A week doesn’t go by where I don’t hear from a reader asking, “Any news about Dr. Bradner’s JQ1?
You remember JQ1, don’t you? You know, the YouTube sensation that featured the most promising, anti-myeloma drug ever, JQ1?
Here are a few links to stories I ran about Dr. James Bradner and JQ1 in the past:
Researchers Hope Shutting-Down MYC May Be Key To Defeating Myeloma
JQ1 discovery worth a second look…
More about Dr. Bradner and JQ1
I received some criticism at the time because I was a bit skeptical about Dr. Bradner’s “stick.” I just felt that his YouTube performance was a bit too polished–and too good to be true.
Well, this latest development takes JQ1 in a totally different and unexpected direction. Will investigative research into JQ1 as a reversible oral male contraceptive slow work on the cancer side of things? You be the judge:
Experimental cancer drug makes mice infertile without side effects, scientists claim male birth control discovery
August 17, 2012 – CBS News
A male birth control pill advanced one step closer to reality, a team of cancer and fertility researchers announced Thursday after their latest discovery.
Prescription drugs that lead double lives
Sperm gene discovery may lead to male birth control, scientists sayScientists had been researching a small molecular compound called JQ1, which was meant to block a cancer-causing gene called “BRD4.” The compound had previously been shown effective in staving off lung cancer and blood cancers, like leukemia and multiple myeloma, in earlier studies.
Part of the problem with finding a male birth control pill is the challenge of getting a drug across the blood-testis barrier. Just like the blood-brain barrier regulates what cells and compounds come in and out of the brain, the blood-testis barrier physically separates blood vessels and the sperm-producing seminiferous tubules that are found in the testes.
That’s when Dr. James Bradner, an oncology researcher at the Harvard-affiliated Dana-Farber Cancer Institute in Boston who had been researching JQ1, wanted to see if the molecule was small enough to cross the blood-testis barrier. He was curious if the compound would affect the BRDT sperm-producing gene associated with that family of proteins he’d been researching for cancer. He called Dr. Martin M. Matzuk, director of the new Center for Drug Discovery and a fertility scientist at Baylor College of Medicine in Houston, and supplied him with JQ1 to begin experimentation.
Matzuk and his colleagues figured out the appropriate amount of the compound to use, then injected mice with a solution over an 18-month period. They saw that the mice had lower overall sperm counts and a decrease in sperm mobility, rendering them infertile but leaving their hormone levels intact. The compound also did not decrease sex drive in mice allowing them to mate normally, nor did it cause other side effects that a hormone-based therapy may cause.
When mice were no longer given the compound, their sperm production went back to normal levels and they were able to have offspring.
The research is published online August 17 in Cell.
“These findings suggest that a reversible, oral male contraceptive may be possible,” Bradner said in a written statement. “While we will be conducting more research to see if we can build on our current findings, JQ1 shows initial promise as a lead compound for male contraception.”
There’s more. You can read the rest by CLICKING HERE.
What? Only one short mention of the cancer cure thing?
Scientists had been researching a small molecular compound called JQ1, which was meant to block a cancer-causing gene called “BRD4.” The compound had previously been shown effective in staving off lung cancer and blood cancers, like leukemia and multiple myeloma, in earlier studies.
Now it’s all about the male contraceptive thing. Which leads me to ask: Mr. Bradner, have you lost your focus? What about curing multiple myeloma and other cancers?
Now I don’t have any proof that Dr. Bradner’s research team will dump the cancer side of their research to focus on the contraceptive side. But you understand that there is a lot more money to be made if JQ1 eventually becomes the long sought-after “male pill,” don’t you?
Maybe that means researchers can skim enough big-time-funds away from the contraceptive side and then use it to continue cancer/myeloma research. One would hope so!
But there are just so many hours in a day. And I’m afraid Dr. Bradner and his colleagues might take their eye of the anti-cancer ball. After all, it’s human nature to follow the money! And like I insinuated in my first articles, these guys seemed a bit too mercenary for my taste.
