DMAPT: targeting leukemic stem cells

Thanks to a Google Alert, yesterday I learned about a new article written by Craig T. Jordan, Ph.D., an Associate Professor at the James P. Wilmot Cancer Center, U of Rochester School of Medicine. Here is the link to the abstract: http://tinyurl.com/695g3g. As usual, I asked Sherlock (gracias!) to get the full study for me. Well, this was quite an interesting (and easy) read, which also gave me a few possible clues as to why the DMAPT clinical trial hasn’t yet begun in the UK. But let’s proceed by degrees, as usual.

 

Dr. Jordan brings up an issue that is no news to us: can the same results obtained in laboratory tests be obtained in patients as well? Eh.

 

He then mentions a series of small molecules, such as a proteasome inhibitor named MG-132, which target leukemic stem cells. But I would like to focus on what he writes about the substance that interests me perhaps above all others right now: parthenolide (PTL). As you may recall, I am currently testing a feverfew supplement that contains 3% PTL (the highest % I could find). I am taking the dosage recommended on the bottle, which is minimal, I know, especially since PTL is poorly bioavailable. I read that a group of cancer patients took as many as 4 grams of PTL/day in a 2004 Phase I dose escalation trial. I am presently taking less than one-fourth of that. But my motto is primum non nocere, and I am going to stick to it. I can always increase the dose, right?

 

So let’s see what Dr. Jordan has to say about PTL: Parthenolide, a naturally occurring molecule found in the medicinal plant feverfew, induces apoptosis in acute myeloid leukemia (AML) stem cells. Interestingly, he then mentions celastrol (see my Page on celastrol or “thunder of god”), which targets both “bulk” and stem AML cells. But his focus is on PTL.

 

And here we get to one of the most promising substances I have come across in my research, one that I dearly hope will quickly turn out to be effective and non toxic in Phase I trials: DMAPT, the PTL analogue. The acronym stands for dimethylamino-parthenolide. (I have a Page on PTL and DMAPT, by the way.)

 

Dr. Jordan tells us that, unlike PTL, DMAPT is readily water soluble and is 70% orally bioavailable. Pharmacologic studies in rodents and dogs have shown the drug to be tolerable well beyond the level at which in vitro activity is observed, without any known associated acute toxicity.

 

As we know from previous studies, in addition to inhibiting NF-kappa B, DMAPT targets ONLY cancerous stem cells, leaving healthy cells alone. And, When canines with severe acute leukemia were treated with 50 mg/kg daily DMAPT, the levels of CD34-positive cells were largely reduced.

 

A detailed description of an experiment conducted on animals (mice, mainly) follows. I won’t go into details, but the results were that leukemic stem cells were impaired, at least in the context of a large animal with a spontaneous leukemia.

 

This paragraph ends with words that sound like a Mozart symphony to my ears: Based on the preclinical findings, the drug is proceeding towards clinical trials. As my darling niece would comment, “Sweet!”

 

Dr. Jordan then provides a possible explanation for why it is taking so long to start the DMAPT clinical trials (this is my own interpretation, mind you, since the reason could merely be endless heaps of red tape): It is still unclear how to effectively assess whether leukemic stem cells are actually being targeted. Ah. Big problem, here.

 

He adds that A targeted agent could be used as part of a maintenance regimen to destroy the residual leukemic stem cells in patients in remission. However, he soon adds, there is no evidence that any of the agents currently available can target leukemia stem cells in a remission patient. Oh.

 

And then we get to a fascinating, thought-provoking excerpt: The biology of cells in minimal residual disease conditions appears to be very different from that of cells found in a de novo and heavy tumor-burden context. This difference can impact whether the drugs work or not. As clinical trials progress, the targeted agents may fail because of the physiology of the tumor cells, not because the drug is ineffective with all leukemic stem cells. Well then, I say, why not test DMAPT also on leukemic/myeloma patients who have never had any conventional treatments? (Not that I have anyone specific in mind… 😉 )

 

Reading on, we stumble upon what might be another reason for the DMAPT clinical trial delay: Cancers are heterogeneous, and this is exceptionally true of leukemic stem cells. From patient to patient, molecular markers for stem cells differ greatly. […] This heterogeneity makes determining the frequency of the leukemic stem cell in an individual patient extremely difficult.

 

Dr. Jordan defines leukemic stem cells as highly dynamic and highly unstable. So the question arises: how can they possibly be monitored? In comparison, it would seem that keeping individual tabs on millions of agitated grasshoppers in a field would be a much easier task…

 

As I see it, these seem to be the main problems facing clinical trial investigators: 1. how to identify the stem cells in each individual patient in the first place; 2. how to determine if these cells are being targeted by the specific treatment (DMAPT, e.g.).

 

And here follows something that perhaps for the first time I have seen spelled out in a study: During chemotherapeutic challenge, patients can experience a dramatic change in the phenotype of their leukemic stem cell. From my layperson’s point of view, it would appear that this “dramatic change” would also be a problem.

 

Furthermore, just because your total tumour burden decreases doesn’t necessarily mean that your stem cells have been affected. Another problem.

 

But there seems to be a way of getting around all of this. Dr. Jordan writes that Clinical trials must be temporal and patient-specific. Specimens must be gathered before, during, and after treatment. The phenotype of each patient’s leukemic stem cell population must be defined up front and verified by a functional assay to help quantitate it. In the course of treatment, the population must be continuously monitored […]. It sounds extremely painstaking and time-consuming, doesn’t it?

 

Dr. Jordan’s final considerations: Just as cancers are heterogeneous, so too are leukemic stem cells, and the ability to target and quantitate leukemic stem cells is complicated by this heterogeneity. As research expands our understanding of leukemic stem cell biology and physiology, investigators must incorporate that knowledge into their strategies for targeting and analyses for quantifying leukemic stem cells. They must also determine where agents that target leukemic stem cells will be of most use: as maintenance therapy that targets minimal residual disease in remission patients, or as treatment for relapsed or refractory patients.

To this, I would add: “…or as treatment for patients who have not yet had any chemotherapy.”

7 Comments

  1. I recently asked a genetics researcher working in myloma whether new monoclonal plasma cells come from stem cells such as memory B cells, or from other monoclonal cells which simply divide. He grinned and said “ask that question at a conference of hematologists and you might get a fistfight.”

  2. Hi Margaret,

    Could you post the Phase 1 study of the cancer patients who tried PTL? Also,
    I hope you received the info about the wild ginger extract tincture made by Tropilab Inc. It gives information on their website about the the anti-cancer agent zerumbone. Does anyone have the time to research this extract further?

    http://tropilab.com/puyangtincture.html

    Thanks!

  3. Hi Margaret. Thanks for a good site! (I just found it today)

    My four year old son have MDS-AML. He`s been trough all standard treatments, including two allogenic bone marrow transplants.

    He`s still got a small possible remaining MRD. If he relapses again he will only get palliative care. I have to find something else to help him.

    I have read about feverfew and found it promising.

    I`m curios about your own DMAPT trial have you noticed any difference?

    Thanks
    ///Anna

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