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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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August 16, 2010

Cancer Cells: Too Unstable For Fine Targeting?

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Posted by Derek

The topic of new drugs for cancer has come up repeatedly around here - and naturally enough, considering how big a focus it is for the industry. Most forms of cancer are the very definition of "unmet medical need", and the field has plenty of possible drug targets to address.

But we've been addressing many of them in recent years, with incremental (but only rarely dramatic) progress. It's quite possible that this is what we're going to see - small improvements that gradually add up, with no big leaps. If the alternative is no improvement at all, I'll gladly take that. But some other therapeutic areas have perhaps made us expect more. Infectious disease, for example: the early antibiotics looked like magic, as patients that everyone fully expected to die started asking when dinner was and when they could go home. That's what everyone wants to see, in every disease, and having seen it (even fleetingly), we all want to have it happen again.

And it has happened for a few tumor types, most notably childhood leukemia. But we definitely need to add more to the list, and it's been a frustrating business. Believe me, it's not like we in the business aiming for incremental improvements, a few weeks or months here and there. Every time we go after a new target in oncology, we hope that this one is going to be - for some sort of cancer - the thing that completely knocks it down.

We may be thinking about this the wrong way, though. For many years now, there have been people looking at genetic instability in tumor cells. (See this post from 2002 - yes, this blog has been around that long!) If this is a major component of the cancerous phenotype, it means that we could well have trouble with a target-by-target approach. (See this post by Robert Langreth at Forbes for a more recent take). And here's a PubMed search - as you can see, there's a lot of literature in this field, and a fair amount of controversy, too.

That would, in fact, mean that cancer shares something with infectious disease, and not, unfortunately, the era of the 1940s when the bacteria hadn't figured out what we could do to them yet. No, what it might mean is that many tumors might be made of such heterogeneous, constantly mutating cells that no one targeted approach will have a good chance of knocking them down sufficiently. Since that's exactly what we see, this is a hypothesis worth taking seriously.

There are other implications for drug discovery. Anyone who's worked in oncology knows that the animal tumor models we tend to use - xenografts of human cell lines - are not particularly predictive of success. "Necessary but nowhere near sufficient" is about as far as I'd be willing to go. Could that be because these cells, however vigorously they grow, have lost (or never had) that rogue instability that makes the wild-type tumors so hard to fight? I haven't seen a study of genetic instability in these tumor lines, but it would be worth checking.

What we might need, then, are better animal models to start with - here's a review on some efforts to find them. From a drug discovery perspective, we might want to spend more time on oncology targets that work outside the cancer cells themselves. And clinically, we might want to spend more time studying combinations of agents right from the start, and less on single-drug-versus-standard-of-care studies. The disadvantage there is that it can be hard to know where to start - but we need to weigh that against the chances of a single agent actually working

Comments (49) + TrackBacks (0) | Category: Animal Testing | Cancer | Clinical Trials | Drug Development


COMMENTS

1. FMC on August 16, 2010 9:45 AM writes...

In light of the previous threads, I would thoroughly recommend to outsource that kind of problem to some outfit in India or China, while at the same time taking credit for this new and visionary approach to increase ROI !!!
:)

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2. alig on August 16, 2010 9:51 AM writes...

I thought it was going to be less depressing topics this week.

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3. BiotechMan on August 16, 2010 10:04 AM writes...

The industry over the past 10 years or so has been progressively more risk-averse. This is in part due to Wall Street not rewarding innovation and this is reflected in the venture world where "repurposing" was the name of the game. Newer approaches to attacking cancer taken by folks at Agios and Ruga targeting tumour metabolism, endoplasmic reticulum stress etc. may be the wave of the future.

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4. A Nonny Mouse on August 16, 2010 10:21 AM writes...

I thought that the new approach was cancer stem cells.

An "add-on" clinical trial (for CML) is currently on-going in Mass using a marketed drug which does just that.

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5. barry on August 16, 2010 10:45 AM writes...

We still don't know how many diseases cancer is. In the extreme, it might be a swarm of many diseases most of which are too rare to warrant drug development. I don't believe that, but we're not doing well here.
Because the genomes of cancer cells are unstable, it is very hard to succeed at killing an old established cancer--it's more likely to end-run anything we blockade. Alas, these are precisely the cases we choose for clinical studies. It is likely that drugs which would have succeeded against some early cancers (which had fewer mutations) have already failed in the clinic because of the clinical population chosen.

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6. metaphysician on August 16, 2010 11:15 AM writes...

[layman]

Honestly, is it even really clear that 'cancer' is a disease, as opposed to a symptom/failure mode?

[/layman]

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7. 杀獁特の鳮芼 on August 16, 2010 2:28 PM writes...

