Acronym games: DMAPT/LC-1

I have had a Google Alert for DMAPT, the parthenolide analogue (see my page on this topic), for ages, now. Whenever I receive a Google Alert on DMAPT, I get all excited, only to discover that it frequently is about a meeting of the Detroit Metropolitan Area Physics Teachers. Aaargh! I am also on a Leukemia and Lymphoma Society alert list for the DMAPT clinical trial, which was supposed to begin months ago in the UK. Until this morning, though, I hadn’t even heard a whisper about the clinical trial that was supposed to begin months ago in the UK.

 

Well, early this morning I discovered why. A blogging friend, Dave, to whom I owe an immense debt of gratitude!, informed me that the acronym DMAPT has been changed to LC-1. You’ve got to be kidding….double-aaargh!

 

Okay, but let’s not get lost in trivial matters, because, guess what?, dramatic drum roll!: the LC-1 clinical trial has begun. Yes indeedie…it began…a few weeks ago…at Cardiff University…in the UK! Hah! I am absolutely delighted, of course.

 

I began doing research immediately, but the more I looked the more I was puzzled. Some sources referred to DMAPT and LC-1 as the same exact thing, whereas others (http://tinyurl.com/dl7go3) called it a novel dimethylamino-parthenolide analogue. An analogue of…an analogue? That made no sense. Moreover, I was left with the doubt that, unlike DMAPT, LC-1 might not attack the leukemic stem cells. I found no mention of this anywhere, you see.

 

So I decided to write to one of the top DMAPT researchers (with whom I corresponded briefly last year), who responded within a few hours in spite of the time difference between the U.S. and Italy. Lovely person, incidentally. Well, it’s simple enough, and I quote from the researcher’s e-mail: LC-1 is simply the commercial designation for DMAPT, they are the same drug. Phew! Relief!

 

The most recent LC-1 news release that I could find is the one that Dave sent to me this morning (the DMAPT researcher sent me the same link, thank you!): http://tinyurl.com/blzqcs As you can see, apart from confirming that the trial has actually begun!, the main titbit is that so far LC-1 has been well tolerated by the patients in the study. Good!

 

Note: LC-1 is not a new acronym, by the way (how could I have missed that??? Dear, dear…). I came across this “Molecular Cancer Therapeutics” study that was published in 2007: http://tinyurl.com/ctuzj8. LC-1 was tested, successfully, together with Sulindac, a COX inhibitor, against pancreatic cancer in vitro and in vivo (= mice).

 

Well, we will just have to be sit back and be patient for a while…but you can rest assured that I will change my Google Alert…! Che roba!

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.”

DMAPT update

This morning I received a Google Alert about DMAPT, which, as you may recall, is the parthenolide analogue (from feverfew, see image on the left) that targets leukemic stem cells and will be tested soon (I hope!) in clinical trials. For more info on this topic, see my parthenolide/DMAPT page on the right-hand of your screen.

The first clinical trial will begin in England. If successful, it will be followed by others in the States. Apparently, there have been some bureaucratic hurdles (such as regulatory approval), but patient selection in the UK may begin this month.

I want to see if I might qualify for this trial, so this morning I decided to write to the chief investigators to obtain more information, if possible.

I have already sent off one e-mail and will write another, more detailed one, later on today. I hope to be a frequent flyer to the UK soon! Fingers crossed!

Late morning update: I just sent a query to the senior author of the DMAPT "Blood" study. Now I just have to sit back and wait.

IL-17 and medical day: stability!

Well, the answer to yesterday’s question is as follows: yes, we can. Curcumin inhibits IL-17. Figures, huh? There are three (possibly more) studies that mention the IL-17-inhibiting role of curcumin. The abstracts can be viewed here: http://tinyurl.com/2rn3jy (a 2003 study), http://tinyurl.com/ynvkdj (a 2005 study). Thanks to Sherlock, I read the full study of the third abstract, a 2004 study published in “Cellular Signaling” and titled, get this: “Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes” (see abstract: http://tinyurl.com/2lfy7t).

All these studies tell us that curcumin inhibits IL-17. Simple as that.

Haematologist appointment. Stefano and I went to see my haematologist at noon today. I asked her outright to classify me. She said that I am definitely not MGUS, no way. My IgGs are too high, and let’s not forget the 40% bone marrow biopsy result (from last year). So it’s official: I’m "smouldering," which means, among other things: "to exist in a state of suppressed activity." Heh. She examined my tests more in detail and pronounced me stable. Stable as a rock. So, all good news.

I asked her what the half-life of a myeloma cell is. She replied that it depends on a variety of factors, such as the type of myeloma and its proliferation rate. It can be calculated using cells from a BMB. She told me that a myeloma cell can live up to several months. MONTHS? Drat, now I am almost sorry I asked!

She confirmed that I am taking the correct amount of vitamin D. She also told me NOT to stop taking curcumin when I get a cold or an infection of any sort. Even though it inhibits NF-kB, she said that stopping cold turkey (odd expression, that one, when you think of it) is not a good thing. Good to know.

Let’s see. I am going down my list of questions and scribbles right now, not necessarily in order of importance. Oh, speaking of importance, this is exciting: I gave her the myeloma stem cell study (she had read the abstract, not the full study) and the DMAPT study, and she is going to find out about the DMAPT trial that should be starting soon in the UK to see if I qualify for it. She is going to contact the researchers that she knows personally. I am at a loss for words. Can’t wait to hear back from her. Gulp!

She is going to push the lab technicians to get more details on my “old” bone marrow samples, which would be fantastic. And, last but not least, she is going to try to attend the upcoming presentation in Calenzano, where I will be giving a brief speech. She is leaving for a conference in Turkey that evening, so it’s iffy. Even if she isn’t able to make it, however, she is sending five people from her lab to the presentation. Five? Fabulous.

Last but not least. For the first time, she wrote that I am stable "perhaps" due to curcumin. And that I should continue with the same treatment. (When my GP read those two sentences this afternoon, he got very excited.)

As we stood up to leave at the end of the visit, she asked me to explain why there are cases of myeloma in India, if curcumin is so effective. I answered that there are only a handful of cases compared to the Western world, and besides, I managed to add with a straight face, those folks undoubtedly didn’t use turmeric in their diet. My husband let out a snort, and she gave me a big smile and shooed us out of her office.  Hehe. I love my haematologist. Good sense of humour.

Yes, today was a good day.