Yesterday I read, and was spellbound by, a study on stem cells conducted by Dr. Matsui et al, and published in “Blood” in September 2005. The full study is available online: http://tinyurl.com/2539p7 An extraordinary study that makes some interesting points concerning “current methodologies used to develop new cancer therapies.” I thought I would highlight some of them (conventional methodologies only are discussed, by the way), even though you can go read the full text for yourselves: it’s easy to read, unlike most scientific texts. A real pleasure!
The abstract starts out with the following statement: “Although most cancer patients respond to therapy, few are cured. Moreover, objective clinical responses to treatment often do not even translate into substantial improvements in overall survival.” As various studies have shown, they write, the response of myeloma patients to chemotherapy does not lengthen their survival. An explanation for this could lie in the cancerous stem cells: “a rare population of cells that exclusively maintain the ability to self-renew and sustain the tumor.”
Now let’s have a look at the full study. The researchers immediately take a strong stance on the issue of “clinical response”: “More than 30 new anti-cancer drugs have been approved over the past two decades. Approval required all of these drugs to show a clinical benefit, which can be documented by objective measurements of tumor response, improvements in quality of life as assessed by questionnaires, or a delay in the time to recurrence. However, these benefits have led to only modest increments in survival for the majority of cancer patients. Emerging laboratory and clinical data are beginning to point out potential flaws in the current methodologies used to develop new cancer therapies.”
What happens today is that when patients respond to a drug in a clinical trial, that drug is developed and made available as quickly as possible, with the idea that it will have an impact on the patients’ survival. If clinical trial designers, however, had to take into account “recurrence or an improvement in overall survival,” they would have to deal with very complex issues, such as large numbers of patients and allowing enough time, probably a lot of time, for follow-up.
The researchers do add that “objective responses” to chemotherapy may decrease side effects and improve quality of life. The issue at hand, though, is survival, for which “there is surprisingly little evidence.” As far as multiple myeloma is concerned, for instance, “neither the magnitude nor the kinetics of clinical response has an impact on survival.”
The researchers strongly criticize the concept of complete remission: “In actuality, the major rationale for the use of objective clinical response as a surrogate for biologic activity is the premise that a complete remission must precede cure.” They declare instead that “a complete remission by standard criteria may be neither a prerequisite nor a requirement for the actual generation of a cure.” This will become clearer as we proceed through the text.
January 28 2008 post: 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)
June 30th 2008 post: “Two new AML stem cell killers.”
In my June 11 post I mentioned reading about two compounds that effectively eradicate AML at the bulk, progenitor and stem level: celastrol and 4-hydroxy-2-nonenal or HNE (AML stands for acute myelogenous leukaemia, by the way). Well, thanks to Sherlock 
, I was able to read the whole University of Rochester/University of Pennsylvania study. The abstract can be seen here: http://tinyurl.com/6ltvw5
The full study begins with an acknowledgment of the importance of cancer stem cells, or CSCs, for studies of basic tumor biology and the development of improved therapies. Like normal stem cells, CSCs are thought to reside at the apex of a developmental hierarchy and are responsible for the continued growth and expansion of bulk tumor populations. Consequently, the biological activity of CSCs may contribute to initiation, maintenance, and relapse of at least some forms of cancer. Yes, this sounds all too familiar…
The researchers further comment that several studies have shown that AML stem cells (AML-SCs) are refractory to commonly used clinical agents such as cytarabine and anthracyclines, thereby further supporting the hypothesis that malignant stem cells represent a probable reservoir from which disease relapse may occur. In vitro studies, they continue, have shown that the combination of the chemotherapeutic drug idarubicin and the proteasome inhibitor MG-132 can effectively eradicate leukemia stem cells via a mechanism involving concomitant inhibition of nuclear factor-kB (NF-kB)–mediated survival signals and induction of oxidative stress.
Then they discuss parthenolide (PTL), a substance that can ablate AML-SCs as a single agent. As a single agent, mind you! Impressive. They add that the SC-killing mechanism is similar to the one used by the idarubicin and MG-132 mixture, and that is: combined inhibition of NF-kB and induction of oxidative stress, thus indicating that common biological principles underlie the anti–AML-SC effects of these agents despite their chemical diversity.
The researchers decided to explore other AML stem cell killing possibilities using gene expression signatures. They examined the natural antileukemia characteristics of PTL, which has been shown to induce very potent and specific effects, mediating rapid death of AML-SCs, but not normal hematopoietic stem and progenitor cells, looking for other substances that provoke a similar response in cancer stem cells. They then tested those compounds against AML stem cells.
For this purpose, they used the GEO or Gene Expression Omnibus, a sort of humongous gene expression warehouse. To their surprise, they found a recurring and chemically diverse group of compounds that mimic the PTL gene expression pattern and, like PTL, are capable of ablating AML cells at the bulk, progenitor, and stem-cell level. The sentence that follows is also important: As with PTL, the mechanism of action for these new compounds involves concomitant inhibition of the NF-kB survival signal and induction of oxidative stress, suggesting their general importance in targeting AML stem cells. Sorry to keep repeating “NF-kB plus oxidative stress,” but this is a crucial point, methinks.
The researchers identified and tested four compounds, including the two that I mentioned the other day and that inhibit NF-kB and proteasomes. These two were found to have molecular characteristics comparable to those of PTL. I should note that these compounds, while known for their anticancer activity and for their ability to inhibit NF-kB, had never before been tested for their specific ability to target leukemic stem cells.
By the way, the other two compounds, gedunin and hemin, did not target the AML stem cells and were therefore discarded.
In conclusion, this study is remarkable not only because of the discovery of two new compounds that exterminate AML stem cells, but also because a gene expression database was used to identify potentially useful compounds. Very very interesting approach…