cancer stem cells – Margaret's Corner

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!

Picking up from where I left off yesterday, the first type of cancer to be linked to stem cells was chronic myeloid leukaemia, or CML. The Johns Hopkins researchers proceed with a lengthy discussion on a drug called imatinib, which is used in CML, but without much success in the long-term. CML patients relapse if they discontinue imatinib (which, the researchers tell us, is currently being used more than interferon-alpha or IFN), or their cancer progresses even while they are on it. There appears to be no survival advantage in taking imatinib. The explanation, the researchers suggest, may lie in the CML stem cell resistance to this drug.

They use the dandelion analogy: “This pattern of activity is analogous to cutting a dandelion off at ground level. Although this will eliminate the visible portion of the weed, the unseen root also needs to be eliminated to prevent regrowth of the weed.”

Contrary to what happens with imatinib, CML patients’ response to the above-mentioned IFN is slow and gradual, “but can be durable.” So IFN would appear to act against the CML stem cells. Then we read “Thus, treatments that selectively attack cancer stem cells will not immediately eliminate the differentiated tumor cells. In this situation, cure (elimination of the cancer stem cells) in effect precedes the clinical demonstration of complete remission (clearance of the differentiated cancer cells) and could occur without actual disease shrinkage.”

This explains why these researchers took such a strong stance against the above-mentioned theory of complete remission. Complete remission may last months or years, but the cancer will return, eventually, unless the cancer stem cells are targeted. A treatment that targets cancer stem cells, however, won’t necessarily affect the circulating non-stem cancer cells. Hence, in this scenario, cure occurs before complete remission. This is contrary to everything I have read on the myeloma patient listservs (where a lot of the focus is on complete remission, or CR as we write it) and in the official myeloma literature. There are heaps of studies on the importance of complete remission in myeloma, in fact.

The researchers go on to discuss bortezomib (marketed as Velcade), a proteasome inhibitor, and lenalidomide (marketed as Revlimid, a derivative of thalidomide) commonly used in the conventional treatment of myeloma. These two drugs “can inhibit myeloma plasma cells but appear to have little activity against myeloma stem cells in vitro,” which means that they are pruning only the visible part of the dandelion, whereas rituximab, a monoclonal antibody, targets myeloma stem cells, i.e., the dandelion’s roots, according to the Johns Hopkins team.

The danger, the researchers point out, is that “As with IFN in CML and rituximab in myeloma, therapy directed against cancer stem cells might be prematurely abandoned if clinical activity is judged solely by criteria that reflect the effects of treatment on the bulk of the cancer.” And in fact, they add,“Not surprisingly, rituximab was found to have limited activity against myeloma in a short-term clinical trial. Rituximab’s activity against myeloma stem cells probably could not have manifested as immediate clinical responses in this trial because of the persistence of the long-lived, but terminally differentiated, myeloma plasma cells.” There you go.

So when we target stem cells, we must be patient. Unfortunately, nowadays, patience is no longer a virtue. We want to see immediate results. Overnight.

The researchers suggest setting up a clinical trial using bortezomib against the bulk of the cancer cells and then rituximab against the myeloma stem cells. Almost two years and a half have passed since this study was published. I went to have a look at the clinical trials being conducted right now. There are 591 trials (!) testing rituximab. I narrowed my search to myeloma, and found that there are 18 trials using rituximab alone or in combination with other drugs, such as lenalidomide or melphalan. Only one study, at the Dana-Farber Cancer Institute, is being conducted with rituximab and bortezomib, but for patients with Waldenstrom’s macroglobulinemia.

Well, these are certainly interesting times. I am all in favour of the dandelion theory, and it is for that reason that I am monitoring the DMAPT clinical trial, which should be beginning soon. (I admit to being more interested in substances such as DMAPT than in rituximab.)

The trees that are slow to grow bear the best fruit. (Molière)