Thursday, May 26, 2011

HER2 Part 3: Drugs that Target HER2

Note: This is the blog of, where you can get personalized information about the latest in breast cancer treatment.

For patients with HER2 over-expressing breast cancer, it is critical to target the HER protein. Here we'll look at an array of HER2 targeted drugs: current, new and future. If you're a patient with metastatic disease whose disease is progressing following Herceptin treatment, accessing one of these newer drugs through a clinical trial might be a reasonable option.

Herceptin (trastuzumab). "The big standard." The first drug to target HER2. Approved in 1998. Currently used for patients with all stages of HER2+ breast cancer. Picture how it works: Herceptin is a very large monoclonal antibody protein. It attaches to HER2 on the portion of the molecule that sits outside the cell. By binding to it, Herceptin effectively "flags" the cancer cell for destruction by the body's own immune system. Herceptin also seems to inhibit HER2 growth signaling more conventionally. But attracting an immune system attack is the primary way the drug works (also called, by pharma nerds, "mechanism of action" or MOA).

Tykerb (lapatinib). "The little newcomer." The second HER2 drug. Unlike Herceptin, Tykerb is a very small molecule that inhibits not only HER2 but also EGFR (HER1). Also unlike Herceptin, Tykerb attaches to EGFR and HER2 inside the cell. HER2 and EGFR still pair up with other members of the HER family, but because of Tykerb binding, the grow signal is never sent to other molecules in the "relay chain." Tykerb is used in patients with metastatic disease if they progress after using Herceptin. The other key point about Tykerb is that because it is a very small molecule, it can travel from the bloodstream into the brain, and it seems to reduce brain metastases in HER2 positive patients.

T-DM1. "Targeted AND chemotherapy." A modified version of Herceptin (trastuzumab). In this case "T" (trastuzumab) is attached to another molecule called "DM1" which is a traditional chemotherapeutic. How about this for tricky: the trastuzumab portion of the drug attaches to HER2 outside the cell. When it does, it causes HER2 to get pulled inside the cell, where there (and only there) the chemotherapy portion of the drug is released and kills the cell. So the chemotherapy only kills HER2-laden cancer cells and isn't released where it could do damage to other cells. T-DM1 appears to be doing well in clinical trials and is generating excitement.

OmniTarg (pertuzumab). "Separate, you two!" Remember that to send the grow signal inside the cell, HER family molecules on the cell membrane have to pair up. Well, Genentech has created a drug that inhibits this pairing ("dimerization"). Pertuzumab is a large monoclonal antibody like Herceptin. Like Herceptin, it binds to HER2 outside the cell. But it binds to a different part of the molecule than Herceptin, effectively inhibiting HER2 from pairing up with EGFR (HER1), HER3 and probably HER2 as well. No pairing, no growth signal. Lone HER2s just float around the cell membrane doing nothing. Cancer cell growth and proliferation slows or halts (in theory).

afatinib and neratinib "Same but (maybe) better." These two drugs are in clinical trials. They both work much like Tykerb, but they might end up being more potent and thus more effective. Like Tykerb, both are small molecules, both are taken orally as tablets, and both attach to HER2 inside the cell to inhibit growth signaling. But unlike Tykerb, they are so-called "irreversible" inhibitors of HER2. They bind and then stay attached to HER2. Tykerb is a "reversible" inhibitor that binds but sometimes detaches.

To find clinical trials for these drugs, you can go to Or, better yet, try out a newer, easier-to-use site called This site provides personalized info about available clinical trials. It's sponsored by UC San Francisco.

Next: How doctors determine if you're HER2 positive

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