BREAST TUMOR INHIBITION BY ANTIPROGESTINS

The use of antiestrogens in women for the treatment of breast cancer, although far from ideal, is one of the few therapies currently available. The following revised proposal outlines experiments to be performed under a SBIR that would clarify the properties of certain new antiprogestins as adjuvant therapies analogous to current therapies utilizing tamoxifen and SERMs. In May 1999, a Licensing Agreement between Zonagen and the NICHD was finalized to develop new antiprogestins. We expect that the new generation of compounds will be used for a number of indications where the etiology is dominated by progesterone. The promise of the first antiprogestin, RU 486, has gone unfulfilled because of its extensive antiglucocorticoid effects and the political backlash to its use as an abortifacient. Indications for antiprogestin use could include oral contraception, labor induction, cervical ripening, hormone replacement therapy (HRT), and treatment of uterine fibroids, endometriosis, and especially breast cancer. It is the overall aim of this proposed SBIR to determine effects on the growth of previously established rodent breast cancers with the ultimate intention of introducing a new adjuvant treatment for human breast cancer. The rat model has been shown to respond to antiprogestins such as RU 486 with a decrease in the growth of lesions following treatment. There is a need to determine whether our lead compound. CDB-4124, has the same anticancer properties as RU 486 as a proof-of-principle. Moreover, we need to determine the dose-response of that lead compound. Phase II would determine whether a secondary class of compounds have similar activity, whether the best compound(s) reduce the ultimate size and appearance of lesions if used prior to frank appearance, and their synergism with antiestrogens. Additionally, the possibility that antiprogestins can inhibit breast tumor growth and development would greatly enhance the potential of such compounds for chemoprevention and other long-term therapies (fibroids, endometriosis, HRT) and such a drug should find wide and unqualified acceptance among women.