In one of my first posts I commented on the challenge of obtaining samples for microarray and other biomarker work. Getting samples for microarrays is at best difficult, painful to the patient and only a little dangerous to them; in many cases the samples are simply unobtainable. Getting a broad range of samples from multiple sites, or a time series is going to be very rarely feasible.
With this backdrop, a recent paper in Nature Biotechnology is quite stunning. Indeed, it is a bit of a surprise that it didn't show up in the mother ship or Science: the paper is well written, audacious in design and shows very nice results.
Using actual liver cancer patients the paper correlates contrast-enhanced CT (aka CAT) imaging features to gene expression patterns detected by microarrays using samples from the same patients. While these patients had to go through biopsies, the approach holds out the hope of calibrating imaging assays for future use.
The imaging-microarray connections have many intriguing possibilities. Some of the linked microarray patterns have clear therapeutic associations, such as cell cycle genes and VEGF. Such an imaging approach might, with much further validation, enable appropriate selection of therapeutic agents -- such as Avastin to target VEGF.
The paper also notes the challenges that lie ahead. The choice of liver cancer was no accident: liver tumors tend to be large and well-vascularized, making them straightforward to image using CT. Some of the imaging features found are generic to tumors, but others have some degree of liver specificity. Expression program to image feature mappings may vary from tumor to tumor.
One potential side-effect of this study would be to increase biopharma interest in liver cancer. Liver cancer is a scourge outside of the Western world (perhaps driven by food-borne toxins) but is not in the top of deadly cancers in the U.S. According to some 2002 figures from the American Cancer Society, liver cancer in the U.S. is about 17K new cases and about 15K fatalities -- a horrible toll, but far less than 160K annual lung cancer deaths. One big attraction for companies is potential payoff, but another is the potential for accelerated development decisions. Being able to subset patients based matching drug mechanism to biology inferred from imaging is potentially a powerful means to do that.
Showing posts with label imaging. Show all posts
Showing posts with label imaging. Show all posts
Tuesday, June 19, 2007
Tuesday, February 20, 2007
Tightening the Border?
Biology is a complex subject and it is sometimes very difficult to properly track one's ignorance of the topic. If you aren't aware of that, then sometimes a remarkable result isn't quite as remarkable.
Yesterday's news contained an item reporting that Genentech's Avastin, an antibody targeting Vascular Endothelial Growth Factor (VEGF), a protein which stimulates the growth of new blood vessels (angiogenesis), shows promise for treating gliomas, a deadly type of brain tumor. A little bit of the newswire item read:
What this item failed to point out is that Avastin is precisely one of those drugs which wouldn't be expected to cross into the brain!
A defining characteristic of cells is a surrounding membrane made of lipids, fat-loving molecules. Embedded in these lipids are proteins. Molecules can enter cells by two routes: either going directly through the lipid layer or being transported across by specific proteins. Lipophilic ("fat loving") molecules go easily through the membrane, but hydrophilic ("water loving") molecules go through slowly if at all on their own. In particular, anything very large or significantly charged will not pass through the cell membrane without the help of a specialized protein, a transporter.
Transporters can be classified a few different ways. Passive transporters consume no energy to move their cargo, and hence can only move things down a concentration gradient. Active transporters can consume energy to move things against a concentration gradient. Exchangers (antiporters) swap one thing for another, such as sodium ions for potassium ions, and can transport one against a concentration gradient -- so long as the other is moving down a concentration gradient. Symporters move two compounds at once in the same direction.
The junctions between cells in a tissue are usually somewhat leaky, and so compounds transiting from one compartment (say the inside of the intestine) to another (such as the interior of a capillary) can either go through the cells or around them. Many drugs are actively transported, hitching a ride on some transporter that mistakes them for their proper cargo. But others simply diffuse between the cells or across the cells separating the two compartments.
The brain is a different story altogether: a system of super-membranes and tightly welded interfaces ("tight junctions") between cells provide a strong barrier. In general, anything which gets across this Blood Brain Barrier (BBB) is moved by active transporters in the cell membranes. Large proteins, and antibodies in particular, are something the BBB keeps out.
When we are healthy, the BBB is clearly a good thing, protecting the brain from stray chemicals that might harm its delicate workings. Many drugs that would otherwise harm the brain are excluded by the BBB, which means the drug can be safe to use. But when we have brain disease, the BBB becomes a serious challenge, as many important drugs will not cross it. And again, antibodies are high on the list of excludees.
I was lucky enough to attend ASCO last summer, the unbelievably yearly U.S. confab of clinical oncologists. There are dozens of things happening simultaneously, so you can never attend everything you want to. One session I did attend was on brain tumors, and there an interesting fact came out: in many brain tumors, the BBB becomes less functional in the neighborhood of the tumor. Indeed, what at least one group was trying was to inject patients with an imaging agent which normally doesn't cross the BBB and trying to correlate the ability to light up the brain with clinical outcome.
