Targeting the bromodomain family? You BET!!!

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.  😯

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 a significant 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!

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? 😀

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

24 Comments

  1. Hi Margaret, I posted it on the myeloma listserv and also sent a long email and the link to the NY Times science writer who in September, 2011 did a feature article on Dr. June’s successful gene therapy work at UPenn. Maybe, she’ll follow up. Her name is Denise Grady. Hopefully, everyone can email her. I also posted about it on the Myeloma Beacon, crediting you of course. You really got me enthused and I will continue sending links, etc. everywhere. Beats my day job as a lawyer!

  2. Hi Margaret, I wrote to Denise Grady, the New York Times reporter who wrote a feature article on Dr. Carl June’s gene therapy trials at UPenn this summer. She just emailed me back as a courtesy and said she will look into JQ1 and Dr. Bradner! Hopefully, others will contact her at the NY Times. I hope she writes an article soon. The video is now on the myeloma listserv and many people have viewed it and are commenting on it favorably. I will continue to send links to everyone I can think of. Thanks for pushing this, Margaret!

  3. (oops lost my comment, i don’t know if it got posted …so i will repeat myself)
    first many thanks to you for turning this into people speak and making the concept clear. I am impressed that what we have here is a double whammy…one being our very highly personal interest target, (a cure? ) but the other is the whole pharmaceutical industry’s highly personal interests of secrecy, proprietal knowledge and high profits.
    so two really big game changers.
    which will put up the bigger fight…the cancers or the drug companies?

  4. Margaret, Thanks so much for spreading the word about JQ1. Near the end of the TED talk video, Dr. Bradner says that an “oral substance for treatment of multiple myeloma will come to bedside” for first clinical trials in July of this year. I assumed he meant July 2011, since the video was made in May 2011 (according to a note on the screen). I hope that actually happened somewhere this past July and can’t wait to hear more about it. I’ve also posted the video on my Blog.
    OPEN ACCESS FOREVER!!!

  5. Hi Margaret,

    That is very exciting indeed. To get them into trials is a must and necessary next step. That still will take quite a while. Will email it to some organisations in the UK.

    Dieneke

  6. St Margaret,

    I’m an avid follower of your blog and yet again you have raised my spirits with the blockbusting news on the humble JQ1 molecule. Thank you so much.

    I also took the opportunity to check out the other myeloma blog sites to see if JQ1 molecule was mentioned. There was some reference, but one thing that hit me on this dull Sunday afternoon was that your blog site was way beyond any others for it’s positive perspective on our disease. Again I thank you for your time, diligence, medical jargon translation and up beat outlook.

  7. Dear Margaret and Friends,

    I simply cannot thank you enough for your generous consideration of our research. First, I must tell you that I am completely blown away by your thorough review of the Cell manuscript. Amazing! You have really hit all the high points, distilling the research to its essentials.

    You rightly identify that the time to bringing a new drug, once identified, to the clinic is approximately 2 years. This is a critical time, to select the ideal molecule among many high-performing prototypes, and to ensure the FDA and patients that we have thoroughly established the safety before human dosing. Still, I too wish it could move faster.

    I assure you and our friends here on your incredible blog, that we are moving with all conceivable pace through our own research, Tensha Therapeutics, and even by helping our “competitors” with model studies and insights in the framework of this Open Innovation model. There are no competitors in this business, except of course cancer itself.

    Thank you again so much for your warmth and support. Please know that these comments have lifted the spirits of our entire research team, and let us know that we are moving in the right direction – and importantly in the right way.

    Take good care, all.

    Jay

    James Bradner, MD
    Dana-Farber Cancer Institute
    Harvard Medical School
    Boston, MA

  8. Hi Margaret…this is truly awesome..your blog is great.
    Dr Bradner….please continue your great work…we as myeloma warriors are truly encouraged by your research!
    We have a great research team here in Calgary ,Alberta as well who have just opened new clinical trial for myeloma patients.
    Life (a long life) is looking better and better!!
    Gentle Hugs to all involved in trying to cure this beast!!
    Carol Westberg
    President
    Southern Alberta Myeloma Patient Society
    7 year Myeloma Warrior

  9. Way to go Margaret! Everything Dr. Bradner said about you is so on target. Not to sound corny, but I am remined of the movie Lorenzo’s Oil and it is not just the Italian connection. Big hugs. Terry

  10. Thank you once again, Margaret, for bringiing us great information in a way we (I!) can understand and also thanks to Dr. Bradner for the research and for the obvious feeling he has for patients above everything else. It gave me such a lift and I’ve told everyone I’ve met for the last couple of days. My consultant will be battered with JQ1 next week (unless he already knows about it)! We have a Myeloma UK info day in Birmingham at the end of November so I shall certainly raise the subject there. Thanks again Dr. Bradner – please work as fast as you can.

