Sherlock (grazie!) sent me the full study mentioned in yesterday’s post. It’s “only” 8 pages long, so I thought I would give it a whirl.
In the Introduction, we can read that the use of prolonged bortezomib therapy has lead to the development of drug resistance. The subsequent paragraphs and quite a bit of online research added a bit to my understanding of how this process occurs.
In order to retain my sanity while going through this complex study, I tried to visualize the dormancy process. For this, I needed a hibernating creature. After considering polar bears, toads and snakes, I went back to my original example: ants. If there are any ant-lovers out there, I sincerely apologize in advance for comparing them to myeloma cells.
Let’s imagine a northern European State at the beginning of a very harsh Velcade winter. As it starts getting colder, the ants aka myeloma cells get cold, too, but quite a number of them have enough forewarning and are able to escape the increasingly frigid, Velcade killer temperatures by hiding inside their underground nests. Their metabolism starts slowing down. In this inactive state, they require no food. It’s clearly a good survival mechanism.
The stubborn ones that remain above ground don’t have a chance of surviving (not in my visualization, at least). As soon as the weather starts warming up, though, the dormant ants wake up again. If I sound obsessed with ants, yes, I suppose I am. Every spring, I find myself battling fiercely with an ant colony that has established itself in my front yard. I don’t mind their being there, don’t get me wrong, but at this time of year some of them desperately and stubbornly want to march through my house, I suppose in order to reach the back yard. So right now, grrr!, I don’t feel badly about identifying them as myeloma cells. But I digress…
Now for a more, er, scientific approach.
First, though, a look at proteasomes. These are large protein complexes that are found in both normal and cancer cells. The relevant (for us) information about proteasomes is that cancer cells depend on these proteins in order to proliferate, metastasize and survive. And, in fact, increased numbers of proteasomes can be found in the blood of myeloma patients.
So one way to kill cancer cells is to inhibit the cancer-friendly activity of proteasomes. Probably the best-known proteasome inhibitor is bortezomib (marketed as Velcade). When Velcade is injected into a patient’s body, it disrupts the proteasome’s activities. As a consequence (simply put), cancer growth is inhibited, and the cancer cells die.
Now we get to our full Velcade-dormant myeloma cell study. Proteasome inhibitors provoke what is called an “ER (which, unfortunately, has nothing to do with the dashing George Clooney but stands for “endoplasmic reticulum”) stress response” in myeloma cells. This type of “stress” kills between 50 and 70 % of them, according to the study…but at the same time it sends out certain survival signals to 30-50 % of these cells that are thus able to avoid apoptosis by slipping into a deep sleep (or, more scientifically, by becoming quiescent).
They basically stop growing. And, since Velcade attacks cells that are in the process of dividing rapidly (=typical of cancer cells), this is an excellent survival strategy, which, incidentally, is used also by other types of cancer cells, such as head and neck squamous carcinoma cells.
At any rate, these quiescent cells can be annihilated, the researchers discovered, by adding to Velcade another drug called salubrinal. The actual experiment is rather neat, so I will attempt to summarize the parts that I understand in a comprehensible fashion. The researchers identified the myeloma cells that survived the Velcade attack and washed them to remove the drug. I confess, I was a bit amused by the image of myeloma cells being washed…anyway, the researchers realized that these cells had stopped growing. They were fast asleep…the little buggers. Velcade was no threat to them.
Now, there is a tremendous amount of detail in the study. I am not interested in the intricate mechanisms that show exactly how myeloma cells avoid death, mechanisms that, to be quite honest, I can barely understand, such as CHOP induction and XBP-1 splicing. So, skip skip skip.
Let’s get to the part that describes what happens once salubrinal enters the picture. After 24 hours, treatment with salubrinal of the Velcade-surviving myeloma cells resulted in a more or less a 10-fold reduction in the number of viable cells. Hey, not bad! And even after 5 days, the cells that are still dormant were highly affected by salubrinal. Ah, an important titbit: salubrinal does not affect the control population.
