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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

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January 10, 2007

Reality, Here In This Little Dish

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Posted by Derek

I've noticed a few stories making the rounds recently about possible new cancer therapies. Johns Hopkins has press-released the work of a group there on, and several news outlets have picked up on a British study on the effect of vanilloid agonists (such as the hot-pepper compound capsaicin) on cancer cells.

And all this is fine, until the word "cure" starts being tossed around. It always is. The number of times you see it, though, is inversely proportional to how reliable your favorite news source is. I wish the Nottingham and JHU people all the best in their research, and I hope that their projects lead to something good. But they have a long way to go, which you might not realize from the "Johns Hopkins Patents Cancer Cure" and "Hot Peppers Can Cure Cancer" headlines.

You see, these studies are all on cell cultures. I've worked on several cancer research programs, and I'm sure that other readers who've done the same can back me up here: unless you've seen cancer drug discovery work at close range, you may have no idea of just how many compounds work against cancer cells in a dish. It isn't that hard. I have absolutely no idea of how many thousands of compounds I could dig up from our files that will just totally wipe out a lot of the common cancer cell lines - in culture, that is.

We don't even bother looking at a compound unless it goes through cultured cell lines like a flaming sword. Problem is, a good number of those compounds will go through normal cells in the same fashion, which isn't exactly what the oncology market is looking for. And of the ones that are left, the ones that aren't hideous toxins - well, a lot of those hit the skids when they go into a live mouse model. Drug candidates that rip through the cell assays but fizzle in the mouse are very easy to come by. Anyone who does oncology drug discovery can furnish you with piles of them, and you're welcome to the darn things.

Now comes the really ugly part. We've ditched the nonselective cell killers, and we've shaken out the compounds that can't cut it in a live animal. How many of these actually work in human beings? Nowhere near as many as we'd like, that's for sure. AstraZeneca's drug Iressa is always useful to keep in mind. That one was going to be a huge hit, back when it was in development. But in real patients, well. . .for the vast majority of them, it just doesn't do much at all. There are a few responders (some of whom we can screen for), but otherwise, you'd have to call the compound a massive failure in the real world. Oh, but you should see it kick through the cell assays, and watch what it'll do for the mice.

Our assays just aren't that predicitive. It's a big problem, and everyone in the field knows it, but so far (despite crazy expenditures of time, money, and brainpower), no one's been able to improve things much. Anyone who does cancer work knows not to celebrate until the human trials data come back, and you'd better be careful even then. So the next time you read about some amazing thing happening to cells in a dish, well - wish the researchers luck. And go back to what you were doing before. There's time.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Assays | Drug Development


COMMENTS

1. christianhauck on January 10, 2007 10:37 AM writes...

I don't think that you could get Capsaicin registered with the FDA if it would be a synthethic drug and not a natural product, and if we had not proof from real-world experience that the side effects are not that dramatic.

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2. BongoP'o'ndit on January 10, 2007 10:50 AM writes...

I think most scientists in the biological field, even if not connected to cancer research, will be skeptical of the long-term curative power of such drugs.

However, to the lay person, a headline such as, 'Hot peppers have less than 99.9% chance of curing cancer' would not be an appealing headline.

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3. agogmagog on January 10, 2007 11:35 AM writes...

So billions has been spent to develop compounds that can cure cancer in mice? Sounds like Douglas Adams was on to something in Hitchhikers Guide to the Galaxy.

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4. Sigivald on January 10, 2007 12:41 PM writes...

On the plus side, think of all the good we can do for mice with cancers!

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5. MTK on January 10, 2007 4:48 PM writes...

This is one of the main arguments that the animal rights folks use in condemning the use of animals in such lab testing. If they aren't good models, then why the heck do them. Gotta admit, they have a point here.

Of course, you still have to collect some type of safety data, but at least there your control group won't suffer needlessly(assuming the vehicle doesn't slowly kill them). In contrast using a bad model on sick animals will generally doom both groups to a bad fate for no good reason.

Don't get me wrong, I'm not an animal rights guy, I just don't think they should suffer in the name of unproductive experiments.

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6. Joe on January 10, 2007 6:53 PM writes...

Derek you scoundrel, I was going to submit this post on digg, only to discover that you already had.

Since you're on job hunt, you should consider moving on to diggland, where you too can cure cancer every week.

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7. Anonymous on January 10, 2007 7:47 PM writes...

Is there reason to believe that the degree of difficulty is always ranked this way--culture, then mouse, then man? Why couldn't something flop in culture but be effective in a mouse? Or fail in a mouse but work in a human? It seems to me that unless you know why it's so much harder to get it to work in people compared to mice, you can't be sure that the set {works in mice} contains the set {works in humans}.

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8. milkshake on January 10, 2007 8:15 PM writes...

Cancer drug that fails in mouse but works in humans: Ftorafur (aka Tegafur) = rac-5-Fluoro-1-(2'-tetrahydrofuryl)uracil. If I remember correctly the latvian guys in former USSR that developed it skipped rodent model.

Ftorafur is basicaly a pro-drug that has sustained-release effect and some other advantageous PK characteristics and it just does not work well in rodents becasue the metabolic rates in rodents are sufficiently different.
is substantialy d

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9. Eric J Johnson on January 10, 2007 8:51 PM writes...

Semi-relevant here are some parallels from bacterial infection -

It's been claimed that the antituberculous drug pyrazinamide (whose activity depends on an acid millieu such as is supposed to be found in inflamed tissue) probably would have been discarded had it been screened on axenic M. tuberculosis - but it was apparantly taken directly to a small mammal screen.

Kim Lewis and others recently published (PNAS, 16801562) on an experiment in moderate-scale HTS in vivo antimicrobial screening. They used bacteria-infected C. elegans, and found several agents (mostly weak) that were active in vivo only, and inactive on axenic bacteria. As the authors note, in-vivo-only antibacterial activity might exist, variously, for non-exciting reasons (such as hyperconcentration of the agent in the worm), but also for very interesting reasons (ie the agent being a prodrug, an immunostimulant, an antagonist of essential immune-evasive molecular physiology of the bacteria, or dependent for toxicity or activation on a host-induced alteration in bacterial phsyiology).

But of course, many more antibacterials are known that are active in vitro but inactive in various mammals... horrible pharmakokinetics presumably being the #1 reason.

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10. Scott on January 12, 2007 3:08 PM writes...

Oh, for crying out loud!!! How long and how difficult can it be to see if the hot-pepper compound capsaicin really works or not IN humans to destroy cancer cells? Time for "Rocket Medicine"? Better get a group with percent receiving placebo...??? 2-4 year studies before submitting to FDA? 10 years in development? Major press has already dropped the story after their 15 second blurbs....heal yourselves, eat & enjoy some peppers LOL!

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11. eugene on January 12, 2007 3:55 PM writes...

Well, the good thing about the story is that any potential "cancer cure" from something as common as hot peppers, is much less likely to be toxic in vivo than something that comes from a library screening. We know that peppers don't kill people who eat them (at least not through toxins), so anything that humans have been putting into their bodies for a long time is already a great step forward if you want to fast track your trials.

It's much less likely to be bad for you in concentrated form than something from a combi chem library.

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