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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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« Into the Clinic. And Right Back Out. | Main | Altermune - Real Stuff or Not? »

May 7, 2009

Angiogenesis Inhibitors: Helping or Hurting?

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Posted by Derek

Now, here’s something to think about: can angiogenesis inhibitors, the famous class of tumor-starving cancer drugs, actually make some kinds of cancer worse?

This unnerving thought comes courtesy of two recent studies on VEGF pathway inhibitors which present what calls "intriguing, almost perplexing evidence" of just that. One team studied the effects of an anti-VEGF-receptor antibody or the VEGF kinase inhibitor Sutent (sunitinib) in mouse models of pancreatic cancer or glioblastoma multiformis. These are two very nasty tumors, and they’re just the sort of thing that people would like to be able to treat when a new drug comes along. But treatment with either the antibody or the small molecule significantly increased the number of metastatic cancers in the animal models, and I mean significantly: like 6% highly invasive tumors in the controls versus over 50% in the treated group. Admittedly, those numbers were in immune-compromised animals, but in mice with normal immune function, the numbers of metastatic tumors still rose by two- to four-fold.

The other study looked at injections of either metastatic breast cancer cell lines or melanoma lines in mouse models. The authors reproduced the effects of Sutent on the former – it inhibits growth of locally placed tumors, as it should (on past evidence). But if you inject cells into the bloodstream, the story is different. Pre- or post-injection treatment of the mice with Sutent led to an increase in metastatic tumors and a decrease in survival relative to untreated mice. Similar results were obtained with Nexavar (sorafenib), which also hits the VEGF kinase, among others.

That “among others” might be significant. The antibody study does make you think that this is a VEGF-driven effect, but it’s important to remember that both Sutent and Nexavar hit a famously wide variety of kinases. And as a Nature item on these results points out:

It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects.

Oh, yes. Among these questions are whether the other VEGF-targeting drugs (like Genentech's Avastin) have this effect. You'd have to presume that they would. And what about other therapies directed at other anti-angiogenic targets?. They might, if the effect is brought on simply by low oxygen levels in tumor cells, or it might be something specific to VEGF. We also don't know, in general, which sorts of tumors respond in this way and which don't. But these findings should have effects on clinical practice, and soon. They didn't quite come out of the blue - it's been known since the anti-angiogenic drugs were developed that they didn't actually seem to cure cancers so much as knock them down for varying lengths of time. And in many cases, patients only survive a few months longer after treatment.

Every time I write something like that, though, I'm tempted to quote Peter Altenberg and say "What's so only"? But there still seems to be so much more potential in the idea - the same potential that led to a lot of hype and craziness a few years ago - and perhaps we're beginning to see where things went wrong. Can they be put right, or not?

And you know, perhaps it's for the best that Judah Folkman himself isn't still around to see these latest results. I don't think he would have despaired, but it wouldn't have been easy news for him to hear. . .

Comments (21) + TrackBacks (0) | Category: Cancer


COMMENTS

1. MarkM on May 7, 2009 9:01 AM writes...

Wow. This is NOT good news.

Sure, it adds to the overall body of knowledge re: molecular intervention to slow or stop cancer.

But jeez, arent we due for some surprising results on the cancer front that is actually good news?

Regarding pancreatic cancer, I have seen with my own eyes the accelerated progression of the disease upon commencement of chemo. Yes, it merely an empirical observation from a limited data set from a non-physician. Still, I will always wonder if another path would have given us more time with my dad.

Man, do we have a LONG way to go in this area.

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2. partial agonist on May 7, 2009 9:24 AM writes...

Hard to say what it is since Sutent hits 70+ kinases. It is vry possible it has nothing to do with VEGF activity. If the antibody has similar issues, I'll buy it.

I hate bio papers / clinical papers that jump to such conclusions. I read one recently where it disparaged the activity of a certain class of compounds targeting a receptor, but the tool compound they used was a awful-looking Michael acceptor, a cyanocinnamate that ought to wreak havoc everywhere by reacting willy-nilly with about every biological nucleophile you can think of.

