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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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August 20, 2007

The Current Cancer Long-Jump Record

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Posted by Derek

As I've mentioned before, advances in molecular biology have continued to make all sorts of brute-force approachs possible - things that would have been laughed at (or, more likely, not even proposed at all) a few years ago.

Another recent example of this is a paper earlier this year in Nature from the group of Michael White at UT-Southwestern. The authors selected a lung cancer cell line that's know to be very sensitive to Taxol (paclitaxel), and looked for possible targets that might increase the drug's effectiveness. (It's a good compound to pick for a study like this, since it's simultaneously quite effective and quite toxic).

So, how do you go fishing for such combinations? These days, you set up 21,127 experimental wells, each one contained some cells and some silencing RNA molecules targeting, one at a time, 21,127 different human genes. And you look to see if knocking down expression of any of those genes increased the potency of a normally ineffective dose of the drug. (There were four different siRNAs per gene, actually, and each one was run in triplicate with and without Taxol, leading to a Whole Lotta 96-well plates. I'm glad I'm not paying for all the pipet tips, I can tell you that for sure.)

As you'd imagine, working up the data from this kind of thing takes as long, or longer, than setting one up. After comparing everything to the control wells and to each other several different ways, they ended up with 87 candidate genes whose knockdown seems to make the drug more effective. Gratifyingly, many of these make one kind of sense or another - there are several genes, for example, that are known to be involved in spindle formation, which is the target of paclitaxel itself.

Even more interestingly, not all the hits were obvioius. Another group of genes code for parts of the proteasome. That part of the cell is targeted by Millennium's Velcade (bortezomib), and it's recently been reported that the combination of Velcade and paclitaxel is more effective than expected. And there's another combination that seemingly hasn't been tried at all: the experiment suggests that inhibitors of vacuolar ATP-ase should synergize with Taxol, and (as it happens) a compound called salicylihalamide A has been looked at for just that target. They tried this experimental combination out on the cells, and it seems to work well - so, in humans?

As a commentary in the New England Journal of Medicine on this work dryly put it, "This hypothesis should be tested." And so it should. I've always had doubts about how far one can extrapolate cell data in cancer studies, but this kind of thing will tell us for sure. If something hits from this work, more such studies will come pouring out - they're getting easier to do all the time, you know. . .

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Assays


COMMENTS

1. SynChem on August 20, 2007 9:22 AM writes...

I worked on a project based on the "Synthetic Lethality" concept. The target turned out to be invalid. I still think it's a great drug discovery paradigm though, albeit a bit elusive and unproven. Nobody understands the mechanism after all. HTS actually has been done looking for such lethality, but it has yet to catch on as a target selection means in pharma. Novartis is the only big pharma I'm aware of who is working on this approach.

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2. Anonymous on August 20, 2007 10:29 AM writes...

Synchem:

I am very interested in this topic. Can you provide any references on screening methods? Thank you very much!

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3. SynChem on August 20, 2007 11:36 AM writes...

Anon,

The reference is on my laptop, which has crashed. You might find the relevent info by a google search.

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4. Anonymous on August 20, 2007 12:17 PM writes...

Synchem:

Thank you very much. Can you elaborate a bit why the approach is "elusive and unproven"? Did you mean rationally design compounds hitting two targets is unproven? Does Tykerb fall into the catagory of synthetic lethality? Also, can you comment on what's unique about the Novartis approach?

Sorry to ask so many questions. I appreciate your insights. I believe multiple ligands will improve the efficacy without posing too much toxicity problems, especially in cancer therapy.

Thanks again.

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5. SynChem on August 20, 2007 12:49 PM writes...

"Synthetic lethality" does not mean simultaneously hitting two targets. In a nutshell it means that knocking out a particular otherwise benign protein in COMBINATION with the presence of another mutant gene causes cell death. When this happens, this protein is "synthetically lethal" to the mutant gene. Inhibiting this protein in the abscence of the mutant gene does nothing, which in principal should mean no mechanism based tox.

The reason for this "synthetic lethality" is not kown, hence I call it "unproven". Here's a paper for your reading enjoyment, where they looked for chemical lethality first and then tried to find the target of the chemical/inhibitor. http://www.genome.org/cgi/content/full/11/2/266

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6. Anonymous on August 20, 2007 4:33 PM writes...

Thank you very much Synchem!

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7. Polymer Bound on August 20, 2007 6:03 PM writes...

Good lord, I hope they didn't use 96-well plates...

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8. befuddled on August 22, 2007 8:51 PM writes...

It looks like a similar technique was used to discover platensimycin, so it's not completely unproven.

Merck researchers used antisense RNA to knock down expression of fatty acid synthesis genes in staphylococcus, then screened extracts on the weakened bugs.

Nature 441, 260-261

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