get through the study without getting into all that…skip skip skip.

Oh, quick aside: I’d like to point out that curcumin also inhibits MYC. Yup.

Now let’s continue with the crazy idea, which, however, helped me visualize what might be going on here, more or less:

  1. Okay, we’ve established (see above list) that JQ1 is the good guy who wants to stop MYC, the bad guy.
  2. But, oh no!, JQ1 can’t shoot the padrino directly. Why not?
  3. Because MYC is one of those slippery and slithery evil characters…incredibly efficient at dodging JQ1’s hits. And he has a lot of bodyguards, too.
  4. No problem. Our superhero is always a step ahead. So he decides instead to identify and hit some members of MYC’s family = the so-called BET bromodomains…
  5. But JQ1, who’s a really smart (and caring) superhero, doesn’t just want to step inside MYC’s headquarters and waste his bullets by shooting at everything that moves. Besides, he reasons, there might be some folks in there who don’t have anything to do with MM progression (in fact, there are: BRD2 and BRD3, e.g.)…
  6. So he does his research and manages to single out one BET family member in particular…one of MYC’s most aberrant cousins who happens to be part of the NUTty branch of the family (actually, I’m not kidding, there really is a NUT branch…).
  7. The aberrant cousin’s name is BRD4. He gets into all sorts of scrapes. But, most importantly, he’s very close to MYC.
  8. Question: by shooting down the aberrant cousin, will JQ1 be able to stop MYC?
  9. We’ll reach that part of the story later…But I think you can already figure out what happens… :)

We get the first mention of multiple myeloma in the abstract: In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc. This simply means that JQ1, this fabulous new molecule, works against myeloma. In three different mouse experiments, to boot!

Now for the full study (many thanks to…well, you all know who you are!), and here we’re going to get a bit technical, sorry: c-Myc is a protein that regulates cell proliferation. In cancers such as myeloma, c-Myc becomes a huge problem. Basically, this protein gets all hyperactive and buzzy, going completely wacky and helping cancer/MM cells survive…with very bad consequences. This gene has therefore become a big target in myeloma treatment.

Food for thought: when c-Myc becomes “inactivated,” even if that occurs only temporarily, tumors shrink. Bingo.

Problem is, as I mentioned, inhibiting this gene directly isn’t that simple. And so this group of Harvard researchers chose to use their new discovery, the fabulous “Post-it-eliminating” molecule (remember that part of the video? Loved it…) called JQ1 to target BET bromodomains to inhibit c-Myc-dependent transcription.

You hit something that’s really close to what you really intend to hit, more simply put. Makes sense.

Check out this direct quote: Multiple myeloma (MM) represents an ideal model system for these mechanistic and translational questions, given the known role of MYC in disease pathophysiology. My goodness! For once, I’m almost thankful to have a cancer that turns out to be IDEAL for research of this quality and promise. I mean, if you have to have cancer, it might as well be an IDEAL sort, no? ;)

A bit further on we can read that the Rearrangement or translocation of MYC are among the most common somatic events in early- and late-stage MM. EARLY STAGE? Bloody ‘ell! But I’m not surprised…

And another thing: The MYC pathway turns out to be hyperbonkerscrazy in more than 60% of patient-derived myeloma cells. Yikes.

The “Results” part mentions MGUS and SMM patients specifically. This is important, so I’ll provide the full quote, hoping not to get into any trouble: Among asymptomatic patients with premalignant disease, we observed increasing expression of BRD4 in monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) compared to normal bone marrow plasma cells. In a second, independent data set, we observed significantly higher expression of BRD4 in plasma cell leukemia (PCL) compared to MM or MGUS samples. Thus, BRD4 expression correlates positively with disease progression. I don’t think I need to comment on this paragraph…except to underline the fact that the evil cousin BRD4 is involved in progression to active myeloma.  8-O

Okay, so BRD4 is like the Voldemort of the BET bromodomain family. His hyperactivity can lead to PROGRESSION…not good!

