14 replies to this topic

[TeddyB]

http://geiselmed.dar...01/22_kurokawa/

Just thought it was worth a read.

[Trey]

Just my observations.  This essentially says that it might be theoretically possible to bio-engineer a drug that can first find a cell with BCR-ABL in it (i.e., a leukemic cell) and then cause it to self-destruct.  That would be different than current TKI drugs which are taken up into all blood cells and inhibit the BCR-ABL signalling process.  I am not sure what is so novel about a "hunt and kill" approach when it is only theory without any potential real drug science.  Our own immune system is a "hunt and kill" system, but the problem is the immune system cannot distinguish the leukemic cells from the normal cells.  I assume the drug would be taken up into every white blood cell, but then it must identify the BCR-ABL at some point (RNA? mRNA?, ???) and after that do something to it which leads to cell destruction.  A leukemia vaccine would teach the immune system to recognize the leukemic cells, which would differentiate them from normal cells so the immune system (T-cells, etc) could kill the leukemic cells.  In theory the hunt and kill approach is possible, but so is cold fusion.  Theory alone does not advance the issue very far.  Often these papers are written because the PhD needs to publish a paper every so often, even if they don't have any good ideas. 

[TeddyB]

Well, if it sounds too good to be true, it usualy is, but it would have been something

Which of the research going on today, do you think will be the most likely to bring on a lasting TKI-free cure Trey?

[Trey]

It will likely come in an unexpected way.  Something truly "novel" yet real. 

I postulated a "wish-theory" several years ago that the TKI drugs might allow us to outlive the residual leukemic stem cells which might some day die off completely because they exhausted themselves by over-dividing, while the TKI drugs kept killing off their offspring.  Stem cells will die if they divide too many times.  The abnormality that makes them leukemic (over-producing cells) might also be their Achilles heel leading to their demise over a decade or so.  Still a theory I invented back in 2007, but I have seen researchers discuss it recently.  This is why I do not believe in stopping drug therapy all together, but rather chose to use half dosage for the longer term. 

[GerryL]

Hi Trey,

I guess they will have to develop better testing equipment - otherwise how can they tell that the CML stem cells are truly dead?

[Trey]

The testing will never be  good enough, so it would need to be shown by lack of relapse by all or most patients over a period of time.  So proof of a cure would take time.

[CallMeLucky]

The one that I hear most talked about is the Hedgehog inhibitors.  That seems to have the most research behind it with regard to specifically going after CML stem cells.  This is from the MDAnderson website.

Hedgehog Inhibitors

Extensive evidence has been developed for a role for Hedgehog (HH) signaling, including the Smoothened transmembrane protein (Smo), in the maintenance and proliferation of CML stem cells. Using a variety of models, activation of Smo was demonstrated in Bcr-Abl+ cells, and their proliferation was shown to be more dependent on Smo than that of normal hematopoietic stem cells²². Conversely, inhibition of HH signaling reduced self-renewal in vitro, in vivo, and in murine retransplantation models.

Additionally, reduction of stem cells (defined as clonal progenitors developing during long-term culture) by Smo inhibition was demonstrated in CML patient samples²². Recently, the importance of Smo signalling in CML stem cell function was independently demonstrated²³; constitutive Smo expression increased whereas conditional deletion reduced this population. In a recent preclinical study, the combination of nilotinib plus the Smo inhibitor LDE225 was reported to provide supra-additive inhibition of primitive CML stem cells²⁴. Thus, the combination of TKI with HH inhibitor provides an important opportunity to potentially cure patients with CML. The sequential combination of TKI and HH inhibitor is planned at our institution for patients with minimal residual disease and/or suboptimal response to TKI. We are currently conducting a phase I study of the hedgehog inhibitor PF-04449913 for patients with CML (and other hematologic malignancies) who have failed prior therapy. The first portion of the study tests this agent by itself. In the second portion of the study, we will combine this agent with a tyrosine kinase inhibitor.

[TeddyB]

And another:

http://www.science20...t_cancer-102347

[Tedsey]

Yeah, I noticed that too.  I was wondering what exactly the therapy was since Dr K mentioned "cleaning" the bone marrow with an autologus stem cell transplant if a donor could not be found.  Sounds kinda like what is being done now.  I am so glad I am not completely dumb about this.  Guess this paper really is a publish or perish thing.

Teds

[Tedsey]

In this article it states:

These cells often demonstrate profound resistance to standard  therapy such as the BCR-ABL-targeted tyrosine kinase inhibition (TKI), and  are considered the root cause  of CML relapse.

Here we go again with the ubiquitous "often" as in, "inevitably", "surely", "likely", "eventually", etc, etc..progress.  It makes it sound like we will all eventually lose response and die from CML.  Unless I am dreaming or someone is playing with us, I have been under the impression that once a patient reaches MMR or PCRU the chances are greatly decreased that the disease will progress. 

Nice to have things in the works in case some of us may lose response.  But I get confused when Drs and reporters write that the disease inevitably progresses. 

Teds

[Tedsey]

May I add, "inevitably progresses" while patients are taking TKIs.  Of course, it progresses without drug therapy. 

Just wanted to clarify.  Sorry.

[Tedsey]

OK, I notice she is talking about LSCs because the TKIs now cannot always touch them.  But I think the way she words it makes it seem like it happens all the time.  For those that lose response, it would often be the cause of the loss of response (because the LSC find a way to survive).  I guess I am very nit picky and a little emotionally driven when it comes to this.

[Trey]

Tedsey,

Maybe I could break into your little self-discussion here.........These researchers revert to outdated  boilerplate verbiage about CML  when they introduce their paper.  They don't care about that part much since they just want to get to their main point.  But it makes us wonder whether they actually know what they are doing in their research since their intro paragraph sounds so dumb.  Often they only understand a very small piece of a  larger puzzle (how some kinase may potentially impact a downstream cell signalling process) and don't know much about the overall disease itself.  However, if enough pieces of the puzzle are developed, it could someday look like a complete picture. 

If enough blind squirrels find enough truffles, there might someday be a truffle quiche.

http://www.yummly.co...he-Food-Network

[TeddyB]

"Jamieson and colleagues further found that pan-Bcl-2 inhibition with sabutoclax can render LSCs sensitive to TKI treatment, and successfully suppress CML relapse. Importantly, sabutoblax appeared to be effective against a broad panel of CML samples from patients in Canada, USA, and Italy.  Based on these results, Jamieson concluded the sabutoclax may be the first drug that can successfully eradicate leukemia stem cells: the root of CML relapse."

It will be interesting though, to see how this works out in human trials, if they ever get that far.

I might be a bit optimistic, but i guess that will settle down as the years go by, if no "cure" is found.

[Trey]

Sabutoclax is a very important new drug with great potential if it actually lives up to the in vitro testing results.  In order to eradicate the high level leukemic stem cells, two things must happen: 1) these high level leukemic stem cells must be forced to expose themselves to drugs, and 2) at the same time these cells must have their alternate survival mechanisms shut down.  TKI drugs are not believed to directly kill high level stem cells due to both the alternate survival pathways and the fact that high level leukemic stem cells can go into hiding for extended periods of time.  This extended hiding occurs in bone marrow niches where there is no blood flow, very little oxygen, and drugs do not readily penetrate.  So this exposure issue is probably the more difficult issue to overcome. 

Sabutoclax is certainly worth watching.

http://www.news-medi...r-relapses.aspx