Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC

摘要/摘要 而前列腺特异性膜抗原靶向放射药物治疗(PSMA-RPT)可改善 转移性去势抵抗前列腺癌(MCRPC)患者的存活率，应答率保持不变 次优，并且复发总是发生在所有患者中。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)进行了剂量学研究，以优化177Lu-PSMA-RPT在 前列腺癌(PCA)模型；(Ii)对来自PSMA-RPT的肿瘤进行了全球磷蛋白质组分析- 治疗小鼠，揭示了DNA损伤反应/修复和TP53通路的上调；(Iii)显示 野生型TP53在介导小鼠对RPT的反应中发挥重要作用；以及(Iv)研究了 PSMA-RPT对肿瘤免疫微环境的影响及协同作用 用环状GMP-AMP合成酶(CGAS)/干扰素基因刺激物的药理激活剂 (STING)途径，一种细胞质DNA传感机制，将DNA损伤与先天诱导联系起来 通过I型干扰素信号的免疫反应。与此相关的是，文献中的数据表明突变体 在mCRPC中频繁出现的TP53干扰了cGAS/STIN/干扰素途径的功能 从而降低肿瘤的免疫原性。总而言之，这些发现使我们假设：(I)177Lu- PSMA-RPT触发肿瘤TP53突变状态依赖的肿瘤和免疫细胞信号改变 MCRPC；(2)分析这些变化将确定对PSMA-RPT反应的新决定因素；以及(3) 以这些决定因素为目标将加强对PSMA-RPT的反应。 我们将通过三个具体的目标来测试这些假设，利用一个集成的平台来系统化 分析RPT诱导的转录、信号和免疫学改变。在目标1中，我们将确定 RPT诱导表达PSMA的人前列腺癌模型肿瘤细胞间的信号变化 验证突变体TP53损害对PSMA-RPT的反应的假设。在目标2中，我们将使用小鼠PCA 野生型或突变的TP53模型研究肿瘤TP53状态如何影响RPT反应和 免疫活性小鼠体内肿瘤的免疫原性。我们将检验突变体TP53干扰 RPT治疗肿瘤中的cGAS/STIN/干扰素信号转导，并降低肿瘤的免疫原性。在《目标3》中，我们将 开发新的联合疗法来增强或恢复mCRPC中的cGAS/STIN/干扰素途径 免疫肿瘤微环境，提高RPT反应的强度和持久性 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， 胞浆DNA传感机制和可用于提高疗效的肿瘤免疫原性 通过合理设计和临床适用的联合治疗，获得针对mCRPC的RPT。

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.