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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 11, 2010

MAGL: A New Cancer Target

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Posted by Derek

I do enjoy some good chemical biology, and the latest Cell has another good example from the Cravatt group at Scripps (working with a team at Brigham and Women's Hospital over here on this coast). What they've done is profile various types of tumor cells using an activity-based probe to search for changes in serine hydrolase enzymes. Those are a large and diverse class (with quite a few known drug targets in them already), and there had already been reports that activity in this area was altered as cancer cell lines became more aggressive.

What they tracked down was an enzyme called MAGL (monoacylglyceride lipase). That's an interesting finding. Cancer cells have long been known to have different ideas about lipid handling, and several enzymes in that metabolic area have been proposed over the years as drug targets. (The first one I can think of is fatty acid synthase (FAS), whose elevated presence has been correlated with poor outcome in several tumor types). In general, aggressive tumor cells seem to run with higher levels of free fatty acids, for reasons that aren't quite clear. Some of the downstream products are signaling molecule, and some of these lipids may just be needed for elevated levels of cell membrane synthesis.

But it looks from this paper as if MAGL could be the real lipid-handling target that oncology people have been looking for, though. The teams inhibited the enzyme with a known small molecule (well, relatively small), and also via RNA knockdown, and in both cases they were able to disrupt growth of tumor cell lines. The fiercer the cells, the more they were affected, which tracked with the MAGL activity they had initially. On the other hand, inducing higher expression of MAGL in relatively tame tumor cells turned them aggressive and hardy. They have a number of lines of evidence in this paper, and they all point the same way.

One of those might be important for other reasons. The teams took the cell lines with impaired MAGL activity, and wondered if this could be rescued by providing them with the expected products that the enzyme would deliver. Stearic and palmitic acid are two of the fatty acids whose levels seem to be heavily regulated by MAGL, and sure enough, providing the MAGL-deficient cells with these restored their growth and mobility. As the paper points out specifically, this could have implications for a relationship between obesity and tumorigenesis. (I'd add a recommendation to look with suspicion at other conditions that lead to higher-than-usual levels of circulating free fatty acids, such as type II diabetes, or even fasting).

It may be that I particularly enjoyed this paper because I have a lipase-inhibiting past. As anyone who's run my name through SciFinder or Google Scholar has noticed, I helped lead a team some years ago that developed a series of inhibitors for hormone-sensitive lipase, a potential diabetes target. We were scuppered, though, by the fact that this enzyme does (at least) two different things in two totally different kinds of tissue. Out in fat and muscle, it helps hydrolyze glycerides (in fact, it's right in the same metabolic line as MAGL), and that's the activity we were targeting. But in steroidogenic tissues, it's known as neutral cholesteryl ester hydrolase, and it breaks those down to provide cholesterol for steroid biosynthesis. Unfortunately, when you inhibit HSL, you also do nasty things to the adrenals and a few other tissues. There's no market for a drug that gives you Addison's disease, I can tell you.

So I wondered when I saw this paper if MAGL has a dual life as well. If I'd ever worked in analgesia or cannabinoid receptor pharmacology, though, I'd have already known the answer. MAGL also regulates the levels of several compounds that signal through the endocannabinoid pathway, and has been looked at as a target in those areas. None of this seems to have an affect on the oncology side of things, though - this latest paper also looked at CB receptor effects on their cell lines that were deficient in MAGL, and found no connection there.

So, what we have from this paper is a very interesting cancer target (whose crystal structure was recently reported, to boot), a new appreciation of lipid handling in tumors, and a possible rationale for the connections seen between lipid levels and cancer in general. Not bad!

Special bonus: thanks to Cell's video abstracts, you can hear Ben Cravatt and his co-worker Dan Nomura explain their paper on YouTube. The journal has recently enhanced the way their papers are presented online, actually, and I plan to do a whole separate blog entry on that (and on video abstracts and the like).

Comments (9) + TrackBacks (0) | Category: Biological News | Cancer | Diabetes and Obesity


COMMENTS

1. Lucifer on January 11, 2010 9:50 AM writes...

If it turns out to not work as an anti-cancer drug, it might one day be used as an anti-protozoal drug.

like Miltefosine (http://en.wikipedia.org/wiki/Miltefosine)

Permalink to Comment

2. anchor on January 11, 2010 10:46 AM writes...

Derek : This goes back to what Prof. Freeman Dyson (my hero and an inspiration) said long back and that is life is all about "metabolism and replication". Terrific paper and we know that this will present with another opportunity for all those med. chemists (if they are still around)and big pharma.

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3. FormerMolecModeler on January 11, 2010 12:05 PM writes...

Sounds too good to be true, but hope it isn't. Wonder if inhibiting this target would also affect nerves (i.e. myelin production).

Permalink to Comment

4. anon the II on January 11, 2010 2:29 PM writes...

OK, I haven't read the paper yet but I always get nervous when one uses a reactive molecule to get biological results. What's to say this isn't hitting a lot of other things as well?

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5. ChePharm on January 11, 2010 8:12 PM writes...

@ 3- I agree, I did not read the paper but how safe it is to target this enzyme. Does it affect normal cells to the same extent?

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6. Cell biologist on January 12, 2010 7:48 AM writes...

I'm baffled that this paper was accepted by Cell. Impress the reviewers with tons of data and come up with a "novel network" and/or a "promising drug target", a recipe that often works even in journals like Cell. Maddening..

The authors have no clue about tumor cell biology. What's more, they confuse de novo synthesis of precursor (housekeeping) lipids with the production of bioactive lipid mediators (receptor ligands). The underlying biochemical routes are completely different.

Permalink to Comment

7. Walt on January 12, 2010 9:11 AM writes...

Hey Derek, The last lipase inhibitor I heard you talk about you called the anabuse of fat. You might have to start giving these lipids some respect.

It was a very in piece of work but the mechanism of action is skimpy. The suggestion that MAGL links to eicosanoids to by fatty acid release is not a direct effect since mammals cannot synthesize arachidonate or other essential fatty acids from stearic or palmitic acid.

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8. thelewdangel.com on January 28, 2010 8:31 PM writes...

thanks about your information

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9. Guppy on July 29, 2013 7:17 AM writes...

>"There's no market for a drug that gives you Addison's disease, I can tell you."

How about as a treatment for Cushing's Disease?

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