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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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« Running Out of Helium? | Main | Lilly Tries to Make It Up in China »

March 20, 2012

Personalized Medicine for Cancer? Try Every Cell.

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Posted by Derek

There's more news in the area of looking at what a cancer really is, cell by cell. This topic has come up here before, and the newer sequencing technologies are going to make it a bigger and bigger deal.

This latest paper (in the NEJM) looked at samples from four patients with metastatic renal cell carcinoma (RCC). (Here are a couple of summaries if you don't have access). In the first patient, they sampled the primary tumor and a metastatic tumor from the chest wall after surgery. These were then divided into zones, and deep sequencing was done on the samples. Consistent with earlier work, they found a lot of heterogeneity:

(We) classified the remaining 128 mutations into 40 ubiquitous mutations, 59 mutations shared by several but not all regions, and 29 mutations that were unique to specific regions (so-called private mutations) that were present in a single region. We subdivided shared mutations into 31 mutations shared by most of the primary tumor regions of the nephrectomy specimen (R1 to R3, R5, and R8 to R9), pretreatment biopsy samples of the primary tumor, and 28 mutations shared by most of the metastatic regions. The detection of private mutations suggested ongoing regional clonal evolution.

A tumor, in other words, is a war zone of mutated cells. It's not so much that a single cell goes rogue and spreads out everywhere. It's that the conditions that allow a cell to become cancerous are conducive to further genetic instability, leading to a competition of different branches and mutant families within what might appear to be a single tumor sample. A single biopsy is not enough to tell you what's going on. The metastatic tumors, as you'd expect, tended to be derived from particular lineages that were more likely to break loose and spread, and then they continued to evolve in their new locations. But the nastiest cells win, and sometimes they end up looking rather similar:

Despite genetic divergence during tumor progression, phenotypic convergent evolution occurs, indicating a high degree of mutational diversity, a substrate for Darwinian selection, and evolutionary adaptation.

This sort of thing is making the earlier attempts at finding cancer biomarkers look rather naive. Not only is cancer not a single disease, and not only is a single type of cancer not a single type of cancer, but individual patients contain a multitude of different cancerous cell lines, which vary by location. We're going to have to do a lot more work to understand what's going on in there - a lot more samples, a lot more sequencing, and a lot more thought about what it all means. Personalized medicine is getting a lot more personal than we thought: cell by cell.

Comments (28) + TrackBacks (0) | Category: Cancer


COMMENTS

1. Rick Wobbe on March 20, 2012 7:49 AM writes...

Obviously, it will be very interesting to see comparative data on non/pre-metastatic tumors as well as primary tumors and metastases of other cancers. If the complexity continues to grow as you suggest, it may be that the biggest contribution of genome sequencing thus far lies not in knowledge that speeds drug discovery, but rather a hint that the unknown is much more vast than we had thought. I wonder if and how that might refocus cancer drug discovery...

To update the French proverb, Plus ca change, plus c'est la meme chose: plus change.

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2. Curious Wavefunction on March 20, 2012 8:08 AM writes...

This reminds of that study where they found no less than 23,000 mutations in a lung cancer cell line. Seems personalized medicine is ripe for a reworked Gibbon quote (quoted by Feynman in his "Lectures"): "The power of personalized medicine is seldom of much efficacy, except in those happy dispositions where it is almost superfluous."

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3. newnickname on March 20, 2012 9:13 AM writes...

For many years, Arnold Glazier has been pointing out "that cancer is an enormously diverse, unpredictable evolutionary process and discusses the logical and practical implications." Elsewhere: "Targeting genetic alterations can provide specificity and can kill or control a sub-set of cancer cells, but cannot generally provide comprehensiveness. Therapies that lack comprehensiveness act as selective pressures and re-direct the flow of tumor cell evolution, but cannot cure or control the disease."

He has some unconventional approaches to a cancer cure consistent with this NEJM report and his own work on the diversity of cell types in cancer. He was pushing "pattern recognition" before others.

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4. luysii on March 20, 2012 9:23 AM writes...

Another paper on the same subject is [ Cell vol. vol. 148 pp. 886 - 895 '12 ] possibly by the same authors. The exons (amino acid coding parts of genes coding for proteins) of 25 different cells were sequences in 25 cells of a clear cell renal cell carcinoma (the most common type of kidney cancer). Many mutations were present in just a few cells, some present in just 2 - 5 of the 25 cells which had their exomes sequenced.

Next up, single cell sequencing of the 98% of the genome NOT coding for protein, or the 99% of the genome NOT coding for exons. I think the results are like to be even worse.

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5. Rick Wobbe on March 20, 2012 9:32 AM writes...

Picking up on the evolutionary theme, it seems important to repeat this sequencing approach on cells recovered during the course of therapy as well. As with infectious diseases, we must consider the hypothesis that some therapies might paradoxically worsen the situation by selecting for more pathogenic subsets of cells.

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6. lynn on March 20, 2012 9:48 AM writes...

So, what's the [process of] the hypermutable state? Perhaps that can be inhibited [as an adjunct].

