Targeted Therapy to Receptors for LH-RH in Prostate Cancer

描述（由申请人提供）：促黄体生成素释放激素受体（LH-RH）在大多数前列腺癌细胞的质膜上表达。我们的初步数据表明，尽管长时间暴露于rh - rh激动剂，这些受体的表达似乎仍然存在。这与垂体LH-RH受体相反，后者被下调。这些发现支持将rh - 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这一靶点的药物，因为它的设计结合了rh - rh激动剂和细胞毒性阿霉素部分。大量的临床前数据证明AN-152对前列腺癌细胞具有抗肿瘤活性。在妇科肿瘤女性患者中进行的I期研究表明，AN-152具有良好的耐受性。在此申请中，我们建议在先前接受过紫杉烷化疗的晚期前列腺癌男性患者中进行an -152的加速I期先导期II期试验。我们将评估这种药物的功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肿瘤细胞（ctc），采用新的膜过滤技术，这将允许直接评估rh受体的表达。我们将把CTC LH-RH受体的表达与结果联系起来，试图确定an -152反应的预测标记。捕获的CTC对AN-152的内在化将通过一种利用该试剂自身荧光研究动力学的新方法进行量化。这种新的CTC捕获方法将通过建立的Veridex CellSearch(R) CTC测定法使用并发CTC测量来验证。还将纳入正电子发射断层扫描（PET），以阐明其在评估对AN-152的反应中的作用。总之，本提案将采用一种针对rh - rh受体的新型靶向细胞毒性药物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CTCs的新方法，这些CTCs的独特分析以及研究药物动力学的新方法。

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.