And now we finally (wiping our sweaty brows) reach the Discussion part where we discover that, after administration of Velcade, 30-50 % of myeloma cells escape death by becoming inactive. The researchers argue that this is more likely due to treatment adaptation than to selection of a cell population genetically predisposed to undergo quiescence. But the fact that so many myeloma cells survive treatment with Velcade is the probable and unfortunate cause of disease recurrence.
The researchers also found that survival of the residual quiescent cells hinges on the down-regulation of eIF2a phosphorylation. Phospho-whaaat? Okay, let’s not get too bogged down by the details of this phospho-thingie process. What we need to know is that the strong phosphorylation of eIF2a is associated with apoptosis. In the Velcade-surviving myeloma cells, you see, eIF2a was attenuated, so that is probably a mechanism whereby the blasted surviving cells are able to avoid apoptosis. Well, let us leave it at that…for now.
In conclusion, the solution to the Velcade-caused “dormancy” problem, as we have seen, lies in the addition of salubrinal to the mix. Salubrinal can virtually eliminate the fraction of quiescent MM cells surviving proteasome inhibition by enhancing the above-mentioned, er, eIF2a phosphorylation.
Quick note: this combination treatment will apparently benefit only myeloma patients. It doesn’t work against other forms of cancer, such as chronic myeloid leukemia.
The study’s conclusion: In summary, we report that the induction of MM tumor cell quiescence and survival can be an undesirable side effect of proteasome inhibition. We also show that, by blocking eIF2a dephosphorylation, proteasome inhibitor efficiency can be maximized during acute treatment and that residual cells can be eliminated by nontoxic doses of salubrinal as a monotherapy for MM minimal residual disease after proteasome inhibition.
Now I need a few days to digest all this stuff…
Thank you for walking us through this study. I’ve also been hearing good things about Velcade combos though the process has never been better explained.
On the horizon is a derivative of bortezomib called carfilzomib. Early trials are encouraging.
Good luck with the ants!
Thanks for all your research on this topic and others related to MM. I’ve been lurking on your blog on and off and have learned a great deal. (I also love the photos of your kitties!) In your looking around did you see any dates about availability of salubrinal, or is it still in development and testing? The sites I could find were either old ones or about the study you referred to. I did find a page on ALEX Biochemicals website where it looked like Salubrinal was for sale, but I think that may only be for research purposes. http://www.alexis-biochemicals.com/Salubrinal.5+M5116857b5ef.0.html
That was a really fascinating study, and an even better explanation (thanks for using ants; I really have an ant prob. now!). Wonder when the cliinical trials with salubrinal will start? My doctor wants to put me back on Velcade (no real response the first time, but I was drinking tea), but I may wait to see when or if this new pairing is available. I am back on curcumin, and anxious to see if it helps this time!
Thanks for the information. What is Salubrinal? What is it usually used for? What dose was used in the study? What is the toxicity of Salubrinal?
Thanks for your clear, excellent explanation of the Velcade/Salubrinal cocktail.
A non-toxic ant-removal suggestion: Sprinkle corn meal outside your door (and possibly inside, too). The ants will eat the cornmeal and retreat to their anthill, where they will…Explode! Good luck.
God, I love synergism. Thank so much for all of your hard work. I know you will let us all know when there is more info. on salubrinal.
“Hope is a good thing. Perhaps the best of things.”
Hi Margret, Your explanation about the Velcade/Salubrinal cocktail was superb. Its contains some really nice information.
Thank you so much!! Your analogy made the study understandable. ANTS!! I keep telling them “live and let live” I am content to share my garden with them, no problem!! BUT they must stop transporting Aphids from one plant to another!!
My father has battled MM for a little over three years now. He has responded well to velcade in the past, but I’m concerned now that docs have discovered a mass in the mastoid which has seemingly created numbness in his tongue and difficulty hearing. He is currently using velcade once a week, when possible, as a maintenance therapy after his second autologous stem cell transplant. Knowing that there may be another potential treatment with salubrinal gives me hope if this mass is indeed a plasmacytoma. I feel fortunate to have googled and found your information. Thank you!!
Thank you Margaret! My dad begins VCD MOnday. I sure hope that salubrinal will be available soon! I wish he could get that too!