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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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« How Many Good Screening Compounds Are There? | Main | Deal of the Year? »

January 3, 2013

Overselling p53 Drugs

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Posted by Derek

You may have seen some "wonder drug" news stories over the holiday break about compounds targeting p53 - many outlets picked up this New York Times story. The first paragraph probably got them:

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Now, to read that, you might think we're talking mutated p53, which is indeed found in a wide variety of cancers. It's the absolute first thing you think of when you think of a defective protein that's strongly associated with cancer. And everyone has been trying to target it for years and years now, for just that reason, but without too much success. If you know drug development, you might have seen this article and done what I did - immediately read on wondering who the heck it was with a broad-based p53 therapy and how you missed it.

That's when you find, though, that this is p53 and MDM2. MDM2 is one of those Swiss-army-knife proteins that interacts with a list of other important regulatory proteins as long as your leg. (Take a look at the last paragraph of that Wikipedia link and you'll see what I mean). Its relationship with p53 has been the subject of intense research for many years now - it's a negative regulator, binding to p53 and keeping it from initiating its own transcriptional activity. Since a lot of that transcriptional activity is involved with telling a cell to kill itself, that's the sort of thing you'd normally want to have repressed, but the problem in some tumor lines is that MDM2 never gets around to leaving, allowing damaged cancerous cells to carry on regardless.

So, as that newspaper piece says, there have been several long-running efforts to find compounds that will block the p53/MDM2 interaction. The first big splashes in the area were the "Nutlin" compounds, from Roche - named after Nutley, New Jersey, much good did it do the research site in the end. The tangled history of Nutlin-3 in the clinic is worth considering when you think about this field. But for some kinds of cancer, notably many lipsarcomas, this could be an excellent target. That link discusses some results with RG7112, which is one of the drugs that the Times is talking about. Note that the results are, on one level, quite good. This is a tumor type that isn't affected by much, and 14 out of the 20 patients showed stable disease on treatment. But then again, only one patient showed a response where the tumor actually became smaller, and some showed no effect at all. There were also twelve serious adverse events in eight patients. That's not the sort of thing that you might have expected, given the breathless tone of the press coverage. Now, these results are absolutely enough to go on to a larger trial, and if they replicate (safety profile permitting), I'd certainly expect the drug to be approved, and to save the lives of some liposarcoma patients who might otherwise have no options. That's good news.

But is it "the beginning of a new genetic age in cancer research", to quote Gina Kolata's article? I don't see how. The genetic age of cancer has been underway for some time now, and it's been underway in the popular press for even longer. As for this example, there are several types of cancer for which a p53/MDM2 compound could be useful, but liposarcoma is probably the first choice, which is why it's being concentrated on in the clinic. And as far as I know, the number of cancer patients with mutated p53 proteins well outnumber the ones with intact p53 and overexpressed MDM2. These new compounds won't do anything for those people at all.

I sound like such a curmudgeon. But shouldn't there be some level of press coverage in between total silence and Dawn Of A Glorious New Era? I suppose that "Progress Being Made On Tough Drug Target" isn't the sort of hed that makes Page One. But that's the sort of headline that research programs generate.

Comments (20) + TrackBacks (0) | Category: Cancer | Clinical Trials | Press Coverage


COMMENTS

1. Anon on January 3, 2013 9:17 AM writes...

Yeah, that piece of news is predictably sensationalist. What also drove me nuts was featuring the VP of Sanofi as the prime mover behind the drug. As usual, the execs and MBAs get all the glory and fame while the real heroes - the scientists - are ignored.

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2. luigi on January 3, 2013 9:21 AM writes...

Not the same Gina Kolata of dinner with James Watson hyping the angiostatin cure for cancer fame?

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3. oldhand on January 3, 2013 9:22 AM writes...

Bad news sells and really bad news sells really well. Good news only sells if it predicts a miracle. In this day of 2 second sound bites and general public illiteracy, there is no chance a well thought out, measured and accurate reporting of hard work on tough problems will sell.

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4. David Formerly Known as a Chemist on January 3, 2013 10:36 AM writes...

I thought the NYT article was quite cautious and balanced and did a nice job of explaining the current status of these developmental compounds. The scientists were prominently featured (not sure what you're talking about, Anon @1). I don't see where Kolata oversold this. Man, this is a cynical bunch.

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5. Helical_Investor on January 3, 2013 11:35 AM writes...

P53 was Science's 'molecule of the year' in what - 1988 (it was 1993, I checked, close enough). Yeah, it has been looked at a bit.

Zz

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6. johnnyboy on January 3, 2013 11:48 AM writes...

@4: "... this as the beginning of a new genetic age in cancer research." Yeah, not oversold at all.

I think the main reason behind the story is that it was during the holiday break, when newsroom actvity is slow (apart from this year's unfortunate political reporters having to stay on to cover that cliff thing), and also a time where editorial focus gets skewed towards 'hopeful' news.
In any case, is anyone actually still looking at mass-market media for proper coverage of medical news ?

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7. Hap on January 3, 2013 11:52 AM writes...

