Discussing the gene silencing study and the Polyhooligans…

Well, here, finally!, are my notes on the Discussion part of the “silencing” study (see my July 16 post). I was forced to skip through the bits that I didn’t really understand..and would therefore welcome comments/corrections from anyone who has a scientific mind/background. Thank you!

Okay, let’s dive right in…the researchers point out that multiple myeloma doesn’t have a common origin that would help provide a universal MM drug target. While it is true that previous studies have identified important signalling pathways (does the infamous NF-kappa B ring a bell?), previous gene expression profiles to date have mainly focused on subdividing MM into genetic entities for prognostic or therapeutic purposes. The aim of this study was instead to find a common denominator for myeloma development and tumor maintenance. A high goal indeed…

The researchers identified a set of “underexpressed” genes located inside MGUS and MM cells. But there is also a second group of genes, a pesky group of hooligans called the Polycomb Group, or PcG for short. The Polyhooligans (=my invention) go after and “silence” all the good guys, I mean, all the good genes. And, as I mentioned a few days ago, this “silencing” activity becomes more frenetic in more advanced stages of myeloma. Bad, bad stuff…

Before going on, let’s take a quick look at the term “underexpression.” In our particular case, as I understand it!, this means that a smaller amount of a particular gene is present in a myeloma cell when compared to a normal plasma cell. Underexpressed = decreased. And here is an example from the study: the researchers found that the CIITA (=Class II transactivator…ah, don’t even ask!) gene was on their list of “silenced genes.” Why am I mentioning this? Because the underexpression of CIITA enables a myeloma cell to dodge the immune system…

Another important finding is that the Polycomb repressor genes appear to be a common feature among the tumor cells, rather than representing a specific subpopulation. The researchers indicate that Epigenetic gene silencing is an attractive drug target due to the fact it can be reverted. So the researchers tested two chemical inhibitors with impossible-sounding names but thankfully-short acronyms: DZNep and LBH589. And yes, these two thingamajigs were able to rouse a selected group of the slumbering genes, including our newest friend, Ms. CIITA.

The chemical substances had other beneficial effects as well. Here is one example: EZH2 is a protein that can become overexpressed (=the opposite of underexpressed…) in multiple myeloma. This is bad, clearly, since the “going crazy” of EZH2 leads to the proliferation and survival of myeloma cells. Well, the above-mentioned chemicals decreased the amount of EZH2 inside the myeloma cells. This is not that surprising, since both chemicals do the same in AML and breast cancer cells…

Another positive effect: In addition to the reactivation of the Polycomb-target genes both DZNep and LBH589 reduced viability and induced apoptosis in two MM cell lines. Yes, that means that, in addition to waking up our sleeping beauties, these two chemical inhibitors exterminated a number of myeloma cells…

The researchers tested LBH589 in vivo (=mice), with the following result: Treatment with LBH589 significantly decreased tumor load and levels of paraprotein AND increased overall survival. They also found that it can overcome drug resistance in MM cell lines and cells from patients with refractory disease, so it might be useful in combination with other drugs.

[Quick aside: the study mentioned that LBH589 was being tested right now in myeloma clinical trials. So off I went to the Clinical Trials website where I found eight clinical trials in the process right now of recruiting relapsed/refractory myeloma patients for an LBH589/Panobinostat trial in combination with other drugs. Interesting. Okay, back to us, now…]

Previous studies have shown that PcGs are involved in the development of other types of malignancy. And they are important in embryogenesis, which is the process whereby an embryo is formed and develops. So they are not ALWAYS violent, bad guys…just in cancer. This bit will clarify, I hope!, the following statement (where “epigenetic mark” = PcG): The fact that an epigenetic mark maintaining self-renewal in embryonic stem cells is found in cancer supports the hypothesis that cancer cells share features with normal stem cells. This is significant because, based on the data, the stem-like features of myeloma cells seem to be crucial for their survival and self-renewal.

In conclusion, the above-mentioned “common denominator” would be the group of silenced/underexpressed genes = the good guys. Then we have the bad guys, the Polyhooligans, who spend all their time lurking in the darkest shadows of our myeloma cells and whose sole purpose in life is to hunt down and knock out a bunch of friendly, nonviolent genes that are then no longer able to function properly, as they would under normal circumstances (in normal plasma cells, that is). This “silencing” process enables myeloma cells to proliferate and survive, completely undisturbed… Well, at any rate, that is how I interpret this incredibly complicated process (and text!)…right or wrong…

Is there anything we can do to stop the Polyhooligans? Well, I hope to have a few suggestions in the next few days…First, though, I have to read the studies…so stay tuned…

Helpful information on the Polyhooligans: http://tinyurl.com/2ecv29s

5 Comments

  1. I love your expression “Pollyhooligans” as it gives me a wonderful image of some out-of-bounds entities that need to be brought under control… thanks for this delivery.

  2. Epigenic modification is a fairly intense area of research. This applies to control of disease alone and as part of combination therapies with traditional cytotoxic chemicals. This applies across lots of types of cancers (I don’t have MM, I have STS). LBH589 is a Histone Deacetylase Inhibitor (HDACi) and if you search for this class of compounds on pubmed you’ll be quickly overwhelmed. There is also some evidence that points to some fleeting aspects of their impact.

    In Feb., 2006 in the journal “Carcinogenesis” a paper titled “Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention?” was published. It really discusses prevention but it’s a great place to start reading I think, and it talks to non-pharma sources of HDACi’s. It’s short, just a few pages plus references.

    There are a number of natural substances that may be HDACi’s but, as usual, questions about their effectiveness at acheivable levels always hold.

    Chris

  3. Hi Margaret,

    PcG inhibitors decreased tumor growth in mice but it still didn’t STOP tumor growth completely. This is so frustrating! How many targets to drugs have to target before we find a cure for myeloma??? There is always something else that comes up that causes this cancer to continue growing!!!!!!!!!!!! Any opinions?

    -Elisa

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