@A Nonny Mouse
I'm still not totally sold on the cancer stem cell theory, and I believe there is still quite a controversy on this topic today, which is nearly 15 years after Dick's first paper on CSC. Particularly, it doesn't make a lot of sense to me that a tumor would waste so much resource to make tons of differentiated tumor cells, if only the tumor initiating cells are the ones doing the harm. Conventional adult stem cell theory states that stem cell is responsible for proliferation and differentiated cells are responsible for interaction with surrounding enviornment in a mature organ and act as functional units.

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8. Anonymous on August 16, 2010 2:30 PM writes...

Nahhhh. There's all kinds of nihilism expressed by frustrated scientists attempting to develop effective anticancer drugs. All the excuses can basically be summarized as "Its not me, its the XXXX characteristic of the cancer cell."

Wrong. Its just very very hard to develop anticancer drugs since cancer cells (unlike, for example bacteria and viruses) are very very similar in almost all respects to normal human cells. Can you think of a single disease that has been cured (other than some forms of cancer) in which the pathogenic cell that needs to be eliminated is human? Me neither.

Cancer is really really hard. No more excuses. Get back to the lab.

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9. Anonymous on August 16, 2010 2:35 PM writes...

BTW, re: the cancer stem cell thing. This is a great example of a situation where the smartest cancer scientists are basically keeping their mouths shut and waiting for the fad to go away. Very few serious cancer biologists believe much of the cancer stem cell hypothesis, and basically no cancer geneticists believe it. There is just no upside re: saying it in public. Just like the incredible focus on apoptosis in cancer 10-15 years ago, the smartest cancer scientists are just waiting for it to peter out while they keep plugging away at the unsexy fundamentals....

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10. barry on August 16, 2010 2:36 PM writes...

any vaccine that elicits a T-cell response eventually works against disease by destroying a host cell. Perhaps that doesn't qualify as "drug".

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11. LAM on August 16, 2010 2:45 PM writes...

It is highly unlikely that a single "new" approach will "cure" cancers in our lifetimes. Success will continue to be defined by incremental or stepwise improvement in treatments toward endpoints that are meaningful. Whatever the "newest and best" approach, be it selective kinase inhibition, protease intervention, manipulation of stem cell function, T-cell stimulation, no single one is likely to be "the magic bullet", the "key in the lock" for bringing the cancer epidemic under control.

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12. Gillespie on August 16, 2010 4:31 PM writes...

What about tageting glycolysis? Maybe Otto Warburg was onto something. No matter how the cancer cells change genetically, they still have to make ATP, and for many reasons, Ox-Phos doesn't cut it for them, while it works in normal cells.

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13. Andy Pierce on August 16, 2010 5:40 PM writes...

There are a few companies (like Agios) taking a look at the Warburg effect.

The genomic instability of cancer cells has been exploited chemotherapeutically already. For example, many cancer cells are checkpoint defective but this means that normal cells when treated with genotoxic agents halt the cell cycle and repair the damage while cancer cells just blithely divide on into catastrophe. Much more could be done in this area.

Personally, I blame mice for the lack of progress in cancer therapeutics. People (especially academics) have been so busy curing cancer in mice that they haven't figured out how to cure cancer in people. The only good animal model for human cancer is humans, so that's where the experimental drugs should go. I think in part lack of a "good animal model" is what has helped propel HIV treatment to where the disease has gone from death-sentence to mostly chronically manageable.

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14. Anonymous on August 16, 2010 8:01 PM writes...

There are a handful of cancer-like conditions that have benefited from cancer research. (The potential use of Gleevec for treatment of NF comes to mind.)

Of course, providing therapies for these rarer diseases may not be as important as taking on cancer, but let's not forget about them.

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15. barry on August 16, 2010 8:35 PM writes...

While mice dominate cancer research, they're not all alone. For a price, one can treat surgically isolated human cancers grown in nude rats, rather than cancer cell lines that have been selected for growing in culture. There are also spontaneous cancers in old pet dogs, but never enough of them to get statistical answers out.

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16. Charlie Abrams on August 16, 2010 9:49 PM writes...

I think epigenetic drugs (eg. Vorinostat) might have some promise. I remember something from a Breslow talk in Chicago: he said the most active in-vitro compound was too toxic, and the breakthrough was in part the result of looking at the less-potent compounds. Also, the treatment is like hitting the reset button - you don't just keep pounding, you treat for a week or two and then stop. Are these two strategies (less potent/short treatment) part of the usual pipeline development methods?

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17. David Young MD on August 16, 2010 11:56 PM writes...

If scientists can get linkers to work correctly, antibody-cytotoxin complexes may be a major advance. Where-as mylotarg was a failure, some second generation compounds may end up working very well. We'll see.