But holy cats he’s even worse than we thought. Based on tests carried out in the Harvard lab, the nutty cousin was found also to be in tight cahoots with the bone marrow stromal cells or BMSCs (= which provide a very friendly environment for myeloma cells…). No question…the cousin must be stopped…

As you know, I read the entire study. I read exactly how the Harvard researchers identified and hit their target, proving their hypothesis–that, by stopping the cousin in his tracks, they’d block the padrino. I’ll spare you the gory, impossible-to-comprehend details, though. By the time I reached the last few words in the Discussion section, I felt as though I’d just finished reading Proust in ancient Finnish…

But we still have a few things to discuss before calling it a day…We haven’t even reached the part about the mice…Let’s keep going…

Interestingly, while certainly having an effect on the nutty cousin, our superhero JQ1 did not have asignificant effect on the traditional pathways that are also targets in MM treatment: NF-kappaB, STAT3 and so on. Hmmm. Don’t know what to make of that, but anyway, let’s keep reading.

The researchers then treated human MM cells with JQ1. And they sat back to observe the consequence of JQ1 treatment on the expression of 230 cancer-related genes in a human MM cell line.

Wait a sec. Did they write 230 GENES??????? Was that a typo? No, it wasn’t! EEEEKKKK!!!!!!

This is what they found: Surprisingly, we observed immediate, progressive, and profound downregulation of MYC transcription itself, a unique finding among all transcripts studied (p < 0.05). Our superhero, in other words, carried out his job perfectly. By hitting the BET family, BRD4 in particular, he hit the evil myeloma-friendly MYC, too…

Important: MM cell proliferation was uniformly inhibited by JQ1 and that included myeloma lines resistant to Dexamethasone and melphalan. Another crucial bit of information is that JQ1 did NOT have the same toxic effect on normal blood cells. Super.

And now we get to the in vivo part of the study: Tumor-bearing mice were treated with JQ1 administered by intraperitoneal injection (50 mg/kg daily) or vehicle control. JQ1 treatment significantly decreased the burden of disease measured by serial, whole-body, noninvasive bioluminescence imaging. SIGNIFICANTLY. By now you must have seen those mice images in the TED Talk video…

The mice treated with JQ1 lived a lot longer than the untreated ones. At the time of writing, two mice with established disease and measurable M-protein have completed 14 days of JQ1 treatment (25 mg/kg daily, adjusted to tolerability). The second mouse was even in complete remission. Now, remember, we’re talking mice with heaps of lesions all over their poor little skeletons. And the poor little critters responded to this molecule…

Now for the Discussion, which begins with this statement: Despite the centrality of Myc in the pathogenesis of cancer, conventional approaches toward direct Myc inhibition have not proven successful. Eh.

And, further on: An unexpected finding was the pronounced and concordant suppression of multiple E2F-dependent transcriptional signatures. (My own note: curcumin also affects E2F…)

And another thing: BRD4 is an evil cousin also in acute myeloid leukemia. So it seems to me as though JQ1 might well have a glorious future…as a superhero defeater of all sorts of blood cancers…Fingers tightly crossed!

In this study/action movie, all ends well…

As for real life…

What can WE do to help? Blog readers have been excitedly sending me all sorts of links and thoughts and ideas. One suggested that a bunch of us go over to Dr. Bradner’s house and cook and clean for him and his family, so he can focus on his research without any distractions. Great idea!  :-)Dr. Bradner, if you are reading this, please let us know how we can help you…

Another reader pointed out that JQ1 probably won’t be in human clinical trials for another couple of years. TWO FULL YEARS??? Bloody hell, I don’t know what the cause of such a delay might be, or if that is the case, in fact…but if anyone can find out, please let me know.

So right now I’m trying to come up with tangible things WE can do to help further Dr. Bradner’s research (by the way, I’ve written to him, but he hasn’t answered, not yet, anyway. I imagine he’s super busy, probably overwhelmed with requests and so on…So I don’t expect a reply. Indeed, I hope he focuses on his research, not on replying to enthusiastic supporters such as myself…).

