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 predic...
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KeAi Communications Co., Ltd.
2025-06-01
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| Series: | Non-coding RNA Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468054025000253 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Andrei Gurau |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d5c179c7caef4fcb9c2f77b886ba6f91 |
| institution | OA Journals |
| issn | 2468-0540 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Non-coding RNA Research |
| spelling | doaj-art-d5c179c7caef4fcb9c2f77b886ba6f912025-08-20T02:00:47ZengKeAi Communications Co., Ltd.Non-coding RNA Research2468-05402025-06-0112344110.1016/j.ncrna.2025.02.003PD-L1 pfeRNAs as blood-based predictors of treatment response of unresectable malignant pleural mesothelioma patients administered Durvalumab with cisplatin and pemetrexed as first-line therapyAndrei Gurau0Suguru Yamauchi1Kaitlyn Ecoff2Kristen P. Rodgers3James R. Eshleman4Charles Conover Talbot Jr5Peng Huang6Joshua Choi7Patrick M. Forde8Valsamo Anagnostou9Malcolm Brock10Yuping Mei11The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA; Department of Esophageal and Gastroenterological Surgery, Faculty of Medicine, Juntendo University, 3-1-3, Hongo, Bunkyo-ku, Tokyo, 113-8431, JapanThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USAThe Pathology Molecular Diagnostics Laboratory, Johns Hopkins School of Medicine, 600 N Wolfe St, Baltimore, MD, 21287, USAInstitute for Basic Biomedical Sciences, Johns Hopkins School of Medicine, 733 North Broadway, Baltimore, MD, 21205, USADepartment of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, MD, 21287, USADepartment of Biology, Krieger School of Arts & Sciences, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA; Corresponding author. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA.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.http://www.sciencedirect.com/science/article/pii/S2468054025000253PD-L1pfeRNAMPMDurvalumabPemetrexedCisplatin |
| spellingShingle | 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 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 Non-coding RNA Research PD-L1 pfeRNA MPM Durvalumab Pemetrexed Cisplatin |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | PD-L1 pfeRNA MPM Durvalumab Pemetrexed Cisplatin |
| url | http://www.sciencedirect.com/science/article/pii/S2468054025000253 |
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