All the same, the continuous mutability of cancer cells is a major obstacle to a cure... no doubt about it.

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18. Phd Biochem on August 17, 2010 9:19 AM writes...

I did a cancer-related postdoctoral fellowship several years ago, on signal transduction. I realized then that cancer was not going to be stopped by signal blockers or anti-angiogenesis drugs. In my opinion, the most likely chance for success is using the immune system to target the cancer. As the cancer evolves, antibodies of different specificities will be needed. The end state would be vaccines against the most common cancers, and immunotherapy for the more rare forms. Chemotherapy-linked antibodies would be a variation on the theme. We must leverage the body's own sophisticated defense system, and teach it to recognize attacks that natural selection has not caught up to yet.

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19. Douglas Cohen on August 17, 2010 9:43 AM writes...

Biological systems strengthen themselves under the influence of moderate stress (think exercise to promote better circulation and stronger muscles) and weaken when underused. With modern medical science (antibiotics) and the relative scarcity of serious bacterial infections -- defined as causing a fever -- in today's developed countries, the branch of the immune system designed to handle single-cell pathogens has, in most people, become a serious couch potato. If this is the branch of the immune system evolution has designed to recognize and suppress cancer cells, we would expect more and more people in developed countries to die of cancer at every age -- including old age -- than do in undeveloped countries due the developed countries' couch-potato immune systems. To get these immune systems into shape, develop pathogenic bacteria bred to be strongly susceptible to your antibiotic of choice, and infect people at regular intervals with this bacteria, arranging for their immune system to generate a meaningful fever before quelling the infection. If it looks like the infection is gaining the upper hand, administer the antibiotic and after recovery try to tone up the patient's immune system with a weaker source of infection. You may even get lucky, and find that cancer patient's can be cured by toning up their immune system with a tailored course of infections (if the disease has not yet progressed too far and the immune system has not been significantly damaged by current treatments for cancer). There is evidence in the medical literature of good results for cancer patients purposely infected by doctors to produce high fevers (in the early years of the twentieth century). Back then doctors suspected that fever was the curative factor, but from the point of view of the couch-potato hypothesis it was the infection itself, building up the immune system (This line of research, by the way, fell out of favor with the discovery that X-rays shrank tumors. Now, of course, we know all too well the limitations of X-ray therapy)

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20. noahp on August 17, 2010 10:25 AM writes...

Retired from Radiation Oncology 7 years ago in part because of frustration with the "standard of care" enforced by the Medical Oncology mafia. Many patients apparently including Christopher Hitchens are treated with toxic cheotherapy regimes without the slightest evidence of efficacy. I practiced in Memphis for eleven years and cured the only patients with esophageal cancer that were cured in that city. Esophageal cancer is a fairly rare disease...the patients with insurance are scooped up by the surgeons and medical oncologists and they all die. The dregs of society were the ones I treated with about a 40% cure rate among those without apparent distant metastases. But I was never able to convince my "colleagues" that my results were anything other than anecdotal.

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21. Chuck Pelto on August 17, 2010 11:11 AM writes...

TO: Derek Lowe, et al.
RE: Cancer Cures

You REALLY need to look into graviola and pawpaw.

I've SEEN pawpaw kill an aggressive squamous carcinoma on a woman's arm in just ONE MONTH. And, based on my understanding of the mechanism, it should be effective against most forms of cancer.

Regards,

Chuck(le)
[God made the Earth and everything therein for Man. Our problem has been trying to figure out how to use it....properly....]

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22. Chuck Pelto on August 17, 2010 11:19 AM writes...

P.S. That graviola was capable of killing cancer cells while leaving healthy cells in vitro was proven at Purdue University in 1997.

My understanding is that major drug companies have been trying to make a synthetic form of the active agent every since then, but have failed completely.

My suspicion is that the information has been kept close-hold because drug companies cannot make billions on a naturally occurring substance.

Likewise, what successful oncologist or radiologist would want to give up their lucrative practice in order to open up a 'tea shop'?

In the meantime, over half a million Americans die every year from cancer....

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23. Chuch Pelto on August 17, 2010 11:24 AM writes...

TO: noahp
RE: Heh

....I was never able to convince my "colleagues" that my results were anything other than anecdotal. -- noahp

I see that happen ALL THE TIME. And it is one of the reasons I have my 'suspicions' about the 'practice' of medicine being more interested in making money than in saving lives and reducing suffering.

Regards,

Chuck(le)
[What disease did 'cured ham' have?]

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24. Chuck Pelto on August 17, 2010 11:35 AM writes...

TO: Gillespie, et al.
RE: On the Nosy!

What about tageti