MELT: Modulation of PSMA Expression for Lutetium Therapy

项目摘要 抗去势前列腺癌是一种一致致命的疾病，尽管有许多 新的治疗药物获得批准后，仍有大量需要更有效的治疗方法。 人口。在这项提案中，我们将研究一种针对前列腺特异性的放射配基治疗(RLT)。 膜抗原(PSMA)，一种在大多数前列腺癌细胞上表达的分子。在多个 小规模研究表明，PSMA RLT对经过大量预治疗的患者有显著疗效，超过40% PSA下降50%以上的患者。PSMA RLT依赖于两个基本前提：以 对PSMA的辐射和组织对沉积的辐射的敏感性。首先，我们将理解 PSMA的表达是如何调节的，使我们能够通过药物靶向肿瘤细胞来增加其 PSMA表达式。其次，我们将了解肿瘤的反应是否是因为对 辐射或高剂量的沉积辐射。这一知识对于确定患者是否需要 提高PSMA的表达或提高肿瘤细胞的敏感性，以提高对该疗法的反应。 我们将测试能够增加肿瘤对辐射敏感性的治疗方法以及潜在的治疗方法。 这可以增加PSMA的表达。这项工作将用于为临床试验的发展提供信息 将涉及PSMA RLT和联合给药疗法，以增加其已经很有希望的疗效。

Project Abstract Castrate resistant prostate cancer is a uniformly lethal disease and, although there have been a number of new therapeutic agents approved, there is still a large need for more effective treatments in this patient population. In this proposal, we will study a radioligand therapy (RLT) that targets the prostate specific membrane antigen (PSMA), a molecule that is expressed on the majority of prostate cancer cells. In multiple small studies, PSMA RLT has shown to have remarkable efficacy in heavily pretreated patients, with over 40% of patients having decreased PSA of over 50%. PSMA RLT relies on two basic premises: targeting the radiation to PSMA and the radiosensitivity of the tissue to the deposited radiation. First, we will understand how PSMA expression is regulated, allowing us to pharmacologically target cancer cells to increase their PSMA expression. Second, we will understand whether tumors respond because of intrinsic sensitivity to radiation or high doses of deposited radiation. This knowledge will be critical to determine if patients need higher expression of PSMA or increased tumor cell sensitivity in order to improve the response to this therapy. We will test treatments capable of increasing the sensitivity of tumors to radiation as well as potential therapies that can increase expression of PSMA. This work will be used to inform the development of a clinical trial that will involve PSMA RLT and a co-administered therapy to increase its already promising efficacy.