They went on YouTube searching for funds. Now that they found an incredibly unexpected, unlimited source of cash, I wouldn’t be surprised it their entire focus changed.
Hope I’m wrong! Feel good and keep smiling! Pat
August 18th, 2012 at 2:25 pm
Hope you are feeling well today. I think this is a perfect example of why patients should try to avoid using both a proteasome inhibitor (Velcade, carfilzomib) and Revlimid (and soon pomalidomide) for long cycles early in treatment course and hope some new therapy comes along before they become resistant to those two classes of drugs. The latest, greatest miracle therapies have a tendency to fizzle out. I could never figure out why JQ1 caused as much excitement as it did. It seemed like just another great theory to me. Unfortunately cancer research is full of great theories that never pan out.
I am going to be out of town part of this week, so I could not participate in the Cure Talk panel discussion on curing myeloma. It does not appear that any of the participants have done the therapy that everyone agrees can cure patients – allo transplants. It would have been great if someone like Jack Aiello, who was cured of myeloma via an allo could have been on the panel. I hope this does not turn into a long discussion of “total therapy”. It would be a real shame if patients think it takes a lot of drugs to cure myeloma. Nothing could be further from the truth. It takes effective immunotherapy combined with the drugs we already have. Unfortunately only younger patients like me that are fortunate enough to be treated by a skilled allo Doctor can currently benefit from effective immunotherapy. Hopefully a new form immunotherapy will come along so older patients can benefit from effective immunotherapy as well.
August 18th, 2012 at 2:50 pm
I agree with most of that, Mark. I want–no we need–more allo related patient info and research. But Mark, even you have to admit that the research data is mixed at best about using allos as a myeloma therapy. And they can certainly be dangerous. I spent much of last week with Pat Harwood, an allo and myeloma survivor, and support group leader in the Twin Cities. I know in her heart that Pat believed she was “cured.” But after more than a decade, she has relapsed. In the meantime, her ongoing battle with graft/host has left her hobbled and worn-down. New techniques are reducing the risk of this. Still, this is serious stuff. And for the record, I don’t know a single patient a decade or so out who hasn’t relapsed. I know a lot who have lived 12 years, 14 years or even 20+ years. But all have relapsed. There are always a few exceptions–and I’m sure Mark will work hard to find a few–but I know a lot (hundreds and hundreds and hundreds) of myeloma survivors. I do know an auto patient who went a decade without relapsing. But she received an early form of immunotherapy as well that has been scrapped do to lack of funding. Mark may be onto something!
August 18th, 2012 at 9:32 pm
Almost surrealistic. One thing that may pan out for us in the myeloma/cancer community is that Bradner is an actual practicing myeloma expert at Dana Farber. Hopefully, he won’t forget us and, remember, he shared the JQ1 formula with multiple facilities worldwide in an open source fashion. Maybe, one of those facilities will keep their eyes on the prize (wiping out cancer first)….I hope.
August 18th, 2012 at 11:55 pm
That’s what I’m hoping, too. Take some of that potentially huge reproductive science money–potentially tens of billions of dollars–and use it to kick-start research that was short of funds!
August 19th, 2012 at 9:37 am
You may not believe this, but I actually do not think the myeloma community should or will put much more time into studying allos any longer. There is one randomized trial going on in Germany that IMO should be the last one done for newly diagnosed patients. Allos need to be tailored to the individual patient, therefore they are not good for randomized clinical trials. Use me for instance. I have a Brother who was not a match. I ended up having an unrelated female donor. Of all the matched pairs, male to male gives the least Graft vs Myeloma while female to male gives the most. My Doctor would have done my transplant differently if my Brother was a Match. An allo is not a simple, one size fits all type of procedure like an auto. I also have faith in my Doctor, not the “myeloma establishment” here in the US that would be writing a one size fits all clinical trial. There is actually personalized medicine going on in myeloma with allo Doctors, not just keep taking Revlimid until you relapse like the “myeloma establishment” Doctors treat.
