GNRH ANALOG TOXINS FOR TARGETED GONADOTROPH ABLATION

激素反应性癌症是美国老龄人口发病率和死亡率的主要原因。 乳腺癌和前列腺癌都可以用性类固醇拮抗剂治疗，但这种化合物的成本和突变逃逸使永久阉割成为更理想的治疗方式。GnRH超激动剂用于“化学阉割”患有此类癌症和其他生殖依赖性异常的个体。这种治疗的主要缺点是GnRH超激动剂必须在患者的一生中连续施用以产生期望的效果。戈尼克斯公司已获得技术许可，可开发单次给药后有可能永久阻止性腺功能的化合物。该技术是基于一种毒性蛋白质与GnRH超激动剂的结合，该超激动剂将特异性地将毒素递送到垂体前叶中的促性腺激素细胞。 然后毒素破坏促性腺激素细胞，导致性腺功能停止。在该II期申请中，我们提出了评估三种不同GnRH毒素缀合物的实验，目的是鉴定对消除性腺功能最有效的毒素和给药方式。具体目标是：1）比较三种不同的GnRH-毒素缀合物在绵羊垂体前叶细胞中的内化速率; 2）评估在公羊的推注给药后不同剂量的GnRH-毒素缀合物的功效和毒性;和3）确定GnRH-毒素缀合物的连续输注是否比推注给药更有效地消除促性腺激素功能。在这些研究结束时，我们将选择一种先导化合物进行毒理学和药理学研究，为提交INDA做准备。拟定商业应用：GnRH类似物-毒素结合物的使用可能提供一种永久抑制促性腺激素分泌的单次注射方法。因此，这些化合物将为目前可获得的用于治疗类固醇依赖性癌症的方法提供上级替代方案。

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.