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3. HelicalZz on May 7, 2009 10:31 AM writes...

Not an area I'm overly familiar with but my ipression was (from an older SciAm article I think) that anti-angiogenisis factors often do initially improve vascularization of some tumors (which is often an unorganized mess to begin with). This paradoxically can intially make tumors worse, but also improve the efficacy of traditional chemotherapy in that early timeframe.

Wasn't there a well known trial where an anti-angiogenisis factor performed worse than a chemo control, but the chemo + anti-ang. arm was substantially (and surprisingly) better.

I wouldn't be surprised that my knowledge is dated in this area (like in so very many), but if that recollection is correct, don't the results make sense.

Zz

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4. Lucifer on May 7, 2009 2:07 PM writes...

But the failed gods at famous universities and pharma understand the precise mechanisms behind various cancers... right?

Look, we barely have a clue about the mechanisms behind the onset and spread of most types/ subtypes of cancer. If we had a clue we would already have effective drugs for most types/ subtypes of cancers!

Let us stop pretending that we know a lot about cancers and start trying various concepts. Example- People are testing many kinase inhibitors nowadays. Why restrict ourself to testing those compounds that have specificity or the desired kinase inhibitory activity. Why not test the other reasonably non-toxic compounds developed in such programs? We could start with animal models.. Maybe we might stumble on something we could never have otherwise discovered.

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5. Sili on May 7, 2009 3:30 PM writes...

But we *do* know a lot about cancers - just not enough.

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6. Lucifer on May 7, 2009 4:23 PM writes...

The doctors of old also knew that TB in poor people was caused by insolence to their masters and moral impurity- not bacteria.

Of course, in their rich patrons TB was caused by humors and climate.

//But we *do* know a lot about cancers - just not enough.//

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7. CMCguy on May 7, 2009 4:29 PM writes...

Sounds like Lucifer wants to take a Combinatorial Library Approach to Clinical Studies. Great if had unlimited resources. Not sure how would get many more reasonably non-toxic compounds since in most cases the entry in to tox study mode is where majority of analogs get left out.

Statement from Nature looks reasonable suggestion that may be more issue of timing and/or co-treatment that makes angiogenesis inhibitors viable although not the miracle cures once proclaimed. Cancer, as with lots of other things, seems the true "more we learn the less we know" (attribution unknown).

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8. Lucifer on May 7, 2009 4:39 PM writes...

CMCguy,

Nope, a more simpler way is to test all "usable" compounds developed for a program in gross toxicity assays. If they do not cause serious toxicity- try using them in animal models.

If you want to save money- Try using the so called binding/ enzyme assay "inactive" analogs of "active" compounds. What are you going to lose? It is not as if the approved kinase inhibitors are cures for cancers anyway.. just less toxic than classical chemo.

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9. CHEMS-R-US on May 7, 2009 9:47 PM writes...

Are highly potent and selective compounds the way to go? Do we REALLY need to have rational drug design to actually find effective drugs?
When you look at compounds like thalidomide, that have low potency in multiple targets but somehow work in the clinic, you realize that we definitely don't know a lot about cancers.

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10. CMC guy on May 7, 2009 10:57 PM writes...

Lucifer still not on same page. As I see it since typical discovery projects generate many active (to varied degree) analogs but transitioning to development candidates weeds out majority (with most places having internal selection criteria). A gating factor is often need for more material above the low mg amounts made for screening and I don't know what gross tox assays you mean but most require a decent amount to run. So to me there are not usually many (or more so enough to test) additional usable compounds just laying around to push into animal models. Further the cost of tox screening and then the animal models you advocate are non-trivial to implement. The Devil is in the Details so unless you overcome practical aspects the proposal seems limited.

I can also think of a counter point which may be relevant although post stages mentioned above is that most cancer compounds in development or more so after approval for one use do get widely investigated to see if they work in broader spectrum of cancers. Sometimes this is based on proposed MOA considerations of drug/cancer type however this can be due to simple desperation attempts because lack of effective treatments. How ever we get there we need more and better ways to tackle cancer.

