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:
- 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…
- 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:
- Okay, we’ve established (see above list) that JQ1 is the good guy who wants to stop MYC, the bad guy.
- But, oh no!, JQ1 can’t shoot the padrino directly. Why not?
- 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.
- 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…
- 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.)…
- 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…).
- The aberrant cousin’s name is BRD4. He gets into all sorts of scrapes. But, most importantly, he’s very close to MYC.
- Question: by shooting down the aberrant cousin, will JQ1 be able to stop MYC?
- 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:
- 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.
- 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…)
- If you have a blog, write about it.
- If you’re on Facebook (Twitter etc.), write about it, making sure you include the link to Dr. Bradner’s extraordinary TED Talk.
- 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.
- Money, of course. Goes without saying.
- 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!!!