Heat shock protein 90 (Hsp90) is a
molecular chaperone that promotes the conformational maturation of numerous client
proteins, many of which play critical roles in
tumor cell growth and survival. The
ansamycin-based Hsp90 inhibitor
17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in Phase III clinical testing. However,
17-AAG is difficult to formulate and associated with dose-limited toxicity issues. A fully synthetic and bioavailable Hsp90 inhibitor,
BIIB021, was evaluated for antitumor activity in a variety of
head and neck squamous cell carcinoma (
HNSCC) cell lines and
HNSCC xenograft models, either as a single agent or in combination with fractionated radiation and the results were compared with that of
17-AAG.
BIIB021 showed strong antitumor activity, comparable with, and in certain instances, superior to
17-AAG.
BIIB021 enhanced the in vitro radiosensitivity of HNSCCA cell lines with a corresponding reduction in the expression of key radioresponsive
proteins, increased apoptotic cells and enhance G2 arrest. In xenograft studies,
BIIB021 exhibited a strong antitumor effect outperforming
17-AAG, either as a single agent and or in combination with radiation, thereby improved the efficacy of radiation. These results suggest that this synthetic and bioavailable Hsp90 inhibitor affects multiple pathways involved in
tumor development and progression in the
HNSCC setting and may represent a better strategy for the treatment of
HNSCC patients, either as a monotherapy or a radiosensitizer. Furthermore, it also demonstrates the benefits of using preclinical models of chemosensitization to
radiotherapy to explore clinically relevant radiation dosing schemes.