PD-L1 pferna作为不可切除的恶性胸膜间皮瘤患者使用Durvalumab与顺铂和培美曲塞作为一线治疗的治疗反应的血液预测因子

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research Pub Date : 2025-02-21 DOI:10.1016/j.ncrna.2025.02.003

Andrei Gurau , Suguru Yamauchi , Kaitlyn Ecoff , Kristen P. Rodgers , James R. Eshleman , Charles Conover Talbot Jr , Peng Huang , Joshua Choi , Patrick M. Forde , Valsamo Anagnostou , Malcolm Brock , Yuping Mei

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引用次数: 0

摘要

在临床试验中，Durvalumab联合顺铂-佩美曲塞（Durva-CP）的新治疗途径为先前未经治疗的不可切除的恶性胸膜间皮瘤（MPM）患者提供了一个有希望的结果。然而，患者对Durva-CP的有限反应需要预测因子来选择最佳候选药物并监测已形成的耐药性。蛋白质功能效应因子sncRNA （pfeRNA）揭示了蛋白质活性调控的基本机制。杜伐单抗、顺铂和培美曲塞的共同机制表明，PD-L1 pfeRNAs （PDLpfeRNAs）是控制治疗反应的关键分子。方法通过sncRNA深度测序确定PDLpfeRNAs，通过免疫沉淀和反向下拉试验证实其与PD-L1的结合，并通过质控药物开发试验证明其在控制PD1/L1相互作用行为中的作用。按照符合clia的LDT所需的标准，我们在PrE0505 II期多中心研究的30例不可切除的MPM患者的60个血浆生物标本中测量了它们的表达水平。使用Cox比例风险模型和Kaplan-Meier分析，我们描述了它们在预测不可切除的MPM患者给予Durva-CP作为一线治疗的治疗反应方面的意义。结果对pdlpferna PDLpfeRNAa和PDLpfeRNAb两种pdlpferna进行了表征，证实它们与PD-L1结合，并控制PD-1/L1的相互作用行为。他们的血浆相对表达水平（REL）对总生存期（p = 0.0019）和无进展生存期（p = 0.019）都有显著的预后价值，在调整组织学亚型（HR 2.59, 95% CI: 1.00-6.70, p = 0.050）和年龄（HR 1.03, 95% CI: 0.98-1.07, p = 0.269）后，相关性仍然显著。结论血浆pdlpferna可作为不可切除的MPM患者以Durva-CP作为一线治疗方案的治疗反应预测因子，以选择最佳候选药物并监测产生的耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

PD-L1 pfeRNAs as blood-based predictors of treatment response of unresectable malignant pleural mesothelioma patients administered Durvalumab with cisplatin and pemetrexed as first-line therapy

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PD-L1 pfeRNAs as blood-based predictors of treatment response of unresectable malignant pleural mesothelioma patients administered Durvalumab with cisplatin and pemetrexed as first-line therapy

Background

A new therapeutic avenue combining Durvalumab with cisplatin-pemetrexed (Durva-CP) has delivered a promising outcome for previously untreated patients with unresectable malignant pleural mesothelioma (MPM) in clinical trials. However, the limited patient response to Durva-CP needs predictors to select optimal candidates and monitor the developed resistance. Protein functional effector sncRNA (pfeRNA) reveals a fundamental mechanism underlying the regulation of protein activity. The common mechanisms underlying durvalumab, cisplatin, and pemetrexed indicate that PD-L1 pfeRNAs (PDLpfeRNAs) are key molecules that control the treatment response.

Methods

We specified PDLpfeRNAs by sncRNA deep sequencing, confirmed their binding to PD-L1 by immunoprecipitation and reverse pull-down assays, and demonstrated their roles in controlling the interaction behaviors of PD1/L1 through quality-controlled drug development assays. Following the standards required for the CLIA-compliant LDT, we measured their expression levels in 60 plasma biospecimens from 30 unresectable MPM patients enrolled in the PrE0505 Phase II multicenter study. Using the Cox proportional hazards model and Kaplan-Meier analyses, we described their significance in predicting the treatment response of unresectable MPM patients administered Durva-CP as first-line therapy.

Results

Two PDLpfeRNAs, PDLpfeRNAa and PDLpfeRNAb, were characterized, confirmed to bind to PD-L1, and identified to control the interaction behaviors of PD-1/L1. Their plasma relative expression levels (REL) demonstrated significant prognostic value for both overall survival (p = 0.0019) and progression-free survival (p = 0.019), and the association remained significant after adjusting for histological subtype (HR 2.59, 95 % CI: 1.00–6.70, p = 0.050) and age (HR 1.03, 95 % CI: 0.98–1.07, p = 0.269).

Conclusions

Plasma PDLpfeRNAs are predictors of treatment response of unresectable MPM patients treated with Durva-CP as first-line therapy to select optimal candidates and monitor the developed resistance.

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来源期刊

Non-coding RNA Research Medicine-Biochemistry (medical)

CiteScore

7.70

自引率

6.00%

发文量

审稿时长

49 days

期刊介绍： Non-coding RNA Research aims to publish high quality research and review articles on the mechanistic role of non-coding RNAs in all human diseases. This interdisciplinary journal will welcome research dealing with all aspects of non-coding RNAs-their biogenesis, regulation and role in disease progression. The focus of this journal will be to publish translational studies as well as well-designed basic studies with translational and clinical implications. The non-coding RNAs of particular interest will be microRNAs (miRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs), U-RNAs/small nuclear RNAs (snRNAs), exosomal/extracellular RNAs (exRNAs), Piwi-interacting RNAs (piRNAs) and long non-coding RNAs. Topics of interest will include, but not limited to: -Regulation of non-coding RNAs -Targets and regulatory functions of non-coding RNAs -Epigenetics and non-coding RNAs -Biological functions of non-coding RNAs -Non-coding RNAs as biomarkers -Non-coding RNA-based therapeutics -Prognostic value of non-coding RNAs -Pharmacological studies involving non-coding RNAs -Population based and epidemiological studies -Gene expression / proteomics / computational / pathway analysis-based studies on non-coding RNAs with functional validation -Novel strategies to manipulate non-coding RNAs expression and function -Clinical studies on evaluation of non-coding RNAs The journal will strive to disseminate cutting edge research, showcasing the ever-evolving importance of non-coding RNAs in modern day research and medicine.