Off the top of my head:

  1. We can pester our MM foundations, insisting that they do something to hasten the process of getting this BET family inhibitor into Phase 1 and 2 clinical trials AS SOON AS POSSIBLE.
  2. We can bring up Dr. Bradner’s research at ALL the patient-doctor myeloma meetings. Had I known about this when we met with Dr. Kyle…ah, but I didn’t. (Oh that reminds me…still have to go over my meeting notes…)
  3. If you have a blog, write about it.
  4. If you’re on Facebook (Twitter etc.), write about it, making sure you include the link to Dr. Bradner’s extraordinary TED Talk.
  5. We can also get it circulating in all the cancer support groups. Anyone whose cancer is driven by the MYC gene should be more than happy to help.
  6. Money, of course. Goes without saying.
  7. But most of all: LET’S GET THE NEWS OUT!!!

When I first began watching that video two days ago, I’d never have imagined anything this big, potentially. By the way, within a few minutes of my having posted the TED Talk link everywhere I could think of posting it, the Page (where it was located) crashed. No kidding. So Internet can be a powerful tool, and we CAN and SHOULD USE IT! Especially for such a good cause!

November 2 2011 post. I know all about disappointments. I’ve tested on myself quite a few promising, non-toxic substances that showed strong antimyeloma effects both in vitro and in vivo. But they had no effect on me. Or, shiver!, as in the case of BCM-95, they made my MM markers worse…

I am also quite aware of the fact that substances that perform acrobatic cartwheels in a Petri dish or inside a sick mouse may end up tripping and falling flat on their faces when tested in human clinical trials. We’re not cells or mice, after all, are we?

But what I find extraordinary about the JQ1 discovery is the fact that it is really something new. NEW with capital letters. And exciting. As one blog reader wrote to me, “the image of that ‘scanned’ myeloma-free mouse will be imprinted on my retina for quite some time.” On mine, too…

This is not just what I call a “shuffling-cards” combination of third or fourth generation drugs…those derived, I mean, from thalidomide or bortezomib, e.g. If you go to the Clinical Trials website, as I did this morning, you will find heaps of myeloma clinical trials…1426, to be exact…

But let’s have a look at those  numbers for a sec: bortezomib (Velcade) is being tested in 289 of those trials. Its derivative, carfilzomib, in 22 trials. Now for thalidomide: 225…Its derivatives:  lenalidomide 168; pomalidomide 13. Dexamethasone: 311.  Melphalan: 249. And then we have those combination studies, that is, two, three or even four drugs tested together. For example: Dex plus lenalidomide plus doxorubicin or even bortezomib plus melphalan plus Dex PLUS thalidomide…I don’t have the time right now to go through and examine all of these studies and combos…But I recognize that it would be a very interesting exercise…For example, I saw and was reminded of TBL-12, the sea cucumber extract that I reported on some time ago (two trials now, with SMM patients). And there are a few other promising studies there, too…a handful, perhaps…

However, and here we get to my first point, which drug or which combo can really give us cause for excitement? I mean, real, body-quivering excitement? Even more, which clinical trial can really give us hope that a CURE is on the horizon?

I’ll leave it at that… An open question that cannot be answered, really…(But you can imagine what I think…).

Next topic…

I took a few days off to sit back and try to figure out what it was about the JQ1 study that got me so enthusiastic and sobbingly emotional in the first place. Hey, I’m not saying I’m not enthusiastic about this molecule anymore. Hah. Not at all. I still think JQ1 is a fabbbbulous discovery with shiploads of promise and potential. But okay, I have to admit I’m disappointed that it will take a couple of years (!) to get it into a clinical trial setting…And that did dampen my enthusiasm just a wee bit. Not much, though…

But now I would like to discuss what Dr. Bradner said about OPEN ACCESS. Now this is exciting pioneering stuff indeed, and it pushes my enthusiasm levels right back up to the SKY HIGH setting.:)

