Positron emission tomography (PET) enables researchers to peer deep into tissues lit up with a radioactive tracer. In the 1 June Nature Biotechnology, Peter Smith-Jones et al. apply the technique to directly evaluate the effects of an antitumor agent on its target.

Credit: Reprinted from Nature Biotechnology

As the target, the investigators chose the receptor tyrosine kinase HER2, which can power tumor proliferation and survival when overexpressed, amplified or mutated. As the antitumor agent, the researchers chose 17-allylaminogeldanamycin (17-AAG), a derivative of the antibiotic geldamycin. 17-AAG inhibits Hsp90, a chaperone protein that stabilizes HER2 and other key signaling proteins. 17-AAG causes HER2 degradation and tumor shrinkage in mouse models and has recently entered phase 1 clinical trials.

To visualize HER2 degradation in response to 17-AAG, the researchers first created an antibody fragment that binds to HER2. They then attached this fragment via a molecular link to an isotope of gallium. Shown is a mouse with a tumor (circled) before 17-AAG treatment, shortly after injection with the label. By 24 hours after treatment, the investigators could see HER2 disappear (not shown).

The technique should enable rapid, noninvasive evaluation of dosing and activity for a variety of drugs. The researchers plan to test a labeled antibody fragment against the HER2 family member EGFR, the target of the drug gefitinib (see pages 577–578), which induces EGFR internalization and degradation. To use the technique for visualizing intracellular events, Smith-Jones envisions linking a label to a nuclear hormone or other amenable intracellular regulator.