Targeted Therapy to Receptors for LH-RH in Prostate Cancer

描述(申请人提供)：黄体生成素释放激素受体(LH-RH)表达在大多数前列腺癌细胞的质膜上。我们的初步数据表明，尽管长期接触促黄体生成素释放激素激动剂，这些受体的表达似乎仍然存在。这与脑下垂体促黄体激素释放激素受体相反，后者是下调的。这些发现支持将促黄体生成素释放激素受体作为治疗晚期前列腺癌的有效靶点。AN-152[AEZS-108]是一种可以有效利用这一靶点的药物，因为它的设计结合了黄体生成素-RH激动剂和细胞毒性阿霉素部分。大量的临床前数据表明，AN-152对前列腺癌细胞具有抗肿瘤活性。对患有妇科肿瘤的妇女进行的I期研究表明，AN-152耐受性良好。在这项申请中，我们建议在既往接受紫杉烷化疗的晚期前列腺癌患者中进行AN-152的加速I期引入II期试验。我们将评估这种制剂的疗效及其对男性的毒性。我们还将使用一种新的方法来收集循环中的肿瘤细胞(CTC)，该方法采用新的膜过滤技术，可以直接评估LH-RH受体的表达。我们将把CTC-LH-RH受体的表达与预后联系起来，试图找出对AN-152反应的预测标记物。捕获的四氯化碳对AN-152的内化作用将以一种新的方法进行量化，以利用试剂的自动荧光来研究动力学。这一新的CTC捕获方法将使用已建立的Veridex CellSearch(R)CTC测试的同时CTC测量进行验证。正电子发射断层扫描(PET)也将被纳入，以阐明其在评估对AN-152的反应中的作用。总之，这项建议将使用一种新的靶向细胞毒剂作为前列腺癌的治疗靶点，并将结合几项相关研究，包括一种收集CTCs的新方法、对这些CTCs的独特分析以及一种研究药物动力学的新方法。 公共卫生相关性：虽然前列腺癌是男性最常见的癌症，但对于需要化疗的男性来说，只有一个选择。为了努力为这些男性找到新的治疗选择，该提案探索了一种针对促黄体生成素受体的新药物，促黄体生成素受体在前列腺癌细胞上高表达，但在正常组织中不表达。相关研究将研究几种新的评估技术，包括一种收集循环肿瘤细胞的新技术，该技术通过利用试剂的自动荧光来可视化药物内化到肿瘤细胞中。

DESCRIPTION (provided by applicant): Receptors for luteinizing hormone-releasing hormone (LH-RH) are expressed on the plasma membranes of most prostate cancer cells. The expression of these receptors appears to persist despite prolonged exposure to LH-RH agonists, as demonstrated by our preliminary data. This is in contrast to pituitary LH-RH receptors, which are down-regulated. These findings support the use of LH-RH receptors as a viable target in the treatment of advanced prostate cancer. AN-152 [AEZS-108] is an agent that can effectively exploit this target due to its design combining an LH-RH agonist with the cytotoxic doxorubicin moiety. Extensive preclinical data provide evidence that AN-152 has anti-tumor activity against prostate cancer cells. Phase I studies conducted in women with gynecologic tumors show AN-152 is well-tolerated. In this application, we propose to conduct an accelerated Phase I lead-in to a Phase II trial of AN-152 in men with advanced prostate cancer previously treated with taxane chemotherapy. We will assess the efficacy of this agent as well as its toxicity in men. We will also use a new method to collect circulating tumor cells (CTCs) employing new membrane filter technology that will permit direct evaluation of LH-RH receptor expression. We will correlate CTC LH-RH receptor expression with outcomes in an attempt to identify a predictive marker of response to AN-152. Internalization of AN-152 by captured CTC will be quantified in a novel approach to studying kinetics exploiting the auto fluorescence of the agent. This new CTC capture method will be validated using concurrent CTC measurements by the established Veridex CellSearch(R) CTC assay. Positron emission tomography (PET) will also be incorporated to clarify its role in evaluating response to AN-152. In conclusion, this proposal will employ a new targeted cytotoxic agent directed to LH-RH receptors as a therapeutic target in prostate cancer and will also incorporate several correlative studies including a new method to collect CTCs, unique analyses of these CTCs and a novel method of studying drug kinetics. PUBLIC HEALTH RELEVANCE: Though prostate cancer is the most common cancer in men, there is only one option for men who require chemotherapy. In an effort to identify a new treatment option for these men, this proposal explores a novel agent that targets LH-RH receptors, which are highly expressed on prostate cancer cells but not on normal tissues. Correlative studies will investigate several novel assessment techniques, including a new technique to collect circulating tumor cells that allows visualization of drug internalization into tumor cells by exploiting the auto fluorescence of the agent.