CYTOTOXIC GONADOTROPIN RELEASING HORMONE DERIVATIVES

Hormonally responsive cancers, such as prostate and breast, are a major cause of morbidity and mortality in the aging population in the United States. These cancers can be treated by sex steroid antagonists by these compounds are costly and mutational escape occurs. Recent innovative approaches have used hormonotoxins to specifically target the cancer cells. Several such approaches are already in human clinical testing. We previously demonstrated that GnRH-toxin conjugates selectively kill pituitary gonadotrophs. Optimizing cell death by this method could result in a novel, single treatment modality for hormonally responsive cancers. In the current proposal, we will look at the toxicity of GnRH- PAP conjugate to fusion protein in a variety of cancer cell lines, and will correlate binding of GnRH-toxins to GnRHR mRNA expression in microdissected tumor and adjacent normal tissue. We hypothesize that cancer cells bearing the receptor will be killed upon exposure to GnRH toxins, and that the conjugate will be more cytotoxic than the fusion protein. This approach will extend the spectrum of utility of GnRH- toxins to hormone-resistant prostate and breast cancer and to cancers not thought of as hormone-responsive which nevertheless express the GnRH receptor, such as ovarian, and possibly pancreatic and hepatocellular carcinoma. PROPOSED COMMERCIAL APPLICATIONS: Use of GnRH-toxin may provide a single-shot approach to treat hormonally responsive as well as some hormone-resistant cancers. This would result in a superior, non-surgical and cost-effective means of treating these cancers.