I have seen very little evidence that allos work well in a relapsed setting for any type of blood cancer. It is relapsed myeloma patients that need the most help currently. Allos will always have some risks associated with them. The non-relapse mortality is in the 6-11% range when done early in disease course and much higher when done in a relapsed setting. I do not see how they will ever get it much lower. It is obvious that most myeloma patients think that rate is too high. The allo is not the therapy for those patients. I would actually be willing to take a little more risk if it would increase the cure rate. I would not be interested in participating in a trial that is trying to make them “safer” and it is obvious few other patients are willing to do them in first CR. Why bother with more upfront allo trials?
I think it may help more patients if the allo Doctors would spend more time on post transplant immunotherapy strategies. I will attach an example. Of course it was done overseas, not in “the more drugs the merrier” USA. This is the kind of trial I would participate in. That would help the few of us that do allos upfront and maybe they will find something that could be applicable to all patients.
http://www.ncbi.nlm.nih.gov/pubmed/19835972
August 19th, 2012 at 12:39 pm
But tell us how your really feel, Mark! You are the expert here. So why would I even bother with a “but.” But here it comes! I disagree. Lots of experimentation going on with mini allos and something my specialist is working on–somewhere in-between a mini and a full allo. Adding Velcade to the high dose chemo–or shortly after–has her going 20+ in a row with no serious graft/host symptoms. Not a single death in 20 patients! What am I missing here?
NOTE: I’m not trying to be difficult or confrontational. Just trying to learn as much as I can from different points of view. Thanks, Mark!
August 19th, 2012 at 7:54 pm
Pat
I have only a cursory knowledge. However, mark makes an excellent observation about personalized medicine which is practiced to a very limited extent in the USA . We appear to
Be in awe of throwing combos at patients and hope they work.
Jq1 is indeed a sad tale but it may have happy ending if the drug works for male contraception..
Look at what we are doing with the morning sickness developed agent thalidomide(what an example).
August 19th, 2012 at 11:32 pm
Even on your Blog patients have more interest in male contraception than allogeneic transplantation! If you need a good laugh, go on Margarets Blog or the Beacon and read what some of the patients said about JQ1. One person even said the MMRF should start following the “open source” model Dr. Bradner was using. The MMRF was only instrumental in getting Velcade to market. Who needs Velcade when JQ1 is right aroung the corner?!?!?!
I agree with you that allos are safe therapy for patients with an otherwise incurable cancer to consider. I did one in my first CR. It was allo or never ending cycles of Revlimid with some Velcade and DEX until I relapsed. I thought a partially T Cell depleted allo had a better established risk/reward profile than Revlimid/Velcade/DEX, so that was the therapy I chose. Just by chance, is Doctor Alsina discussing an allo with you? If not, it really does not do you and other myeloma patients a whole lot of good if improvements in allos are being made if myeloma patients are not actually doing them.
You wrote an excellent article about allo transplants with Velcade back on April 6. It got zero responses and less than 500 views. I am sure you do not get weekly emails asking if you have heard any updates on that trial. Compare that with views of 1,100 and 750 with multiple comments in articles about JQ1.
Most myeloma patients and Doctors have a negative view on allos. Why should skilled allo/immunotherapy Doctors like Nicolaus Kroger, Hermann Einsele, and Ghosta Gharon that know how to do something other than write “Revlimid 25 MG” on a Prescription Card spend their time trying to prove to patients that have no interest in doing allos that they are safe? IMO it is not going to change any patients opinion if the non-relapse mortality is 6%, 10%, 4% or whatever in the next allo trial. It certainly would not change my view that the allo was the best choice for me.
I bet if you ran a poll of myeloma patients asking if they would be willing to do an allo sometime other than “after all other therapies have failed”, I am sure the number would be close to zero. If Dr. Bradner was giving out samples of JQ1 last November, he would have had myeloma patients lined up from Boston to Providence RI waiting to get some!
August 20th, 2012 at 8:26 am
What does this all mean? I foresee a lot of 60+ year old MM’ers suddenly concerned with their chance of fathering children! (I kid, I kid, just trying to lighten the mood a bit).