4: Most of the article seems reasonable and measured as a description of how the drugs might come to be and what they might do, but the introduction (talking about how new therapies might be approved based on their mechanisms rather than by their sites of origin, and a "new age of genetic research") seems somewhat premature and overblown.

Even if the initial drugs work, it seems like a leap to assume that the FDA would start looking at mechanism to the exclusion of site of origin to approve cancer drugs. Is there any guidance to suggest that they would do so, given the data?

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8. David Formerly Known as a Chemist on January 3, 2013 12:11 PM writes...

6: Read the very next sentence: "Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones." Not what I would call hype.

7: I don't think that's what the article is saying. The introduction is talking about how the target (p53/MDM2) may be an effective means to combat many tumor types because it's a growth regulatory process common to many cancer types of many different origins. And I don't see any suggestion that FDA would approve drugs based solely on mechanism of action; where did you read that?

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9. barry on January 3, 2013 1:37 PM writes...

p53 is mutated or deleted in a majority of human tumors. It is the archtype of a molecular defect correlating with and driving cancer. A therapy that could restore p53 function to--or just kill--such cells would be revolutionary. That therapy however is still just an aspiration. A far smaller class of tumors are driven by MDM2 inhibition of wild-type p53. A therapy that relieves this inhibition is an exciting prospect. But to bill that as solving "half" the p53 problem is to misrepresent a great piece of work.

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10. Hap on January 3, 2013 2:55 PM writes...

No - the ACS spokeman said that more emphasis would be placed on mechanism of action and less on organ of origin, not (nearly) that site of origin would not be a factor in approving cancer drugs. It does seem premature, though, to assume that this will provide enough evidence to start shifting approvals away from site of origin, since lots of good ideas in drugs have been treated roughly by their targets.

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11. Anonymous on January 3, 2013 4:07 PM writes...

I thought the main premise of the article - that this is is the first in a class of new drugs that are target-specific rather than tumor-type specific and therefore have potential efficacy against lots of different cancers - was an intentional lie to get the story on the front page of NYT. Kolata is not stupid (and I often like her writing and love her book Natural Obsessions). So, I can only conclude that this was an intentional lie.

What about B-Raf inhibitors? EGFR inhibitors? All targets shared by multiple tumor types. My guess is that in response to this comment she would try to semanticize her way out of it...

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12. Eskimo on January 3, 2013 4:22 PM writes...

Derek, your commenters will probably know this better than me. Do these drugs target the protein-protein interaction between p53 and MDM2? Targeting the protein-protein interface, as opposed to an enzyme, is something relatively new and different, right?

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13. Crimso on January 3, 2013 7:30 PM writes...

A very quick and very cursory look through some of the literature seems to indicate that nutlins (and thus perhaps this mysterious RG7112) bind to the p53-binding site of mdm2. Apparently the sites/surfaces of interaction between p53 and mdm2 are quite minimal (and very well-characterized), making it an especially attractive target for disrupting protein-protein interactions. The site targeted on mdm2 is (IIRC) a hydrophobic pocket that p53 docks into.

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14. Curious Wavefunction on January 3, 2013 10:05 PM writes...

11 Anonymous: "Natural Obsessions" is by Natalie Angier and is indeed a great fly-on-the-wall account. I agree that Kolata is a good writer.

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15. Anonymous on January 3, 2013 10:19 PM writes...

@14

Sorry I screwed up by blaming the outstanding science writer Natalie Angier for this article. I should have blamed Gina Kolata. Now the basis of this fictional premise makes much more sense to me.

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16. Old Lab Rat on January 4, 2013 10:02 AM writes...

@Eskimo #12. Yep. The p53/MDM2 and p53/MDMx protein-protein interactions are among the few PPIs that have only a few key residues involved, so it seems a relatively more tractable site for small molecules.

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17. PC_skibum on January 19, 2013 6:46 PM writes...

What I find most interesting about Kolatas' article is her complete failure to mention the fact that a P53 compound is currently in it second cohort Stage 1 clinical trials at no less than Harvard's Dana Farber Cancer Center and partner Beth Israel Deaconess Medical Center. Furthermore, Cellceutix, the companay that has developed the compound recently announced the University of Bologna, Italy, will be starting its own trials shortly and that a soon to be announced major southwestern cancer center will be conducting its own trials on myeloma. Kotatas is a good writer, which leads me to question if this omission was purposeful?

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18. Anonymous on March 10, 2013 9:30 AM writes...

One word.

Kevetrin.

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19. Alexander on March 22, 2013 12:46 AM writes...

3/22/2013:

Kevetrin

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20. Doug on July 23, 2013 1:22 PM writes...

My wife has Liposarcoma and I try and follow these drugs very closely. She was on the first Nutlin trial at MD Anderson, and while her tumors slowed to half their growth rate if no adverse side effects she was still kicked off the trial due to its protocols, the tumor grow >20% in 6 months. They previously were growing at 2x that speed. She had surgery to resect and continues to fight with recurrence. We will likely need to start on a new trial soon and it's extremely difficult to find any information on the top 3-4 current pipeline compounds, we obviously want to chose the best. Kevetrin's seems to be advancing the fastest in trials, the Sanofi drug mentioned in the article doesn't even appear to have made it into a Phase 1 yet...

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