Cytotoxic Gonadotropin Releasing Hormone Derivatives

激素反应性癌症，如前列腺癌和乳腺癌，是美国老龄人口发病率和死亡率的主要原因。这些癌症可以通过性类固醇拮抗剂治疗，但这些化合物价格昂贵，并且发生突变逃逸。最近的创新方法使用激素毒素来特异性靶向癌细胞。几种这样的方法已经在人体临床试验中。我们以前证明GnRH-毒素结合物选择性杀死垂体促性腺激素细胞。通过这种方法优化细胞死亡可能会导致一种新的，单一的治疗模式，用于对肿瘤有反应的癌症。在目前的建议中，我们将在各种癌细胞系中观察GnRH-PAP结合物对融合蛋白的毒性，并将GnRH毒素与显微切割肿瘤和邻近正常组织中GnRHR mRNA表达的结合相关联。我们假设携带该受体的癌细胞在暴露于GnRH毒素后将被杀死，并且缀合物将比融合蛋白更具细胞毒性。这种方法将扩大GnRH毒素的应用范围，使其适用于抗GnRH前列腺癌和乳腺癌，以及不被认为是抗GnRH反应性的但表达GnRH受体的癌症，如卵巢癌，可能还有胰腺癌和肝细胞癌。拟议的商业应用：使用GnRH毒素可能提供一种单次注射的方法来治疗卵巢反应性以及一些卵巢癌耐药的癌症。这将导致治疗这些癌症的上级、非手术和成本有效的手段。

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.