The development of second-generation heat shock protein 90 (Hsp90) inhibitors has reached Phase 3 trials of these agents in several types of cancer.  The success of the second-generation Hsp90 inhibitors is paving the way for major advancements with the third-generation Hsp90 inhibitor drugs.

Heat shock proteins protect cells stressed by elevated temperatures by assisting in protein folding. Hsp90 helps proteins that are associated with the underlying causes of various cancers, including the insulin growth factor-1 receptor in myeloma. Hsp90 inhibitors degrade tumor cells containing mutant forms of specific proteins and are effective in combination therapy.

The first second-generation Hsp90 inhibitor at the Phase 3 stage is retaspimycin hydrochloride. Its clinical trial was initiated in late October, involving 200 patients with refractory gastrointestinal stromal tumors in 20 countries. In the next year, retaspimycin is expected to enter into Phase 3 registration trials in women with breast cancer and myeloma patients.

The anticancer properties of the first-generation Hsp90 inhibitor (17-AAG) were discovered 20 years ago. The second-generation inhibitors use alternative formulations that have greater bioavailability and are less toxic. However, they still require intravenous administrations weekly and risk possible liver damage. In contrast, the third-generation drugs are small-molecule agents and are taken orally, allowing for daily dosing. They are also less toxic, more stable in the body, and have greater anticancer properties.

Source: OncologyStat