Tag: myeloma stem cells

New myeloma stem cell study

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Sherlock (grazie!) came across and sent me a study by Carol Ann Huff and William Matsui recently published in the “Journal of Clinical Oncology” (June 10 2008) and titled “Multiple myeloma cancer stem cells.”. The abstract can be viewed here: http://tinyurl.com/4yx38s

 

The full study tells us that most myeloma cells are mature and quiescent and lack the ability to clone themselves. The fact that the majority of plasma cells are quiescent suggests that tumor growth is restricted to a specialized cell population.

 

A bit of history. In the 1970s Salmon and Hamburger showed that more than 86% of tumor samples from patients with multiple myeloma were capable of colony formation, and clonogenic growth occurred at a frequency of 1 in 100 to 100,000 cells. This could be explained by one of the following hypotheses: 1. only a small, functionally unique, subset of cancer cells was able to clone itself or 2. all myeloma cells can clone themselves, but only a few express this property at any point in time.

 

From what I wrote in my second paragraph, we can figure out that Huff and Matsui believe that hypothesis 1 is correct. Based on scientific data, they suggest that myeloma stem cells are clonotypic B cells: The ability of clonotypic B cells to recapitulate multiple myeloma in immunodeficient mice suggests that these cells represent the cancer stem cell in multiple myeloma. This part wasn’t easy to follow, but basically some features of clonotypic B cells are similar to those of healthy adult stem cells, such as resistance to toxic injury, and the continual risk of relapse among patients treated with standard therapies suggest that myeloma stem cells should also be relatively drug resistant. They can also self-renew and give rise to differentiated effectors (ie, plasma cells).

 

The scientists tested various novel chemotherapy drugs recently approved for the treatment of myeloma. The myeloma cancer stem cells were relatively resistant to both standard cytotoxic compounds and novel agents in vitro compared with the myeloma plasma cells. This suggests that these drugs work against the bigger population of myeloma cells, the ones that don’t have a cloning ability, but have no effect on the smaller population of stem cells. Nothing new here.

 

For the more scientifically-minded, here are a few comparisons between myeloma stem cells and normal ones: it appears that myeloma stem cells display properties common to normal stem cells, such as expression of membrane-bound drug transporters, intracellular detoxification enzymes, and quiescence. Thus, the chemoresistance of cancer stem cells may be mediated by multiple processes similar to those that protect normal stem cells.

 

The paragraphs that follow deal with therapeutic ways to target myeloma stem cells. For instance, as we know, the aberrant functioning of the Notch, Wnt and Hedgehog pathways is fundamental for the well-being of myeloma stem cells. These pathways therefore represent a good target. Let me add that we have non toxic ways to affect these pathways: curcumin, cyclopamine (by the way, I just read that a new water-soluble form has been developed!), zerumbone, DMAPT…

 

Then we are immersed in a discussion concerning telomerase activity…mamma mia, I confess I had to resort to parts of my brain that I never thought I possessed (!) in order to attempt to understand this section…not easy stuff! But, in essence, telomerase activity is an important process in myeloma, and its inhibition means that myeloma stem cells end up not being able to clone themselves. So, telomerase becomes another target.

 

Another promising target seems to be SOX2 (I wrote a post and page about SOX2 a while ago, by the way), an embryonic transcription factor that is normally turned off after embryonic stem cells differentiate; however, in both MGUS and myeloma patients it becomes reactivated (hah! Figures…).

 

Anyway, even if you don’t understand what this all means (as I don’t, to be honest), the point is this: SOX2 antibodies are present in folks with MGUS but not in those with myeloma. If you are lucky enough to possess those antibodies, you are less likely to develop myeloma. So targeting SOX2 could be another way to injure the myeloma stem cells, since, as Huff and Matsui write, SOX2 is a feature of clonogenic myeloma cells, and stimulation of anti-SOX2 immunity could limit clonogenic tumor growth of primary samples in vitro.

