GNRH ANALOG TOXINS FOR TARGETED GONADOTROPH ABLATION

激素反应性癌症是美国老龄化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得永久性阉割成为更理想的治疗方式。GnRH超级激动剂用于“化学阉割”患有此类癌症和其他激素依赖性异常的个体。这种治疗的一个主要缺点是GnRH超级激动剂必须在患者的一生中持续使用，以产生预期的效果。Gonex公司已经获得技术许可，开发一种化合物，在一次给药后就有可能永久地阻止性腺功能。该技术是基于一种有毒蛋白与GnRH超级激动剂的结合，该药物将特异性地将毒素传递给垂体前叶的促性腺激素。然后毒素破坏促性腺激素，导致性腺功能停止。在这个II期申请中，我们提出了实验来评估三种不同的GnRH毒素偶联物，目的是确定毒素和给药方式，以最有效地消除性腺功能。具体目的是：1)比较三种不同gnrh -毒素偶联物在羊垂体前叶细胞内的内化率；2)评价不同剂量gnrh -毒素偶联物给药后对公羊的疗效和毒性；3)确定持续输注gnrh -毒素缀合物是否比一次性给药更有效地消除促性腺功能。在这些研究结束时，我们将选择一种先导化合物，该化合物将进行毒理学和药理学研究，以准备提交INDA。拟议的商业应用：使用GnRH类似物毒素偶联物可能提供一种单次注射的方法来永久抑制促性腺激素的分泌。因此，这些化合物将为治疗依赖类固醇的癌症提供一种更好的替代方法。

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.