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7. PharmaHeretic on March 20, 2012 9:52 AM writes...

Oh come on..

People love scams that offer false hope. Reality is such a drag.. plus it comes in the way of making profit.

Stealing from desperate, vulnerable and dying people to enrich MBAs and a few connected 'scientists' is just good business and the american way.

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8. RD on March 20, 2012 10:06 AM writes...

>We're going to have to do a lot more work to understand what's going on in there

Gee, too bad we're all laid off. Bummer.

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9. A guy on March 20, 2012 11:26 AM writes...

Kind of makes the Gerson method look even more silly. How are coffee and ozone enemas supposed to help this?

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10. Hap on March 20, 2012 12:04 PM writes...

Doesn't this imply that treating the phenotype might be more effective than going after specific mutations? Since cancer cells with particular mutations are likely to be genetically unstable and susceptible to resistance pressures, drugs focused on specific mutations would seem to be fighting an uphill battle to remain efffective. If they converge to similar phenotypes, however, then the strengths and weakness of those phenotypes can be used against all of them - if it kills them, great. If it forces them to mutate to be less virulent, that might also be OK. Am I confused?

I think there's a dropped backslash after the first quote (or first italic).

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11. Rick Wobbe on March 20, 2012 12:15 PM writes...

Hap, 11,
I was thinking exactly the same thing. In effect, you could argue that the first classes of chemotherapeutic agents, by focusing on the phenotype of metabolic hyperactivity, did exactly that.

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12. Nitpicker on March 20, 2012 12:21 PM writes...

Derek, looks like you forgot to close the quote in this post. The whole blog is in italics past this point.

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13. Charlie Abrams on March 20, 2012 12:54 PM writes...

I'm a chemist, not a biologist, so please help me understand this. If the hallmark of cancer is continuous mutations, what can be learned from drug studies with HeLa cells? Aren't they all the same, i.e. they don't continue to mutate? Does this report mean that HeLa cells are a poor model for cancer because they don't have constant mutations? (But it is nevertheless a good model for the phenotypic hypermetabolism?)

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14. SP on March 20, 2012 1:07 PM writes...

Following up on a post from a couple month ago- SCOTUS unanimously bounced Prometheus for their claim of "If a patient hasn't had enough drug to give the desired blood levels, give them more."
pipeline.corante.com/archives/2011/12/12/dont_dose_that_patient_until_you_pay_up.php

Permalink to Comment

15. SP on March 20, 2012 1:14 PM writes...

14- No, it's a well known problem that supposedly identical cancer cell lines in different labs can be very different, making it hard to reproduce results. Passage number, mutation, and unfortunately contamination are all things confounding reported results.
That said, it's important to distinguish "driver" mutations from "passenger" mutations. A lot of mutations are just picked up by the general instability of a cancer cell and are along for the ride and probably don't affect the underlying sensitivity of the cells. Unfortunately, when you treat with a drug you select for the few mutations that do result in resistance. That's how Darwin said it works.

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16. newnickname on March 20, 2012 1:25 PM writes...

@14 and 16: I posted on Mar 12 ("Brute Force"):

Cell pathologist Gerald B Dermer has long argued that cell-based cancer research is a losing proposition. See his book The Immortal Cell (not to be confused with the life extension book with the same title by Michael D West of Advanced Cell Technologies in Marlboro).

(As I recall, he had trouble getting his research funded because of this criticism of the mainstream.)

Permalink to Comment

17. barry on March 20, 2012 1:32 PM writes...

one big lesson many of us haven't yet taken from the Gleevec story is that it's very effective in early CML when there's just the BcrAbl ("philadelphia chromosome") defect, and inefficacious in later (blast crisis) disease. That first recombination even makes the genome unstable and mutations snowball after that. Some of those mutations are lethal. We don't see those cells. A few of those mutations are beneficial to the cancer. These come to dominate the cells we do see when we do late biopsy.

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18. Anonymous on March 20, 2012 1:51 PM writes...

#16 -- Driver mutations are certainly a cause for the hope that just attacking them would cure (or slow down) cancer. But look at this

[ Nature vol. 458 p. 721 '09 ] 350/22,000 protein coding genes show recurrent somatic mutations in cancer with strong evidence that they contribute to cancer development. 35/350 can be found in the germ line where they cause familial cancer syndromes. Some (p53) are found in many cancers, while others are restricted to one type of cancer. 315/350 are dominant.

The work gives evidence that there are 'many more' driver mutations than can be accounted for by known cancer genes. The drivers are distributed across a large number of genes, each of which is mutated infrequently, 'suggesting' that the repertoire of somaticlly mutated human cancer genes is much larger than the 350 cited above.

If a few driver mutations are a cause of a particular type of cancer (say lung), then mutations in all should be found in samples from multiple patients. Sadly, this is not the case. This has been shown again and again.

There has been significant criticism of the cancer genome atlas as a waste of money, but has certainly shown this.

Permalink to Comment

19. luysii on March 20, 2012 1:52 PM writes...