 

The development of new evil-stem-cell-focused treatments won’t happen overnight. That much is clear. New trial designs that incorporate novel end points will be needed to study myeloma stem-cell–targeted therapies. One potential strategy is to incorporate these approaches with existing therapies to determine whether they prevent tumor regrowth and prolong the duration of remissions after cytoreduction with chemotherapeutic or novel agents.

 

The researchers admit that the exact phenotype of the clonogenic cell has not been definitively established and controversy remains. Resolution of the controversy will probably depend on how well patients respond to stem-targeted treatments (read: on long-term outcomes…). Time…time…

 

The study ends as follows: growing knowledge regarding the basic biology of multiple myeloma, such as the identification of prognostic categories based on cytogenetic alterations or transcriptional profiling may allow multiple myeloma to serve as a model system to address general questions regarding cancer stem-cell biology.

 

As a myeloma patient, I confess that I (selfishly) don’t care that much about setting up a model system. I care much more about getting the promising, non toxic, stem-cell-targeting treatments into clinical trials as soon as possible. I’m ready and willing to try them!

 

So, where do I sign?!!!

Update on cyclopamine

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Yesterday a myeloma list member reported his test results after five cycles of cyclopamine. He authorized me to post about it. If you have no clue as to what I am writing about, see my August 2 and 3 2007 posts about cyclopamine, or my permanent page (see my Pages on the right, and look under "Other anti-myeloma/cancer supplements").

Here are some details posted by the cyclopamine-taking list member (from now on, I will refer to him as CT, or cyclopamine-taker) took a water-soluble form of cyclopamine for a year and a half. More specifically, he took 200 mg of cyclopamine a day for 14-15 days at a time, every 2-4 months. His m-spike went from 1.0 (achieved after two stem cell transplants two and a half years ago) to 0.2, then to 0.1, and he is convinced that these decreases, the first since his transplants, were due to his cyclopamine intake. Coincidental? Possibly. He reported, by the way, no side effects. Indeed, he feels great.

Okay, but we should not get TOO excited about this substance. The main reason, at least as far as I am concerned, is that it costs an arm and a leg. I had the brilliant idea of seeing if I could order some and ask my parents bring it over to me when they fly to Italy for their regular summer visit, but when I saw what it cost, i.e. thousands of dollars, my eyes almost popped out of my head. No way I could afford it. CT has a cheaper source than what I found online, but it’s still way beyond my budget.

Another list member pointed out that he would be anxious about potential side effects that might not manifest themselves immediately, but perhaps 20 years down the road. But CT (good sense of humour!) said that he would be happy to survive 20 years with myeloma! Indeed. He added that he is well aware that there are possible risks involved in taking a substance that hasn’t been approved by the FDA, but after all, we are dealing with myeloma, not an ingrown toenail (my analogy, actually). So true.

CT reminded us that Dr. Matsui reported in April 2006 at the American Association for Cancer Research (AARC) meeting that cyclopamine caused differentiation of  myeloma stem cells. In other words, the myeloma stem cells were eliminated because they did not produce any more cancer stem cells. The stem cells turned into mature plasma cells that eventually died out. Normal cells were not affected, he reported.

For an interesting Science Daily article (2002) on cyclopamine, see: http://tinyurl.com/2zcwut

In PubMed there are 260 studies on cyclopamine. But there is not one clinical trial. Typical.

As usual, I hope this situation will change soon. If it does, I might be first in line!

Update on the update: with this post, I wanted to report on an interesting case, perhaps (I hope!) a crucial one in the battle against myeloma stem cells. I would like to underline, though, that I am not encouraging folks to take cyclopamine. Even though we aren’t pregnant sheep (if you are puzzled about that statement, read my page on cyclopamine: all will be clear ), we still don’t know if there might be harmful side effects (etc.). CT did report that he had none, which is extremely important. In sum, I think this substance should definitely be put on our watch-and-see list. Yes, indeedie!

