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:

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!