  11. Dear Margaret,

    Thank you, thank you, thank you, for deciphering the article. The night before I read your post, I confided to my wife that chemo I’ve been taking had addled my brain so much because I simply could not fully understand the intricacies of the paper. I got the basics, but nothing more.

    And thanks to JQ, Dr. Bradner, his team and all the others who are making a difference in the lives of others. Their work cannot be more noble or meaningful.

    Ralph Perez

  12. As a newly diagnosed, surprised, and somewhat freaked out SMM patient, I am so heartened by this work, and no less by this very articulate community.
    Margaret, you are a gem!
    Thank you Jay, and all!

    Where can I sign up for the clinical trials??

  13. Margaret…I wasn’t kidding when I said…”The Margaret?”, your like our little “Alice in Wonderland”, jumping into anything and everything about MM!

    I’m so impressed with your sight, when I was MGUS, I didn’t want to look as far as smoldering out of fear.
    You sight dispelled that fear, as I was a mess for several days. Then I remembered “Margaret’s Corner” and how many Great things were said about you! I’m so happy your sight has gotten the attention of Dr. Bradner, that’s very impressive indeed!

    Again, I personally want to Thank You for calming my fears and those of many others without even knowing it! Love and Prayers, Teresa

  14. Margaret

    You truly do have a talent for making the most of complicated medical reports making them understandable and funny but retaining the serious tone. Fantastic work once again, you inspire so many and lift their hearts. Although my levels have dropped since the Velcade and dex I am still suffering from their effects on my eyes and can only read for a short time before they become tired, so your blog is great for getting the basic info without trawling through the whole piece.

    Sue

  15. Margaret,
    I am sending the link to Dr. Bradner’s video to Dr. Fritz van Rhee at the Myeloma Institute for Research and Therapy in Little Rock, Arkansas. This is one of the best (if not THE best) myeloma research centers in the USA. I hope he doesn’t mind me mentioning his name publicly! He’s a fine doctor and I so appreciate his opinion. I remember a quote I heard a few years ago that said, “None of us is as skilled as all of us!” If all the brilliant medical minds can put their heads together, I am certain a cure for cancer can be found…hopefully sooner than later! God bless us every one until then!

  16. Dear Dr. Bradner and Margaret,

    Thank you both for your tireless work. The many of us with multiple myeloma are greatly encouraged by your effort– and by this recent development.

    In particular, Margaret, your perspectives over the last year have helped me in my own particular struggle. I think it very possible that your many suggestions are responsible, in part, for my continued remission, even with high risk disease. No one can know the future, but with greater knowledge of the disease and practical advice to salt my chances, I have more arrows in my quiver. I am grateful.

    And with this latest news, there is some long term hope for us all.

    For now, I look forward to helping in any way possible.

    All the Best,
    Danny Parker

  17. Dear Margaret, I’m very impressed by Dr Bradner contribution to your blog. I’ve always been convinced that modesty is a virtue of great people (which makes me feel even more hopeful). Thank you for bringing up all this, Margaret, and thank you, Dr Bradner, for your work and for your open access attitude.

  18. Hi Margaret,
    There are so many positives that gladden the heart in this post and the responses that you have received. However, for me, there is one sentence that stands out above all:
    “There are no competitors in this business, except of course cancer itself.” (Dr. Jay Bradner above).

    Dr Bradner’s open-source, collaborative, model for pharmaceutical development promises enormous benefits for mankind if it becomes the norm and it is long overdue. If the scientific work of Dr Bradner and his team doesn’t earn him a Nobel Prize, (and if it fulfils it’s promise I think it might), I hope that the open-source movement they have founded will.

    And Margaret: I further hope you will be first in line for a cure. You certainly desrerve it for all your hard work and for the help, advice, and hope that you have given to many of us.

    Paul

  19. Margaret, I just showed the video to my doc here in Sydney. I particularly pushed the OPEN ACCESS approach these guys are taking. If anything is going to help sort cancer out I believe it will be the extraordinary ability we have now to interact and share info globally. Open Access allows that potential to be utilized fully.

  20. Just wondering if we are folloiwng up on this,…as in how are the mice doing?? since this was written?
    Can we find out…the latest updates??

    “And now we get to 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…”

  21. Cam
    This is very interesting. It appears that HDAC inhibition causes degradation of SAE2. And you know what causes HDAC inhibition?
    Curcumin, yes

    Ron

  22. Cam, this sounds super promising. It is nice to see a recent quote from Dr. Bradner and, hopefully, we will soon see a clinical trial or two related to JQ1 or one one its derivatives. I know I would be ready to sign up!

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