Honestly though it does not bode well for current patients that were looking at JQ1 as their saving grace. If there was indeed promise you will see it come to market for MM AFTER it gets approval for contraception, that is a given. Any time you can use your drug for other uses it can extend the patent on the existing use as well (not a patent lawyer so can’t speak to specifics but this does occur). So it may not be done specifically FOR MM patients, but it can have a positive effect down the road. But that is a long road…
August 20th, 2012 at 8:59 am
As usual, Mark and Justin make good, thoughtful points. Mark, Dr. Alsina has stopped doing allos on myeloma patients, period. I understood that most transplant patients don’t do well when it is used as salvage therapy and a last resort. That applies both to allos and autos. But I didn’t realize how important it was to undergo an allo right away, even before first relapse. Studies are proving that autos work just as well after one or two relapses. Is there similar data that this is not the case for allos?
And about JQ1… Maybe this is a good thing. At least researchers working on the project will get paid!
August 20th, 2012 at 12:26 pm
Right on que the Beacon ran an article about a small study Dr. Kroger did on relapsed patients with autos. Great job getting the NRM down to 6%, but he is top notch when it comes to allos. As is usually the case when allos are done in a relpsed setting, the relapse rate is high. There was a study presented at ASH 2011 that compared allos done as planned upfront therapy as opposed to in a relapsed setting. More than 50% had not relapsed at 5 years when done upfront as opposed to only 20% when done in a relapsed setting. In my Doctors opinion, allos should only be viewed as a potential cure when done upfront. The data I have seen only show about 10-20% not relapsing when the allo is done in a relapsed setting and 50% seems to come up when Centers report data.
https://ash.confex.com/ash/2011/webprogram/Paper37067.html
“Risk factors being associated with diminished PFS and OS (given data) were >1 prior ASCT (OS:HR=2,80, p=0,00;PFS:HR=2,76; p=0,00), allo-HSCT more than 10 months after last ASCT (OS:HR=2,09, p=0,012;PFS:HR=2,47, p=0,001), no partial remission (PR) at time of HSCT (OS:HR=2,41, p=0,002;PFS:HR=2,31, p=0,002), application of a “reduced intensity conditioning” (OS:HR=2,11, p=0,009;PFS:HR=1,93, p=0,015) and a lower CD 34/MNC count (OS:HR=1,89, p=0,047;PFS:HR=1,82, p=0,040) in univariate analysis.
In multivariate analysis >1 prior ASCT (OS:HR=2,81, p=0,001;PFS:HR=2,89, p=0,000) and “RIC” (OS:HR=2,00, p=0,022;PFS:HR=2,09, p= 0,010) could be confirmed as independent risk factors. Patients reaching at least a PR prior to HSCT and lacking the latter two risk factor reached an OS of 60% and PFS of 50% with a follow-up till 17.5 years.”
“Summarizing the results, we established >1 prior ASCT as an independent risk factor for subsequent HSCT, contradictory to the use of double ASCT as standard therapy, especially in younger patients. Furthermore we saw moderate TRM rates after “myeloablative” HSCT, resulting in a significant better outcome compared to the RIC regimen. This observations raise the question if early and myelablative HSCT might be the key to cure multiple myeloma.”
https://www.eventure-online.com/eventure/publicAbstractView.do?id=190223&congressId=5650
August 20th, 2012 at 12:40 pm
Reading this–and combining it with what I already know–it seems to me that a “10-20% “cure” rate is still pretty high in relapsed setting. So if a patient could get several years (or more) of myeloma control–along with a 10-20% chance that it could last indefinitely–then why wouldn’t more patients and docs do it? I would! Something is missing here…
And why wouldn’t more patients go up-front for the “50% cure” rate? Again, what gives? Seems at least a third of myeloma patients under the age of 70 or so would be getting allos up-front. And for the record, not buying the “cure” thing. Unlike other cancers, 5 years “clean” only means you are more likely to relapse in subsequent years, not less chance. Sorry Mark! I know my stuff. If allos could really “cure” people (I’ve read 5% chance, not 20%) then again, a lot more patients would be doing it. And docs would be excited, pushing it, tons of research…
August 20th, 2012 at 5:16 pm
I almost cannot believe I am going to do this, but I am going to put a piece here written by the biggest “Big Pharma Shill” there is, Andrzej Jakubowiak. Andrzej is writing a piece on relapsed myeloma that was published in 2012. I think this is accurate and I believe most myeloma Doctors would agree with this. I actually agree with most it, and I never agree him!
