Resistance Isn't Quite Futile

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This is a copy of a Blog on the internet, you can read it and the comments

it generated below or you can go directly to the link to read it and get a

short bio on the author. This post reminds us how important it is for us to

help keep researchers focused on a cure. Otherwise we will find ourselves

continually stuck in the " high-stakes " drama of waiting for the next new

" magic bullet " to extend our time here on earth or give us relief from one

set of side effects only to have to deal with another. On the one hand we

are very happy to be alive...

Here's the link:

http://pipeline.corante.com/archives/2006/06/04/resistance_isnt_quite_futile

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June 04, 2006

Resistance Isn't Quite Futile

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Over the last few years, there's been more attention paid to a problem in

cancer therapy that is going to keep us all very busy: drug resistance.

Everyone's heard about this topic in reference to antibiotics, and with good

reason. But the same thing happens in oncology, which makes sense. Despite a

lot of major differences, in both cases we're trying to kill off robust,

fast-dividing cells that have a lot of genetic variation in them. Anything

that doesn't respond to the drug is going to have an open field in front of

it.

The situation in cancer might actually turn out to be worse than in

antibiotics, disturbing though that sounds. For one thing, cancer cell lines

are often rather genetically unstable, which may well be how they ended up

becoming cancer cell lines in the first place. So mutants are pretty easy to

come by. Counterbalancing that, they don't have a quick way of transferring

genetic material to each other like bacteria do, which means that we don't

have to restrict the use of the therapies like we have to with antibiotics.

Each patient is an island, fortunately.

The real difficulty is that antibiotics are typically taken for a set course

of treatment - you knock the infection down enough to where the patient's

immune system can clean up the rest, and everything's done. But cancer

therapies, the kind that we're turning out now, are likely going to be more

like insulin is for diabetics - you're going to be taking them for a long

time, quite possibly for the rest of your life, which gives plenty of time

for something bad to happen. It's impossible to know whether all the cancer

cells disappear, or whether they're just lying low. So no one's sure yet

what will happen if you go off of the drugs, and as you can imagine, that's

data which is going to be hard to obtain.

Gleevec (imatinib) is a good example. There are all too many patients who

have taken the drug for longer periods and have seen it lose its

effectiveness, which must be really a wrenching experience. The kinase that

the drug targets (Bcr-Abl) turns out to have a

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=A

bstract & list_uids=16642048 & query_hl=5 & itool=pubmed_docsum> number of mutant

forms that are unaffected by Gleevec, so any cells that have (or develop)

these variants are free to cut loose. Interestingly, it may be the case that

Bcr-Abl itself sets up conditions inside the cell that

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=A

bstract & list_uids=16527898 & query_hl=5 & itool=pubmed_DocSum> favor development

of mutations, which for cancer cells could be something of a survival tool.

The only way around such problems is to make new drugs, just like in the

antibiotic field. Two of the most advanced ones are

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=A

bstract & list_uids=16721371 & query_hl=5 & itool=pubmed_docsum> AMN107

(nilotinib) and

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=A

bstract & list_uids=16542059 & query_hl=5 & itool=pubmed_DocSum> BMS354825

(dasatinib). Dasatinib had a good ASCO meeting, with an FDA committee

recommending its approval, and with new data being presented comparing it

<http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104 & STORY=/www/story/06-0

3-2006/0004373606 & EDATE=> head to head with Gleevec. So far, it looks like

it's superior to higher doses of Gleevec in CML patients who've started to

show resistance, but this is all with blood markers (as opposed to real

survival data, which naturally takes longer to come in). But so far, so

good.

These might

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=A

bstract & list_uids=16614241 & query_hl=5 & itool=pubmed_DocSum> remain useful for

longer, since their binding modes are somewhat different than Gleevec, and

whole classes of mutant Bcr-Abl forms are still susceptible. But resistance

will surely keep cropping up. We're going to be a this for a long time.

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e.php#120982> 1. <http://terrasig.blogspot.com/> Abel Pharmboy on June 4,

2006 09:50 PM writes...

A great analysis, as usual, .

As a grant-fed researcher I have no dog in this fight either way, but I'm

honestly surprised to see the kinase inhibition working so well in the

clinic. Given the sustained, high-level inhibition needed to get cells to

die, I'll be interested to see how drugs coming down the pipeline work that

target survival factors like IAPs.

One would think that even briefly knocking out survival pathways (IAPs,

aerobic glycolysis) might be more effective than kinase inhibitors since

tumor cells normally survive in environments where no self-respecting cell

would be found. That's without even getting into the long-awaited

realization of anti-angiogenic therapies, surprisingly low impact this ASCO

meeting. But, then again, I think I'm wise enough to know that there is

plenty of biology known in pharma that never makes it to the stuff I read.

Also, I think that pharma might somehow find a way to capitalize on

chemoprevention, the most effective cancer " treatment " known. Statins are

nicely analogous in CV disease but there's no easy serum surrogate like

cholesterol for cancer...yet.

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e.php#121021> 2. <http://stevenjens.blogspot.com/> Jens on June 5,

2006 12:08 AM writes...

I would think the " each man is an island " factor would help the

pharmaceutical industry in the long-run, too; just as cancer doesn't

propagate from one person to another, strains of cancer don't evolve in the

population over time. Bacteria can get more sophisticated over time, and

penicillin doesn't do much, but even if a cancer drug loses its

effectiveness for a given patient, Gleevec should still be useful in a new

cancer patient 50 years from now. No part of the arsenal becomes obselete

(unless, I suppose, something better comes along that operates against the

exact same target).

Or do I not know what I'm talking about? I'm not always sure.

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e.php#121041> 3. DLIB on June 5, 2006 01:23 AM writes...

,

Assuming simple target variation ( versus efflux...) what makes one drug

more susceptible to resistance versus another. How do med chemisits optimize

to prevent this? Does med chem exacerbate this?

DLIB