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. . .