Targeted Therapy to Receptors for LH-RH in Prostate Cancer

描述（由申请人提供）：促黄体生成激素释放激素（LH-RH）的受体在大多数前列腺癌细胞的质膜上表达。这些受体的表达似乎持续存在，尽管长期暴露于LH-RH激动剂，我们的初步数据表明。这与下调的垂体LH-RH受体相反。这些发现支持使用LH-RH受体作为治疗晚期前列腺癌的可行靶点。AN-152 [AEZS-108]是一种可以有效利用该靶点的药物，因为其设计将LH-RH激动剂与细胞毒性多柔比星部分相结合。大量的临床前数据提供了证据，证明AN-152对前列腺癌细胞具有抗肿瘤活性。在患有妇科肿瘤的女性中进行的I期研究显示AN-152耐受性良好。在本申请中，我们建议在先前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期导入至II期试验。我们将评估这种药物的疗效及其在男性中的毒性。我们还将使用一种新的方法来收集循环肿瘤细胞（CTC），采用新的膜过滤技术，将允许直接评估LH-RH受体的表达。我们将CTC LH-RH受体表达与结果相关联，试图确定对AN-152反应的预测标志物。通过捕获的CTC对AN-152的内化将在一种新的方法中进行定量，以研究利用试剂的自体荧光的动力学。将通过已建立的Veridex CellSearch（R）CTC检测试剂盒同时进行CTC测量，对这种新的CTC捕获方法进行验证。还将纳入正电子发射断层扫描（PET），以阐明其在评估AN-152反应中的作用。总之，该提案将采用针对LH-RH受体的新靶向细胞毒性剂作为前列腺癌的治疗靶点，并将纳入几项相关研究，包括收集CTC的新方法，这些CTC的独特分析和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，但需要化疗的男性只有一种选择。为了确定这些男性的新治疗选择，该提案探索了一种靶向LH-RH受体的新型药物，该受体在前列腺癌细胞上高度表达，但在正常组织上不表达。相关研究将调查几种新的评估技术，包括一种收集循环肿瘤细胞的新技术，该技术通过利用药物的自体荧光来观察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.