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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: Twitter: Dereklowe

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August 20, 2002

HER-1 And HER-2, Too

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Posted by Derek

AstraZeneca's revelation yesterday was quite disturbing. Their experimental cancer therapy (Iressa) doesn't seem to offer any added benefits when given in chemotherapy combinations, at least in non-small cell lung cancer. That's a type of tumor that the approach really should have worked in, and one that the compound had shown some efficacy in as a monotherapy. The data were particularly unexpected, given that preclinical models had shown that the compound should have added to the effects of standard chemotherapy agents (taxol, cisplatin, etc.) So much for the model systems.

This news sure didn't do AstraZeneca any good, but it really torpedoed the stock of competitor OSI, whose similar compound (Tarceva, developed with Genentech) is a much greater percent of that company's future. Two others in the field, Abgenix and everyone's favorite, Imclone, also declined.

The reporting on this story in the general press has been pretty poor (but with the Wall St. Journal doing a much better job than the New York Times, for example.) The problem is that it's a fairly complex biological issue, and some of the key issues are still unresolved.

All of these companies are nominally targeting EGFR, the epidermal growth factor receptor. But they're doing it in different ways, and there's more than one type of EGFR, too. The two that are most well-understood are HER1 (technically the only one that's really called EGFR) and HER2 (there's a HER3 and a HER4, too.) When activated, these stimulate cell growth and proliferation. The activating molecules can be just floating around, but in some cases the tumor cells are thought to make their own activating ligands, a particularly vicious mechanism. An added complication is that the active form of the receptor is actually a dimer of two HER types, and they seem to be able to mix-and-match. This fact is surely significant, but the details are still obscure.

HER2 is known to be overexpressed in many breast cancers, and overexpression of either it or HER1 seems to make a tumor more difficult to treat. How much the overexpression levels correlate with activity isn't well understood, either - the "tone" of the system seems to vary in different sorts of cancers.

One way that drug companies have gone after these targets is through antibodies. The antibodies bind, presumably, to a big swath of the surface of the receptor, blocking it from being activated. There's a possible bonus here, since this sort of antibody technique also seems to be toxic to the cells. There's a commercial HER2 antibody from Genentech, Herceptin, which seems to have decent activity (alone or in combination) in HER2-rich tumors. Imclone's Erbitux is an antibody to HER1, and Abgenix is the other antibody player.

The other way to attack these receptors is through small molecules. No one's ever found anything reasonable that'll do the job of an antibody (that is, physically blocking the receptor.) There is a target downstream, though. The receptor phosphorylates itself to activate, and this kinase activity is suitable for a small molecule inhibitor. That's Iressa, OSI's Tarceva, and some others from GSK, Novartis, Pfizer, and others.

These drugs vary in their potency against HER1 and HER2. Iressa and Tarceva are pretty similar - more HER1 than HER2. (thus the swoon in OSI's stock, which I'd say was justified, given the data.) GSK's GW-2016 is very potent against both, and Pfizer's CI-1033 is not only potent, but binds irreversibly. That's normally not a mechanism you'd want to see, but in oncology all the gloves are off.

As far as comparing the antibody therapies with the small molecules, though - well, the Wall St. Journal today suggested that Imclone could be in major trouble. I think that that's getting ahead of the science. The kinase inhibitors and the antibodies have differences in mechanism, HER selectivity aside. This certainly wasn't good news for Imclone, but it wasn't the red alert that it was for OSI and Genentech.

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