Let’s take a look at the transcription of the TED Talk. By the way, the joke’s on me: a few days ago, with my flying, typing fingers I transcribed some of the most relevant parts of the TED talk…only to discover, once I’d finished!, that a transcript already exists…online…freely accessible, goes without sayin’. ARGHHHH! :) Well, without further ado, here is the transcription link:http://goo.gl/is3kU

Let’s start with what happened after the Harvard team discovered JQ1’s effect on myeloma and other cancers: So we started to wonder, what would a drug company do at this point? Well they probably would keep this a secret until they turn a prototype drug into an active pharmaceutical substance. And so we did just the opposite. We published a paper that described this finding at the earliest prototype stage. We gave the world the chemical identity of this molecule, typically a secret in our discipline. We told people exactly how to make it. We gave them our email address, suggesting that, if they write us, we’ll send them a free molecule. We basically tried to create the most competitive environment for our lab as possible. And this was, unfortunately, successful.

I repeat: We gave the world the chemical identity of this molecule, typically a secret in our discipline. A secret. A SECRET.

And here let me state the obvious. Drug companies aren’t on our side. I don’t care how nice and warm and friendly and sympathetic their representatives are or how many patient-doctor meetings they organize and finance. That’s fluff. A smoke screen.

Drug companies exist to make a profit. Nothing else. Mind you, theoretically, there isn’t anything wrong with that. After all, these are businesses. And businesses have to make profits. A no-brainer, that one. Unfortunately, though, while they’re busy making profits and possibly/probably being secretive about potentially life-saving discoveries, cancer patients are dying…But that makes me crazy, so let’s keep going…

To be super honest, none of this stuff–secrets and Big Pharma and so on–comes as a surprise to me. But this is the first time I’ve actually heard a researcher, an MD!, come out and say it openly and very matter-of factly…And therein lies the “surprise!” element. For me, at least.

Now, as we know, the Harvard research team mailed their molecule to 70 labs around the world. Probably more, by now. For free. And they received feedback from those labs.

And this is where things get rrrrreally interesting: “…the science that’s coming back from all of these laboratories about the use of this molecule has provided us insights that we might not have had on our own. Leukemia cells treated with this compound turn into normal white blood cells. Mice with multiple myeloma, an incurable malignancy of the bone marrow, respond dramatically to the treatment with this drug.”

(Another thing I really like about this guy is his humility…”insights that we might not have had on our own”…)

And then, wham!, we are hit with can only be seen as a revolutionary approach to medicine and science. In Dr. Bradner’s own words, this was a social experiment, an experiment in what would happen if we were as open and honest at the earliest phase of discovery chemistry research as we could beThis string of letters and numbers and symbols and parentheses that can be texted, I suppose, or Twittered worldwide, is the chemical identity of our pro compound. It’s the information that we most need from pharmaceutical companies, the information on how these early prototype drugs might work. Yet this information is largely a secret. And so we seek really to download from the amazing successes of the computer science industry two principles: that of opensource and that of crowdsourcing to quickly, responsibly accelerate the delivery of targeted therapeutics to patients with cancer.

The “sharing for free” approach. The open access approach. To get stuff streamlined and down to patients more quickly and responsibly…

If a cure for cancer, a cure for myeloma, is to be found, labs all around the world are going to have to share their findings and work together. I’m convinced of that now.

And, mark my words, this will take place only thanks to researchers such as Dr. Bradner, researchers with open minds, or rather, with open access minds!… :)

No more secrets! No more secrets! No more secrets!

P.S. I’ve begun following what the online media is saying about JQ1. You might be interested to read about the research being done at Notre Dame, e.g., on JQ1 and NUT midline carcinoma, the cancer mentioned by Dr. Bradner in his TED talk: http://goo.gl/r6ACG (Please note that Dr. Bradner and Harvard are not mentioned here…Odd, eh?).

And here is a Science Daily report, which I totally missed back in September…better late than never, I guess: http://goo.gl/jvRbu

And perhaps, some day in the future, we will be able to say that we were THE ones to begin the campaign that ultimately led to THE CURE…Okay, so I’m getting a bit carried away…can you blame me? :D

And remember the battle cry: OPEN ACCESS FOREVER!!!

