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 而前列腺特异性膜抗原靶向放射药治疗（PSMA-RPT）则改善了 转移性cast割的前列腺癌（MCRPC）患者的存活率，反应率仍然 所有患者的次优且复发总是发生。改善治疗需要更好 了解肿瘤对PSMA RPT的遗传，分子和免疫学决定者。 为了识别此类决定素 前列腺癌（PCA）模型； （ii）对PSMA-RPT-的肿瘤进行了全球磷酸蛋白质组学分析 治疗的小鼠并揭示了DNA损伤响应/修复和TP53途径的上调； （iii）显示 野生型TP53在介导小鼠对RPT的反应中起着重要作用。 （iv）调查了 PSMA-RPT对肿瘤免疫微环境的影响，并证明PSMA-RPT协同作用 与循环GMP - AMP合酶（CGA）/干扰素基因刺激剂的药物激活剂 （Sting）途径，一种将DNA损伤与先天诱导联系起来的胞质DNA感应机械 通过I型干扰素（IFN）信号传导的免疫反应。相关，文献中的数据表明突变体 在MCRPC中经常发生的TP53会干扰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）177lu- PSMA-RPT触发肿瘤TP53突变状态依赖性肿瘤和免疫电池信号变化 MCRPC; （ii）分析这些改变将确定对PSMA-RPT的响应的新决定者； （iii） 针对这些决定者将增强对PSMA-RPT的响应。 我们将通过三个特定目标来测试这些假设，以利用集成平台进行系统 RPT诱导的转录，信号传导和免疫学改变的分析。在AIM 1中，我们将确定 RPT诱导的表达PCA模型的肿瘤细胞室中的信号改变和 测试突变TP53损害PSMA-RPT的反应的假设。在AIM 2中，我们将雇用鼠PCA 具有野生型或突变TP53的模型，以研究肿瘤TP53状态如何影响RPT反应和 免疫能力小鼠中的肿瘤免疫原性。我们将测试突变体TP53干扰的假设 RPT处理的肿瘤中的CGA/STING/IFN信号传导可降低肿瘤免疫原性。在AIM 3中，我们将 开发新型组合疗法，以增强或恢复MCRPC中的CGA/IFN途径 免疫肿瘤微环境并通过增加的RPT响应的幅度和耐用性提高 肿瘤免疫原性。 这些目标的成功完成将确定MCRPC TP53突变状态之间的新联系， 胞质DNA感应机制和可以利用以提高效率的肿瘤免疫原理 通过合理设计和临床适用的组合疗法对MCRPC的RPT。