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 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 提高治疗效果需要更好的治疗。 了解肿瘤对 PSMA RPT 反应的遗传、分子和免疫学决定因素。 为了确定此类决定因素，我们 (i) 进行了剂量测定研究，以优化 177Lu-PSMA-RPT 活性 前列腺癌 (PCa) 模型；(ii) 对 PSMA-RPT- 肿瘤进行全局磷酸化蛋白质组学分析； 治疗小鼠并揭示 DNA 损伤反应/修复和 TP53 通路的上调 (iii) 野生型 TP53 在介导小鼠对 RPT 的反应中发挥重要作用；并且 (iv) 研究了 PSMA-RPT 对肿瘤免疫微环境的影响，并证明 PSMA-RPT 具有协同作用 含有环 GMP-AMP 合酶 (cGAS) 的药理激活剂/干扰素基因刺激剂 (STING) 途径，一种细胞质 DNA 传感机制，将 DNA 损伤与先天性诱导 通过 I 型干扰素 (IFN) 信号传导的免疫反应相关地，文献中的数据表明突变体。 TP53 经常出现在 mCRPC 中，干扰 cGAS/STING/IFN 通路的功能 总的来说，这些发现使我们发现（从而）177Lu-。 PSMA-RPT 触发肿瘤 TP53 突变状态依赖性肿瘤和免疫细胞信号传导改变 mCRPC；(ii) 分析这些改变将确定 PSMA-RPT 反应的新决定因素； 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，利用集成平台来测试这些假设 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 模型肿瘤细胞区室中的信号传导改变 测试突变 TP53 损害对 PSMA-RPT 反应的假设 在目标 2 中，我们将使用小鼠 PCa。 具有野生型或突变型 TP53 的模型，以研究肿瘤 TP53 状态如何影响 RPT 反应和 我们将测试突变型 TP53 干扰的假设。 RPT 治疗的肿瘤中的 cGAS/STING/IFN 信号传导并降低肿瘤免疫原性 在目标 3 中，我们将。 开发增强或恢复 mCRPC 中 cGAS/STING/IFN 通路的新型联合疗法 免疫肿瘤微环境，并通过增加 RPT 反应的强度和持久性来改善 肿瘤免疫原性。 成功完成这些目标将确定 mCRPC TP53 突变状态之间的新联系， 可以利用胞质 DNA 传感机制和肿瘤免疫原性来提高疗效 通过合理设计和临床适用的联合疗法，RPT 对抗 mCRPC。