The myeloma tap: part II

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Day before yesterday, in part one, we saw that the only myeloma cells capable of cloning themselves are the ones that do not express CD138. The following excerpt from the Johns Hopkins study says it well: “multiple myeloma cell lines and primary bone marrow contain small populations of clonotypic B cells that do not express the characteristic plasma cell surface antigen CD138 and are capable of clonogenic growth and differentiation into multiple myeloma plasma cells in vitro and in vivo.”

Myeloma stem cells, therefore, don’t have CD138 sticking to their surfaces. Herein lies a big difference between regular myeloma cells and myeloma STEM cells: the former have CD138, the latter don’t. Enough said on CD138. Let’s look at other findings now.

I mentioned in my January 12th post that the capable-of-cloning-themselves myeloma cells are resistant to chemotherapy AND look like normal memory B cells AND also display "cellular properties characteristic of normal stem cells, suggesting cancer and normal stem cells share multiple mechanisms that promote drug resistance.” In fact, according to the 2008 stem cell study, both myeloma and normal stem cells have “intracellular detoxifying enzymes,” enzymes that, as I understand it, shoo away the chemo toxins, thus protecting the stem cell from apoptosis. This would provide a good explanation for why myeloma eventually becomes resistant to chemotherapy agents.

So, in sum, what does all this mean? In the researchers’ words, “Because cancer stem cells are a relatively low frequency population in most tumor types, the true inhibition of these cells is likely to be difficult to assess early after treatment, and a prolongation of disease remission would be required to establish such activity.” Well, that doesn’t sound very encouraging, does it?

Back in the middle of November, in a private exchange, a blog reader compared myeloma to a tank of water with a tap and a drain, an analogy he took from the film "Lorenzo’s oil," (those interested can go read a 2007 update on the real ALD story: http://tinyurl.com/2yjyjx). Anyway, the blasted paraprotein shoots out of the "tap," and the drain hole (our kidneys) gets rid of it. Myeloma cells, he was told by his haematologist, have a half-life of 5-6 weeks (I have been trying to find an online reference to this, but so far, on the UK freelite website, I found only that the “the serum half-life of intact immunoglobulin IgG is 20-25” days, so I will ask my haematologist about this in February). In other words, the cells stay in the body for that time and are then expelled via the kidneys.

Point is, are stem cells our "tap"? If so, how can we turn it off? I sure would like an answer to those questions! I would like to add that during yesterday’s meeting, Dr. Benelli suggested another "tap" theory to me, which I will be looking into in the next few days. Interesting times.

Concluding remarks. In the short term, yes, this stem cell research is exciting news but that’s what it remains: news. It has little relevance to us patients. For now. It holds promise for the future, though, indeed let’s hope the very near future. A finding that may prove to be useful is that “the developmental signaling pathway Hedgehog is up-regulated in multiple myeloma stem cells and regulates cell fate decisions.” So we meet again, Mr. Hedgehog! Back in early August, on August 2 and 3 to be precise, I wrote about cyclopamine, a poison contained in corn lilies that was found to be a Hedgehog pathway inhibitor (see my page on cyclopamine).

A couple of days ago, in a private exchange, an MMA list member asked me if the stem cell study had changed my supplement plans for the future. I answered yes, it has, in the sense that I hadn’t really thought seriously about taking parthenolide until I read about myeloma stem cells and how parthenolide and DMAPT (water-soluble form of PTL) annihilate leukaemic stem cells in vitro. So parthenolide shot right to the top of my supplements-to-try list. I am now planning to test parthenolide in March, after the Biocurcumax experiment has ended.

Summary of the main points made in the stem cell study, from my point of view:

  1. clonogenic myeloma stem cells do not express the characteristic CD138 antigen.
  2. myeloma stem cells constitute less than 2% of the myeloma "population."
  3. myeloma stem cells look like memory B cells.
  4. myeloma stem cells display normal stem cell characteristics that protect them "from toxic injury."
  5. like normal stem cells, nearly all myeloma stem cells (>98%) studied were in the quiescent (dormant, inactive) state, which is possibly another "major mechanism of drug resistance."
  6. conventional chemotherapy doesn’t affect myeloma stem cells.