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11. anon on May 8, 2009 8:06 AM writes...

"Are highly potent and selective compounds the way to go? Do we REALLY need to have rational drug design to actually find effective drugs?
"

We need lots of dead-flat kinase inhibitors that crash out in the kidneys. *snark*

Or maybe we need to cut R&D to the bone to increase executive bonuses. This improving the human condition thing is expensive, complicated, and not predictably profitable. *snark*

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13. Howie Feltersnatch on May 8, 2009 1:57 PM writes...

I read these papers and I believe the suggestion was made that the problem with VEGF and PDGFR inhibitors was not how they were altering pathways in the cancer cells, but rather that they were making other tissues more welcoming for metastases. I believe the term they used was "metastatic conditioning".

Permalink to Comment

14. quack on May 8, 2009 4:25 PM writes...

It seems to make a little sense to me. If I was a tumor and the neighborhood got nasty (i.e. not enough oxygen), I would get up and move. It would not surprise me if a nasty neighborhood is one of the triggers for a tumor to metastasize. I could imagine that a large tumor may have localized low oxygen/nutrient levels that causes it to move. The angiogenesis inhibitors just mimic this effect.

Permalink to Comment

15. David Govett on May 8, 2009 5:08 PM writes...

The human body is a fantastically complex system of systems. Until we are able to reliably model individuals as unique, recursive systems, we will be shooting in the dark. I wager that we won't understand enough until the Singularity arrives, at which point everything (good and bad) will seem to happen simultaneously. Mirabile dictu!

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16. Joel Hammer on May 8, 2009 8:14 PM writes...

As a pathologist, I never understood the rationale for VEGF inhibitors. It is just not true that cancer cells need to recruit a blood supply. High grade tumors just invade normal tissue. Really high grade tumors don't even their own capillary bed.

Somethings are just obvious under the microscope. It is a shame that the vast majority of oncologists never look through a microscope.

Confused? Follow the money.

Permalink to Comment

17. Fat Man on May 8, 2009 11:30 PM writes...

"perhaps it's for the best that Judah Folkman himself isn't still around to see these latest results. I don't think he would have despaired, but it wouldn't have been easy news for him to hear. . ."

I did not know Judah Folkman z"l, well. I did know his father, the late Rabbi Folkman, z"l, as he was my rabbi for many years.

I do not think that Judah would have been upset to hear this news. He never claimed that he could cure cancer. That was newspaper hype.

I think he would have been energized. He would have wondered what this means. Nature has given us a clue about how living things work. We must work hard to understand its meaning. I think that would have been his attitude.

Permalink to Comment

18. mjaybee on May 10, 2009 8:40 AM writes...

"Angiogenesis inhibitors" means drugs that inhibit angiogenesis and who knows what else. Off target specificity may enable a host of other functions.

Someone above cited an article noting this is "old news". It is.

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19. @drsteventucker on May 11, 2009 1:31 AM writes...

Sounds frighteningly like ESA's. I use these drugs daily with patient care and you can only glean bits and pieces when you are that close. What I see is straight forward. A few patients get dramatic favorable results, a few get miserable/ineffective results, most we have no idea. All get a very large pharma bill!

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20. damien bove on May 11, 2009 2:24 AM writes...

This is an issue that has recentley raised its head in my work and I must say that its very compelling. we all know that metasasis is an ordered process, but some of these new theories give the cancer a chilling kind of "inteligence" in terms of its response to anti-cancer therapies, but the more I see the more I beleieve (not inteligence mind - just programmed to survive)

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21. Reyn on May 26, 2009 11:05 PM writes...

This isn't really surprising at all. Hammer makes the point that less vascularized tumors are known to be more invasive. THe molecular mechanisms of this have recently been investigated and its that hypoxia induces a stem cell like, invasive, EMT, whatever-you-want-to-call-it phenotype. Recent pubs show transfecting cancer cells with myoglobin causes terminal differentiation and complete inhibition of progression. There is also a decent amount of work out there talking about HIF expression and chemo/radio resistance, etc.

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