Cancer Stem Cells

Read through this and let me know what you think. A lot of folks believe that there are cancer stem cells, and those need to be the target of research.

> Dear Friends,

> Dr. Matsui sent this wonderful reply to me late this evening.
> Describing the difficulties of getting people to believe the findings
> and then to test appropriate agents, he supports Dr. Richardson
> description of Matsui’s work as “preliminary.” I think he’d like
> the patient community to spread the word. (Or I would. Probably just
> reading between his lines!)
> His message clarifies (for me) why Hopkins is using Rituxan despite
> the fact that it will likely affect all B cells. They feel they can
> support those whose immune systems are suppressed as is already done
> for persons with genetic disorders that prevent normal development of
> antibodies. He is testing many other agents. He also mentions that
> proteasome inhibitors may attack cancer stem cells. This raises both
> velcade and NPI-504 in my mind. (Recall, taking Rituxan could
> disqualify one from the NPI-504 trial, as it does the PR-171 trial.)

> Finally, I note that he thinks that the active ingredient in fever
> few would be a good agent to test. Since I can buy some form —
> probably not strong or pure enough to matter — nonetheless, I’m
> giving it to my guy NOW.

> What an amazingly generous communication from such a busy, high-
> powered researcher! (Nick, thank you for helping refine the
> questions!)

> Best wishes,
> D.

> Begin forwarded message:

>> From: William Matsui
>> Date: February 22, 2006 10:53:50 PM EST
>> Subject: Re: Follow-up questions?

>> Dr. Wicha passed this message on to me and I had a few thoughts…


>> Like our colleagues at Michigan, we (at Hopkins) believe that cance
>> stem cells lie at the heart of developing effective therapies that
>> can truly result in long-term remissions. The cancer stem cell
>> hypothesis currently is just that, a hypothesis. We believe that we
>> have solid evidence that specific cell populations (stem cells) are
>> able to give rise to myeloma in the laboratory, but the ultimate
>> proof will come from finding effective stem cell targeting agents,
>> then testing them in patients and showing that they can prolong their
>> lives. As you might imagine, this is a formidable task…. Using
>> acute leukemia (AML) as an example, the stem cells in this disease
>> were first identified in the early 90’s. Potential leukemic stem
>> cell targets (the interleukin-3
>> (IL-3) receptor and proteosomes) were described a few years later,
>> but neither of these targets have been seriously studied in the
>> disease (Velcade is a proteosome inhibitor and should have activity
>> against the cells, and has been tested only in a limited fashion in a
>> single published study). So AML (in which few would argue the
>> existence of stem
>> cells) illustrates the difficulties decscribing the laboratory
>> findings, getting people to believe the data, then carrying out a
>> clinical trial that would ultimately prove the point. Hopefully,
>> trials that suggest that the theory is correct, like our Rituxan
>> trial or the Michigan Bexxar trial (that would hopefully extend the
>> length of remissions, but are not likely to cure myeloma-since each
>> agent has curative benefit in only limited cases of lymphoma) will
>> give us the evidence we need to perform future clinical trials using
>> drugs that we think may truly eliminate myeloma stem cells.

>> For our trial at Hopkins, we chose to use Rituxan largely because of
>> its lack of serious side effects and our data from the laboratory.
>> I do
>> not know whether any other investigators have repeated our
>> experiments, but I do know many researcher have asked me to help them
>> with the laboratory assays to detect growth of the stem cells (so
>> maybe confirmatory results are coming). I agree that parthenolide is
>> a promising drug in leukemia and would certainally make sense to test
>> in MM. We are looking at several agents in the lab to test their
>> anti- stem cell activity. Some are focused on agents that can
>> inhibit B cells (regardless if they are myeloma derived or not),
>> others on pathways that we think are shared my stem cells from many
>> different tissues and organs. For the latter set of drugs, there is
>> certainally concern that they will affect normal stem cells so much
>> testing is likely needed prior to their standardly being used. As
>> for myeloma, my hope is that we can eliminate most all B cells since
>> the greatest risk of this approach would likely be a period of
>> immunodeficiency (due to the loss of normal antibody production).
>> But there are individuals with genetic defects that lead to
>> immunodeficient states that can really lead normal lives with
>> antibodies given every 1-2 weeks, and I would expect that the B cell
>> pool to be “replenished” by new B cells made from hematopoietic stem
>> cells.

>> Hope that this answers a few questions. Please don’t hesistate to
>> contact me if you have any others.

>> Bill

>> William Matsui, MD
>> Assistant Professor of Oncology
>> Division of Hematologic Malignancies
>> The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins The
>> Bunting Blaustein Cancer Research Building Room 245 1650 Orleans
>> Street Baltimore, MD 21231

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