#16 -- Driver mutations are certainly a cause for the hope that just attacking them would cure (or slow down) cancer. But look at this

[ Nature vol. 458 p. 721 '09 ] 350/22,000 protein coding genes show recurrent somatic mutations in cancer with strong evidence that they contribute to cancer development. 35/350 can be found in the germ line where they cause familial cancer syndromes. Some (p53) are found in many cancers, while others are restricted to one type of cancer. 315/350 are dominant.

The work gives evidence that there are 'many more' driver mutations than can be accounted for by known cancer genes. The drivers are distributed across a large number of genes, each of which is mutated infrequently, 'suggesting' that the repertoire of somaticlly mutated human cancer genes is much larger than the 350 cited above.

If a few driver mutations are a cause of a particular type of cancer (say lung), then mutations in all should be found in samples from multiple patients. Sadly, this is not the case. This has been shown again and again.

There has been significant criticism of the cancer genome atlas as a waste of money, but has certainly shown this.

Permalink to Comment

20. johnnyboy on March 20, 2012 2:27 PM writes...

@11 (Hap): you're not confused, but perhaps you're reading too much into the author's comments about 'phenotype convergence' - by which I think they just mean that even though the cells from one tumor may have very different mutations, they all look pretty similar under the microscope. The phenotypic 'strength and weaknesses' that you allude to are already pretty well known (high metabolic rate, high mitotic rate, etc...) and are already the basis of the prior oncology therapies that are not genome-driven, namely anti-mitotic agents, and anti-angiogenics. Other more subtle approaches are under development, such as SGEN's approach, which combines a cytotoxic payload to an antibody targeting the tumor cell surface. As you know, the challenge with any such approach is affecting the tumor cells while minimizing effects on normal host cells; this challenge is the reason why targeting mutations sounded so promising 20 years ago, as it theoretically would have allowed tumor regression without significant effects on non-mutated, normal cells. Clearly, reality has not lived up to the theory...

To me what this and other research on tumor mutations indicates is that targeting single mutations in advanced tumors will in most cases lead only to a growth delay, at best.
The broader lesson is that advanced, metastatic tumors will probably never be curable. Research on cancer therapy should be seriously re-focused on methods of early detection and early removal, which is by far the best way to effect a cure. More and more, I think the current focus of much of biotech, ie. developing drugs that target advanced, non-responsive tumors (as is generally the case in clinical trials of new drugs) is a fool's game, and will be recognized as such in the coming years; already the flagging VC investment into biotech is pointing towards this. Any hope for the future should be directed at developing new non-invasive imaging techniques, blood or body fluid biomarkers for early detection, etc...

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21. David Formerly Known as a Chemist on March 20, 2012 3:08 PM writes...

Perhaps this is the start of an unfortunate U-turn back to surgery, radiation, and cytotoxics. Which we never really left.

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22. metaphysician on March 20, 2012 3:59 PM writes...

Random thought: harness the evolutionary process for the patient's benefit. Instead of treatments aimed at killing the cancer, treatments aimed at encouraging the cancer to evolve along lines that make it more benign to the patient. The holy grail would be a way to induce a cancerous growth to become entirely harmless, or near enough not to matter.

Aside from the obvious "how?" question, are there any obvious gaping holes in the idea?

Permalink to Comment

23. Student on March 20, 2012 4:22 PM writes...

@23. What do you mean by benign? Slowed/stopped growth? Stopped invasiveness? That is what people are already trying to do.

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24. SP on March 20, 2012 5:25 PM writes...

An analogous approach in anti-infectives is to target quorum sensing, which is how a lot of bugs know to become virulent once they've reached a certain critical mass. Or just target virulence factors, independent of the quorum concept. The idea is that turning off virulence is not the same as targeting growth so you won't be applying selective pressure and can avoid resistance. I'm not sure what the equivalent of virulence in cancer would be.

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25. Clueless on March 20, 2012 7:07 PM writes...

Okay, personalized medicine is not for cancer.

Wait, actually it could still be if personalized further more.......

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26. Morten G on March 21, 2012 5:54 AM writes...

Weird, I think I sat next to one of the authors on the train last Friday.

There's still a lot that can be achieved with traditional cytotoxics. Recently there was a paper where side effects were significantly reduced by having the patients fast for two days before and one day after the chemotherapy. Theory is that the healthy cells go into a temporary stasis while the cancerous cells keep chugging. That can probably be improved significantly and there's tricks like cancer cells that are glucose dependent because of being in a hypoxic state that aren't really exploited.

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27. David Young on March 22, 2012 1:00 PM writes...

We may still get a lot out of cytotoxics (dna damaging agents or poisons of mitosis) if we can link them better to antibodies that target cancer cells. At least this is one notion of how to improve the therapeutic ratio.

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28. tans on March 23, 2012 6:20 AM writes...

For all that heterogeneity and "mean cell wins," it's amazing how close to quantitative effectiveness with CA19-9+CSLEX tissue stained targeting, advanced colorectal cancer can be treated by cimetidine plus continuous 5FU or UFT.

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