So this suggests the explanation for the curious anomaly which the newswire item overlooked. Antibodies shouldn't work in brain tumors, but perhaps Avastin works precisely because the brain tumor changes the rules -- and because Avastin may be working exactly where the rules have changed. Even with partial BBB functional breakdown, most of the tumor may still be inaccessible to many chemotherapeutic agents. However, right where the BBB is breaking down may be where angiogenesis active (indeed, this may be part of the driver of the breakdown) -- and so Avastin, by targeting this very process, can function. The exception to one rule works precisely because of another exception to the same rule!
Yesterday's news contained an item reporting that Genentech's Avastin, an antibody targeting Vascular Endothelial Growth Factor (VEGF), a protein which stimulates the growth of new blood vessels (angiogenesis), shows promise for treating gliomas, a deadly type of brain tumor. A little bit of the newswire item read:
An estimated 18,000 people are diagnosed with gliomas in the United States each year, according to the American Cancer Society.
They are difficult to treat because many drugs cannot reach the brain.
What this item failed to point out is that Avastin is precisely one of those drugs which wouldn't be expected to cross into the brain!
A defining characteristic of cells is a surrounding membrane made of lipids, fat-loving molecules. Embedded in these lipids are proteins. Molecules can enter cells by two routes: either going directly through the lipid layer or being transported across by specific proteins. Lipophilic ("fat loving") molecules go easily through the membrane, but hydrophilic ("water loving") molecules go through slowly if at all on their own. In particular, anything very large or significantly charged will not pass through the cell membrane without the help of a specialized protein, a transporter.
Transporters can be classified a few different ways. Passive transporters consume no energy to move their cargo, and hence can only move things down a concentration gradient. Active transporters can consume energy to move things against a concentration gradient. Exchangers (antiporters) swap one thing for another, such as sodium ions for potassium ions, and can transport one against a concentration gradient -- so long as the other is moving down a concentration gradient. Symporters move two compounds at once in the same direction.
The junctions between cells in a tissue are usually somewhat leaky, and so compounds transiting from one compartment (say the inside of the intestine) to another (such as the interior of a capillary) can either go through the cells or around them. Many drugs are actively transported, hitching a ride on some transporter that mistakes them for their proper cargo. But others simply diffuse between the cells or across the cells separating the two compartments.
The brain is a different story altogether: a system of super-membranes and tightly welded interfaces ("tight junctions") between cells provide a strong barrier. In general, anything which gets across this Blood Brain Barrier (BBB) is moved by active transporters in the cell membranes. Large proteins, and antibodies in particular, are something the BBB keeps out.
When we are healthy, the BBB is clearly a good thing, protecting the brain from stray chemicals that might harm its delicate workings. Many drugs that would otherwise harm the brain are excluded by the BBB, which means the drug can be safe to use. But when we have brain disease, the BBB becomes a serious challenge, as many important drugs will not cross it. And again, antibodies are high on the list of excludees.
I was lucky enough to attend ASCO last summer, the unbelievably yearly U.S. confab of clinical oncologists. There are dozens of things happening simultaneously, so you can never attend everything you want to. One session I did attend was on brain tumors, and there an interesting fact came out: in many brain tumors, the BBB becomes less functional in the neighborhood of the tumor. Indeed, what at least one group was trying was to inject patients with an imaging agent which normally doesn't cross the BBB and trying to correlate the ability to light up the brain with clinical outcome.
So this suggests the explanation for the curious anomaly which the newswire item overlooked. Antibodies shouldn't work in brain tumors, but perhaps Avastin works precisely because the brain tumor changes the rules -- and because Avastin may be working exactly where the rules have changed. Even with partial BBB functional breakdown, most of the tumor may still be inaccessible to many chemotherapeutic agents. However, right where the BBB is breaking down may be where angiogenesis active (indeed, this may be part of the driver of the breakdown) -- and so Avastin, by targeting this very process, can function. The exception to one rule works precisely because of another exception to the same rule!
Tuesday, January 09, 2007
Nanodiamonds are forever
My first science was geology: as a kid I collected rocks. A key test in geology is the scratch test for hardness, with a set of ten index values known as the Moh's Scale -- and I had all but #10, as Mom would not lend me her engagement ring.
Diamonds have all sorts of amazing properties, and a report in PNAS describes one more. Nanodiamonds around 35nM in size can be used as fluorescent tags. This entry's title derives from one interesting property: they don't photobleach. Organic dyes exposed to light for an extended period bleach out, but not these diamonds.
You'll need a subscription to view the article (alas, I'm without easy access to one at the moment), but the supporting information is freely available -- including a movie of a single nanodiamond inside a HeLa cell.
Diamonds have all sorts of amazing properties, and a report in PNAS describes one more. Nanodiamonds around 35nM in size can be used as fluorescent tags. This entry's title derives from one interesting property: they don't photobleach. Organic dyes exposed to light for an extended period bleach out, but not these diamonds.
You'll need a subscription to view the article (alas, I'm without easy access to one at the moment), but the supporting information is freely available -- including a movie of a single nanodiamond inside a HeLa cell.
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