MELT: Modulation of PSMA Expression for Lutetium Therapy

项目摘要 去势抵抗性前列腺癌是一种一致致命的疾病，尽管已经有许多研究表明， 尽管新的治疗药物已经获得批准，但仍然需要对这种患者进行更有效的治疗。 人口在这个建议中，我们将研究一种放射性配体治疗（RLT），靶向前列腺特异性 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 在小型研究中，PSMA RLT已被证明在重度预治疗患者中具有显著疗效，超过40%的患者 PSA降低超过50%的患者。PSMA RLT依赖于两个基本前提： 组织对PSMA的辐射敏感性和组织对沉积的辐射的辐射敏感性。首先，我们将了解 PSMA表达是如何调节的，这使我们能够靶向癌细胞， PSMA表达。第二，我们将了解肿瘤是否因为对肿瘤的内在敏感性而产生反应。 辐射或高剂量的沉积辐射。这些知识对于确定患者是否需要 更高的PSMA表达或增加的肿瘤细胞敏感性，以改善对该疗法的反应。 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 可以增加PSMA的表达。这项工作将用于通知临床试验的发展， 将涉及PSMA RLT和联合治疗，以增加其已经有希望的疗效。

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.