Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC

多维分析可提高 PSMA-RPT 在 mCRPC 中的疗效

• 批准号: 10637709
• 负责人: JOHANNES CZERNIN
• 金额: $ 52.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637709
• 关键词: Agonist; Antigen Targeting; Attenuated; Cancer Patient; Cell Compartmentation; Cell Line; Cells; Clinical; Combined Modality Therapy; Cyclic GMP; Cytometry; DNA; DNA Damage; Data; Development; Engineering; FOLH1 gene; Future; Genetic; Genetic Transcription; Histone Deacetylase Inhibitor; Human; Immune; Immunocompetent; Immunologics; Impairment; Innate Immune Response; Interferon Type I; Interferons; Knock-out; Link; Literature; MEK inhibition; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Molecular Analysis; Mus; Mutate; Mutation; Pathway interactions; Patients; Play; Pre-Clinical Model; Production; Prostatic Neoplasms; Radiopharmaceuticals; Resistance; Role; Signal Induction; Signal Transduction; Stimulator of Interferon Genes; TP53 gene; Testing; Time; Treatment Efficacy; Tumor Immunity; Up-Regulation; castration resistant prostate cancer; clinical application; clinical translation; dimensional analysis; dosimetry; immunogenicity; improved; mouse model; mutant; mutational status; neoplastic cell; novel; pharmacologic; phosphoproteomics; prostate cancer model; rational design; repaired; response; single-cell RNA sequencing; synergism; targeted treatment; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Summary/Abstract While prostate-specific membrane antigen-targeted radiopharmaceutical therapy (PSMA-RPT) improves the survival of metastatic castration-resistant prostate cancer (mCRPC) patients, response rates remain suboptimal, and relapses invariably occur in all patients. Improving therapeutic efficacy requires a better understanding of the genetic, molecular, and immunological determinants of tumor responses to PSMA RPT. To identify such determinants we (i) performed dosimetry studies to optimize 177Lu-PSMA-RPT activity in prostate cancer (PCa) models; (ii) conducted global phosphoproteomic analyses of tumors from PSMA-RPT- treated mice and revealed the upregulation of DNA damage response/repair and TP53 pathways; (iii) showed that wild type TP53 plays an important role in mediating responses to RPT in mice; and (iv) investigated the impact of PSMA-RPT on the tumor immune microenvironment and demonstrated that PSMA-RPT synergizes with pharmacological activators of the cyclic GMP–AMP synthase (cGAS)/Stimulator of Interferon genes (STING) pathway, a cytosolic DNA sensing machinery that links DNA damage with the induction of innate immune responses via type I interferon (IFN) signaling. Relatedly, data in the literature indicate that mutant TP53, which occurs frequently in mCRPC, interferes with the function of the cGAS/STING/IFN pathway thereby decreasing tumor immunogenicity. Collectively, these findings led us to hypothesize that (i) 177Lu- PSMA-RPT triggers tumor TP53 mutational status-dependent tumor and immune cell signaling alterations in mCRPC; (ii) profiling these alterations will identify new determinants of response to PSMA-RPT; and (iii) targeting these determinants will enhance responses to PSMA-RPT. We will test these hypotheses via three Specific Aims leveraging an integrated platform for systematic profiling of RPT-induced transcriptional, signaling, and immunological alterations. In Aim 1, we will identify RPT-induced signaling alterations in the tumor cell compartment of human PSMA-expressing PCa models and test the hypothesis that mutant TP53 impairs responses to PSMA-RPT. In Aim 2, we will employ murine PCa models with wild-type or mutated TP53 to investigate how tumor TP53 status impacts RPT responses and tumor immunogenicity in immunocompetent mice. We will test the hypothesis that mutant TP53 interferes with cGAS/STING/IFN signaling in RPT-treated tumors and reduces tumor immunogenicity. In Aim 3, we will develop novel combination therapies that enhance or restore the cGAS/STING/IFN pathway in the mCRPC immune tumor microenvironment and improve the magnitude and durability of RPT responses via increased tumor immunogenicity. Successful completion of these aims will identify new connections between mCRPC TP53 mutational status, cytosolic DNA sensing mechanisms, and tumor immunogenicity that can be leveraged to increase the efficacy of RPT against mCRPC through rationally designed and clinically applicable combination therapies.

摘要/摘要 虽然前列腺特异性膜抗原靶向放射性药物治疗（PSMA-RPT）改善了前列腺的功能， 转移性去势抵抗性前列腺癌（mCRPC）患者的生存率，缓解率保持不变 次优的，并且在所有患者中总是发生复发。提高治疗效果需要更好的 了解肿瘤对PSMA RPT反应的遗传、分子和免疫决定因素。 为了确定这些决定因素，我们（i）进行剂量测定研究，以优化177 Lu-PSMA-RPT活性， 前列腺癌（PCa）模型;（ii）对来自PSMA-RPT- 治疗小鼠，并揭示了DNA损伤反应/修复和TP 53途径的上调;（iii）显示 野生型TP 53在介导小鼠对RPT的应答中起重要作用;以及（iv）研究了野生型TP 53在小鼠中的作用。 PSMA-RPT对肿瘤免疫微环境的影响，并证明PSMA-RPT协同 与环GMP-AMP合酶（cGAS）的药理学激活剂/干扰素基因刺激剂 （STING）途径，一种将DNA损伤与先天性免疫缺陷的诱导联系起来的细胞溶质DNA传感机制。 通过I型干扰素（IFN）信号传导的免疫应答。相关地，文献中的数据表明，突变体 在mCRPC中频繁出现的TP 53干扰cGAS/STING/IFN途径的功能 从而降低肿瘤免疫原性。总的来说，这些发现使我们假设（i）177 Lu- PSMA-RPT触发肿瘤TP 53突变状态依赖性肿瘤和免疫细胞信号传导改变， mCRPC;（ii）分析这些变化将确定对PSMA-RPT应答的新决定因素;和（iii） 针对这些决定因素将增强对PSMA-RPT的反应。 我们将通过三个具体目标来测试这些假设，这些目标利用一个集成平台进行系统的 RPT诱导的转录、信号传导和免疫学改变的分析。在目标1中，我们将确定 RPT诱导的表达人PSMA的PCa模型的肿瘤细胞区室中的信号传导改变， 测试突变体TP 53损害对PSMA-RPT的应答的假设。在目标2中，我们将使用鼠PCa 用野生型或突变的TP 53建立模型，以研究肿瘤TP 53状态如何影响RPT反应， 免疫活性小鼠的肿瘤免疫原性。我们将检验突变型TP 53干扰 在RPT处理的肿瘤中，CGAS/STING/IFN信号传导的作用并降低肿瘤免疫原性。在目标3中，我们 开发增强或恢复mCRPC中cGAS/STING/IFN途径的新型联合疗法 免疫肿瘤微环境，并通过增加RPT反应的幅度和持久性 肿瘤免疫原性 成功完成这些目标将确定mCRPC TP 53突变状态， 细胞溶质DNA传感机制和肿瘤免疫原性，可用于提高疗效 通过合理设计和临床适用的联合治疗，降低RPT对mCRPC的作用。