MELT: Modulation of PSMA Expression for Lutetium Therapy

MELT：调节 PSMA 表达以进行镥疗法

• 批准号: 10220901
• 负责人: Felix Yi-Chung Feng
• 金额: $ 65.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220901
• 关键词: Aftercare; Animal Model; Biological Markers; Biopsy; Blood; CRISPR screen; Cell Culture Techniques; Cell Line; Cell surface; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Computational Biology; Data Set; Deposition; Development; Diagnostic; Diagnostic radiologic examination; Disease; Dose; FOLH1 gene; Gene Expression; Genes; Genome; Genomics; Heterogeneity; Image; Intervention; Knowledge; Lesion; Lutetium; Measures; Mediating; Modeling; Molecular; Neoplasm Circulating Cells; Oligonucleotide Microarrays; PSA level; Pathway Analysis; Pathway interactions; Patients; Pharmacology; Phase III Clinical Trials; Positron-Emission Tomography; Publishing; Radiation; Radiation Tolerance; Radioisotopes; Randomized; Sampling; Serology; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment Efficacy; Work; base; cancer cell; castration resistant prostate cancer; dosimetry; effective therapy; genomic biomarker; genomic data; imaging biomarker; improved; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; patient population; phase III trial; predicting response; prospective; prostate cancer cell; radiation response; radioligand; receptor; response; single photon emission computed tomography; targeted treatment; transcriptome; transcriptomics; treatment response; tumor; uptake

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.

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 新的治疗药物已获批准，该患者仍需要更有效的治疗 人口。在本提案中，我们将研究一种针对前列腺特异性的放射配体疗法（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 小型研究表明，PSMA RLT 对接受过多次治疗的患者具有显着疗效，超过 40% PSA 下降超过 50% 的患者。 PSMA RLT 依赖于两个基本前提： 对 PSMA 的辐射以及组织对沉积辐射的放射敏感性。首先我们要了解 PSMA 表达是如何调节的，使我们能够通过药理学靶向癌细胞以增加其活性 PSMA 表达。其次，我们将了解肿瘤是否因对药物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至关重要 更高的 PSMA 表达或增加肿瘤细胞敏感性，以改善对此疗法的反应。 我们将测试能够增加肿瘤对放射敏感性的治疗方法以及潜在的疗法 可以增加 PSMA 的表达。这项工作将用于为临床试验的开发提供信息 将涉及 PSMA RLT 和联合治疗，以提高其已经有希望的疗效。