“Allogeneic transplant shows limited clinical benefit for the treatment of relapsed/refractory MM. Few patients, even those with poor-risk disease, are ultimately cured with this approach.27 The majority of studies evaluating allogeneic transplant in the relapsed/refractory setting have demonstrated long-term, disease-free survival of 10% to 20%, with a significant proportion of patients developing chronic graft-versus-host disease, other treatment-related toxicities, or relapse.28, 29 Given these substantial limitations, the use of allogeneic transplant for patients with relapsed/refractory MM should be discouraged until more effective and tolerable approaches are established.”
http://www.seminhematol.org/article/S0037-1963(12)00037-6/fulltext
August 20th, 2012 at 5:47 pm
In terms of if allos are curable, here is what Dr. Rajkumar of Mayo wrote in 2011. There is no discussion of percentages:
“Third, in most cases, it is probably impossible (with the possible exception of allogeneic transplantation where true complete eradication is possible for a minority of patients), unnecessary, and prohibitively toxic to attempt to eradicate all clonal plasma cells.”
“Fourth, the tests used to define CR in MM are still inadequate and often vary considerably between laboratories. Although CR defined using molecular methods with patient-specific primers after allogeneic transplantation is more prolonged,39 it cannot predict cure with certainty.”
http://bloodjournal.hematologylibrary.org/content/118/12/3205.full
Here is what Dr. Alsina wrote in 2010:
“AlloHCT from HLA-antigen matched related or unrelated
donors is a treatment modality with curative potential for
myeloma patients. HCT from autologous or syngeneic
donors provides little or no immunologic effect against
myeloma cells. Long-term follow-up of recipients of auto-
HCT indicates a continuous risk of disease recurrence for
many years following transplant, and patients are rarely
cured. In contrast, studies of alloHCT with long-term
follow-up appear to show durable remissions and a lower
risk of recurrence.48 Advantages of an alloHCT include
the use of a tumor-free graft and the immune-mediated
graft-vs-myeloma effect.”
“Although high-intensity conditioning followed by
alloHCT results in long-term durable remissions and has
a curative potential, transplant-related mortality (TRM)
is the major challenge and thus not all patients are candidates
for this treatment approach. AlloHCT with myeloablative
conditioning has been traditionally offered
to younger patients with good performance status or
to those who were refractory to conventional chemotherapy
primarily due to the high TRM and morbidity
associated with the intense myeloablative conditioning
regimens.”
http://www.moffitt.org/File%20Library/Main%20Nav/Research%20and%20Clinical%20Trials/Cancer%20Control%20Journal/v18n4/258.pdf
Neither of them are exactly allo advocates and both seem to think they can cure patients.
August 20th, 2012 at 6:00 pm
“And for the record, not buying the “cure” thing. Unlike other cancers, 5 years “clean” only means you are more likely to relapse in subsequent years, not less chance.”
I do not think myeloma Doctors agree with that statement. This sentence is in Dr. Alsina’s quote above:
“Long-term follow-up of recipients of auto-
HCT indicates a continuous risk of disease recurrence for
many years following transplant, and patients are rarely
cured. In contrast, studies of alloHCT with long-term
follow-up appear to show durable remissions and a lower
risk of recurrence.”
Dr. William Bensinger from the SCCA wrote the exact same thing in 2007:
“Long-term follow-up of recipients of autologous stem-cell transplants indicate a continuing risk of disease recurrence after 5 years, and arguably few if any patients are cured. In contrast allogeneic stem-cell transplants with long-term follow-up appear to result in durable remissions and a lower risk of recurrence after 5 years.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017399/
Dr. Ken Anderson of Dana Farber:
“Nonetheless, long-term complete responses were observed in patients with responsive disease treated early after diagnosis. In comparative trials of patients undergoing myeloablative allogeneic versus autologous grafting, the early toxicity of the former contrasts with the ongoing risk of relapse in the latter.”
http://www.hematology.org/Publications/Hematologist/2010/5894.aspx
Relapses after 5 years do happen, but unlike in the allo setting the risk of relapse goes down after 5 years according to the experts.
