GNRH ANALOG TOXINS FOR TARGETED GONADOTROPH ABLATION

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Hormonally responsive cancers are a major cause of morbidity and mortality in the aging population in the Unites States. Both breast and prostate cancer can be treated by sex steroid antagonists, but cost and mutational escape from such compounds make permanent castration a more desirable treatment modality. GnRH superagonists are used to "chemically castrate" individuals affected with such cancers and other hormonally dependent abnormalities. A major disadvantage of this treatment is that the GnRH superagonists must be administered continuously for life of the patient to produce the desire effect. Gonex Inc. has licensed technology to pursue development of compounds that after a single administration have the potential to prevent gonadal function permanently. The technology is based on the conjugation of a toxic protein to a GnRH superagonist that will specifically deliver the toxin to gonadotrophs in the anterior pituitary gland. The toxin then destroys the gonadotrophs resulting in cessation of gonadal function. In this Phase II application, we propose experiments to evaluate three different GnRH toxin conjugates with the goal of identifying the toxin and mode of administration that is most efficacious for eliminating gonadal function. The specific aims are to: 1) To compare the rate of internalization of three different GnRH-toxin conjugates in ovine anterior pituitary cells; 2) To evaluate the efficacy and toxicity of different doses of GnRH-toxin conjugates after bolus administration of rams; and 3) To determine if continuous infusion of GnRH-toxin conjugates eliminates gonadotroph function more efficiently than bolus administration. At the end of these studies, we will select a lead compound that will be taken forward into toxicological and pharmacological studies in preparation for filing of an INDA. PROPOSED COMMERCIAL APPLICATION: The use of GnRH analog-toxin conjugates may provide a single-shot approach to permanent inhibition of gonadotropin secretion. As such, these compounds would provide a superior alternative to currently available methods for treating steroid-dependent cancers.