Michael Grever, M.D.
Former Associate Director, DTP

The COMPARE program was developed by Dr. Ken Paul and his colleagues within the Developmental Therapeutics Program. And it was an effort to provide a graphic representation of a plethora of data that resulted from screening compounds in the 60 cell screen assay. Each compound is screened by the National Cancer Institute is tested against these cancer cells in vitro at five different concentrations. So each agent has a dose response curve against each tumor cell.

Well you can imagine the amount of data when you have 60 different dose response curves for each agent and then when the agents are evaluated a second time and several times for confirmatory validation purposes, one ends up with an enormous amount of data that's very hard to work with.

The way Ken Paul structured this graphic representation in the COMPARE program, we were able to get an instantaneous view of which cancer cell lines are more sensitive than others. One of the fascinating observations was that if an agent has a similar graphic pattern it's probably hitting in a very similar target in a cancer cell.

This was very dramatically demonstrated when a testing of crude natural products was sent through the tumor cell line screening. When we looked at the data for these crude natural product extracts and compared them to other agents that had been run through the screen, we found that every single one of the set of extracts we were looking at showed that it had a similarity to camptothecin or its derivatives.

And it was really remarkable that these extracts were taken from the bark of camptothecin. And I think the demonstration that this COMPARE program was able to look at a crude natural product soup, for want of a better word, and be able to identify within that mixture there was a chemical structure that was probably impacting on the same target as all the camptothecin derivatives. It was one of the most convincing moments that we had. It showed us that this program called COMPARE was able to identify how a drug might be impacting on a cancer cell, what targets might be hit.

Now the reason that this is very important is in the past the way that we would try to find the mechanism of action would be through a series of very laborious and systematic studies to examine each common mechanism of how drugs might be impacting a cancer cell. To have the ability to send a drug through the cancer screen and to have an instantaneous graphic demonstration showing you how this drug might be working really remarkably reduces the amount of time it takes to identify the mechanism of action or the potential target within a cancer cell.

So I believe that the impact of COMPARE really introduced us in some ways to molecular targeting and to screening. Because what we then did is we went back and we re-assayed all of the tumor cell lines and Dr. Chabner was a major proponent of doing this.