November 9 2011 post: I have subscribed to Harvard Magazine since graduation (let’s see, that would add up to more than, yikes!, a couple of decades ago ;) )…but not to the Harvard Gazette, so that explains why I didn’t read a certain article back in September. Luckily, yesterday an attentive blog reader sent me the link…many thanks, DP!!! Here it is: http://goo.gl/wRLzH

As you listen to the interview with Dr. Bradner, please keep in mind that “Mick” is not the name of his next door neighbour ;) , but rather is the “Myc” gene that I have written about in my JQ1 posts.

A lovely image: JQ1 cuts the cable between “Mick” and the (cancer) growth genes, Dr. Bradner says at one point. Meaning, cancer cells can’t grow anymore. Thumbs UP!

But the following is most definitely far from…lovely. Dr. Bradner states (at minute 2:40, more or less) that myeloma cells can become resistant to JQ1…that basically, their cellular operating system shuts down in the presence of JQ1. Ooooooh. Not good, of course. We all know that myeloma cells eventually become resistant to chemo drugs…and, to be honest, I’d hoped that things would be different with JQ1. But it seems that those crappy little cells have a cunning little “brain” of their own…

But hey, the JQ1 research is still in an early phase, and, food for thought!, perhaps this resistance could be overcome by using curcumin or other non-toxic compounds, which are known to chemosensitize even the most stubbornly resistant cancer cells. Here is an example…On October 21st I reported on this bortezomib (=Velcade)-curcumin study: http://goo.gl/UrDj1 And there are dozens of similar studies in PubMed…dozens…

Anyway, HOPE with capital letters is still the name of the game….And this is mainly thanks to the Harvard team’s Open Access philosophy, which is the most exciting thing I’ve heard or read about in ages, but OK I’ve written enough about that… In the meantime, do your research, take your curcumin and vitamin D and whatnot, avoid stress, laugh a belly laugh every day, eat your watercress and celery…aaaaaaaah, speaking of which!, stay tuned for tomorrow’s post, which will discuss yet another important veggie that we should add to our intake…Hint hint hint: it’s the main ingredient in a popular kind of pie…hehe.

Exciting times…lots of information pouring in…mostly thanks to y’all! :)

May 23 2012 post (http://margaret.healthblogs.org/2012/05/23/new-study-on-jq1/): Remember my posts on Jay Bradner and his Harvard team’s discovery…JQ1, the molecule that turns cancer cells into normal cells? if not, do a search of my blog…and look for my October/November 2011 posts. Well, we have a new Boston University (School of Medicine) study showing that JQ1 treatment dramatically reduces inflammatory responses in vitro and in vivo.

Here is the link to the abstract: http://goo.gl/Zed62. Now, even though I get reaaaaaally queasy now whenever I read about mice being injected with lethal substances and “sacrificed,” I couldn’t ignore the fact that 90% of JQ1-treated mice survived endotoxic shock while 0% survived in the non-treated group.

One thought on “JQ1, the Bradner-Harvard team molecule…

  1. Grace

    Hi Margaret

    Thank God for you and your blog. I too watched Jay Bradner Open Source and have been searching the web ever since trying to find who is doing the clinical trials with JQ1. I have made several phone calls and sent numerous emails to Jay Bradner with no reply as of yet, in the hope of learning more about JQ1. My husband has small cell lung cancer and if we don’t find some cure soon he will die. You have helped me understand exactly what it does and I loved your script. I wondered if you have anymore information about it and also notice at the bottom of the blog you mention Vitamin D. I was unsure about my husband taking it as I read on pubmed it could be toxic to the liver, kidneys and lungs – what do you know about this. I am desperate for any information that may lead to a cure or an extension of his life and thank my angels for leading me to your blog. I truly hope you reply to me so I have someone to communicate with who appears to be well on the ball. Many many thanks Grace xx

    Reply

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