August 20th, 2012 at 10:30 pm
Dr. J’s assessment fits clearly with my understanding. Big difference between, as he writes, “long-term, disease-free survival of 10% to 20%.” and curing 10-20% I believe the definition of “long-term, disease free survival would be five years. Not cured, but at least five years without measurable myeloma. But I still might take the risk as a salvage therapy. No worse than carfilzomib! Pat
August 20th, 2012 at 10:40 pm
Hope you are correct. Not rooting against you, Mark. You took a big risk for a potentially big gain–sort of like Nick and his Total Therapy. But when Mpls group leader and successful allo survivor, Pat Harwood, relapsed last year after 12 years or so, she was the longest allo transplant that I knew. Mark, did your doc give you contacts who have lived 15 or 20 years?
August 20th, 2012 at 11:30 pm
Mark-
Did you already forward me this link from today’s Myeloma Beacon about German study using Rev maintenance following allos in relapsed, refractory patients?
http://www.myelomabeacon.com/news/2012/08/20/donor-allogeneic-stem-cell-transplantation-plus-revlimid-lenalidomide-maintenance-for-relapsed-refractory-multiple-myeloma/
August 27th, 2012 at 10:13 pm
Thanks, Pat, for prompting this lively discussion.
My lab and I are blown away by your interest in and support for our work. Make no mistake, our lab is still totally committed to developing the next generation of cancer molecules. In fact, we have already completed the optimization of the drug-like JQ1 molecule, now being developed for clinical investigation as early as next year. And we have enjoyed significant progress on three new classes of drugs this year, owing to the tireless and relentless effort of my lab and collaborators.
Please try to consider this article, which has captured so much attention online (it’s just wild), as an exemplary illustration of open-innovation in drug discovery. We have enjoyed an incredible collaboration with the Matzuk laboratory at Baylor in assessing this activity of JQ1 in reproductive biology. Through collaboration we were able to expand our bandwidth *without* jeopardizing our total commitment to cancer research, enjoyed cross-pollination with a sophisticated community of scientists, and contributed an important observation to a very mature field in need of new approaches to male contraception. The accompanying, generous perspective in Cell by William Bremner, a long-time champion of the field of reproductive biology, really drove home how meaningful this type of interaction can be. And this would simply not be possible without making the compound freely available, providing further evidence that open-source drug discovery is very much a new and promising paradigm. You might know that we recently published a very cool, and hopefully important, story about JQ1 in reactivation of latent HIV with Monty Montano and colleagues at BU School of Medicine. Also very exciting. In fact, the activity of JQ1 on spermatogenesis may actually provide an important biomarker for the Phase I study, for those who can and are willing to provide samples.
Now, you have asked whether we are ‘selling out’. If it’s any reassurance, I am still driving the old Ford Fusion and moonlighting on the weekends – so I assure you that we are not in this for the money. There is only one thing we want – responses in the clinic.
Take care, and thank you so much for following our work.
Fondly, Jay.
August 27th, 2012 at 11:37 pm
Thank you for taking the time to respond, Doctor! I’m more than impressed by your thoughtful response to my posts. It is easy to become jaded when you view the myeloma world from a patient’s perspective. I am asked for updates about your research often. Maybe you could email me occasional updates. Pat@HelpWithCancer.org. You have a lot of “fans” out here!
August 28th, 2012 at 2:05 pm
Thanks Mark and Pat This has been a very helpful discussion for MM patients like myself considering the options.
And all of us patients greatly appreciate Dr Bradner and his efforts.
August 28th, 2012 at 2:29 pm
I’m going to do a follow-up post tomorrow. JQ1 is one of the most followed experimental therapies I cover.