The next Gleevec

Gleevec is the first of the “targeted therapy” drugs. A targeted therapy drug is one that’s specific to the defective chemistry of a cancer. In this case, some cancers have a mutated enzyme called tyrosine kinase which Gleevec inhibits. So far, Gleevec has been approved for use against two kinds of cancer[sup]1[/sup] and it is being tested for several others.

OK, my question is: What’s the next one of these targeted therapy wonder drugs likely to be approved? And what cancer(s) is it effective against? It’s been a couple years since Gleevec was approved, and I don’t think we’ve seen another such drug approved since then. What’s going on?
[sup]1[/sup] Chronic Myeloid Leukemia (CML) and Gastrointestinal Stromal Tumors (GIST).

dtilque, I’m afraid I’m unable to answer your question without a whole lot more research than I have time for. However, I will point out that Gleevec (or Glivec, as it’s known here in Oz), was successful largely because of the nature of the disease (CML). Pathogenesis of CML is very well understood, and can be tied down to a single chromosomal translocation (called the Philadelphia Chromosome) leading to production of an aberrant hybrid protein (Bcr-Abl, the tyrosine kinase you mentioned). Bcr-Abl forms as a result of two genes, which are normally on different chromosomes, being stuck together. This results in increased function of the Abl kinase. Glivec inhibits the Abl kinase (as well as the Kit kinase which is involved in GIST pathogenesis).

The reason we can’t just jump in and do this for other cancers is that in most cases pathogenesis is not so well understood, and may involve multiple mutations and malfunctions in the malignant cells. There was also an element of luck in the development of Glivec - noone was quite sure what side effects it would have until the clinical trials, and AFAIK it’s still not entirely clear why the adverse effects are so minimal.

Sorry if you already knew all this, but IMO it goes some way towards explaining why we haven’t yet managed to create “silver bullet” drugs for other forms of cancer. There was an excellent review article on Glivec by Brian Druker published in the journal Cancer Cell in February this year. AFAIK it is not available free online, however if you are interested in this area you should be able to find the article at your nearest university library. You might also want to search MedlinePlus for recent clinical trials of cancer drugs.

The huge one that I am aware should be going into human trials in the next month or so.

It is called the Icon molecule. It was developed at Yale. Unlike Gleevec, this one is designed to go after solid tumers (not Leukemias).

Theory of operation: What they have found is that blood vessels that support tumor growth have a unique chemical marker displayed on their walls. This icon molecule is designed to stick to this marker. The other end of the molecule is designed to attract the attention of the immune system, effectively marking this blood vessel for destruction. With no blood supply, the tumor dies.

Summary of testing so far: Hybrid mice with human style immune systems have had metastatic prostate cancer induced in them. Mice that were given the Icon injection were all still healthy at the end of the trial (180 days). Mice that did not get Icon injections lasted at most 63 days. Yes, that was 100% of treated mice lived. None of the treated mice exhibited any obvious symptoms related to typical chemotherapy, (i.e. this seemed to be very well tolerated, low side effects).

Interesting data: It is my understanding that they actually have an engineered virus that produces the Icon molecule. The inject/infect one of the tumors with this virus and it keeps the bloodstream full of the icon molecule while it is dying and takes all the non treated tumors with it. While the tests were done with prostate cancer tumors, it appears that at least a large fraction of solid tumors cause tumor vasculature to display the same chemical marker. That potentially makes this a rather broad spectrum anti cancer agent.

The Icon human trials are planned to take place at the Sidney Kimmel Cancer Center in San Diego, CA. (www.skcc.org).

You can find articles about the molecule in the archives at www.yale.edu and www.yaleherald.com .

Wow, scotth, that is way cool! I’ll have to go look it up!

OK, thanks for the replies. tritone, I knew some of that before I posted and learned more afterwards.

One thing I learned is that many cancers start off with only one mutation, but accumulate more as they go along. This is probably mostly a result of their rapid growth. These additional mutations are probably why some CML and GIST patients become resistant to Gleevec and why Gleevec doesn’t work very well against those with advanced cases of CML. Gleevec removes all the cancer cells that just have the mutant tyrosine kinase, but can’t do anything about the ones with other chromosomal errors that also cause them to be cancerous.

So the idea is to find more simple cancers that can be targeted by single drugs. Then maybe the complex ones will respond to a combination of drugs that target single mutations. Well, it’s an idea anyway.Whether it works in practice is another question.

Thanks for the clue about Icon. I’ll have to read up on that.

OK, I’ve read up on icon, at least as much as I could find on the net. But that brings up a question.

Basically I don’t understand how they engineered the virus. The icon molecule is a hybrid of two other molecules, one that binds to the blood vessels in a tumor and one that’s part of an antibody that causes the blood vessel to break down. Since it’s not a molecule that the body normally produces, there’s no naturally occuring gene that can inserted into the virus. So they must have engineered the gene, right?

You got me on that one.

I could only suggest that there are genes for producing both ends of the molecule, and they might have just brought them toghether.