Cancer Science最新文献

{"title":"Targeting Cancer With Bifunctional Peptides: Mechanism of Cell Entry and Inciting Cell Death","authors":"Maria F. Setiawan,&nbsp;Oliver Rudan,&nbsp;Ingo G. H. Schmidt-Wolf","doi":"10.1111/cas.70065","DOIUrl":"10.1111/cas.70065","url":null,"abstract":"<p>Antimicrobial peptides have gained much attention in clinical research due to their extensive possibilities of application beyond antimicrobial use. The modification of antimicrobial peptides enables the peptides to target particular cancer cells, improving the specificity and efficiency of the treatment. In this study, TP2-<i>D-</i>Tox, a derivative of TP-<i>D-</i>Tox, demonstrated a superior anti-tumor activity towards renal carcinoma, Caki-2, and breast carcinoma, SK-BR-3. TP-Tox was previously reported to inhibit tumor growth in a mouse model, increasing the overall survival. TP- and TP2-<i>D-</i>Tox were shown to penetrate the cells via clathrin-mediated endocytosis, triggered by binding to the subunits of non-muscle myosin IIa and S100A9. HSPB1 was observed to have a protective effect towards TP2-<i>D-</i>Tox against the immediate proteolytic inactivation. The intracellular presence of the peptides evoked mitochondrial permeability transition, generation of reactive oxygen species, and formation of MLKL oligomers in the plasma membrane. Our investigation revealed that TP- and TP2-<i>D-</i>Tox induced a similar but distinctly regulated cell death in Caki-2 and SK-BR-3 cells. Both peptides established toxicity without activating any caspases, suggesting the possibility of TP- and TP2-<i>D-</i>Tox as a promising approach to bypass the caspase-dependent apoptosis-resistance issue impairing therapeutic responses of many cancer treatments.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1730-1744"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiation of Cytotoxic CD8+ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?","authors":"Ryo Koyama-Nasu,&nbsp;Yangsong Wang,&nbsp;Hinata Miyano,&nbsp;Motoko Y. Kimura","doi":"10.1111/cas.70055","DOIUrl":"10.1111/cas.70055","url":null,"abstract":"<p>Tumor-specific CD8⁺ T cells play a pivotal role in anti-tumor immunity. Here, we review the heterogeneity of CD8⁺ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8⁺ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8⁺ T cells, whereas the identification of TCF1⁺ stem-like CD8⁺ T cells has highlighted their importance in anti-tumor immunity. During tumor progression, TCF1⁺ stem-like CD8⁺ T cells differentiate into cytotoxic Tim-3⁺ terminally differentiated CD8⁺ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8⁺ T cell responses and showed that blocking CD69 function, either through the administration of anti-CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim-3⁺ terminally differentiated CD8⁺ T cells in both tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti-tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti-tumor CD8⁺ T cell response.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1500-1507"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNDP1 Overexpression by Promoter Hypomethylation Predicts Poor Prognosis and Immunotherapy Response in Mucosal Melanoma","authors":"Jia Jia,&nbsp;Junjie Gu,&nbsp;Lina Gao,&nbsp;Kaihua Liu,&nbsp;Jie Dai,&nbsp;Fanshuang Zhang,&nbsp;Pei Yuan,&nbsp;Lili Mao,&nbsp;Xiaoting Wei,&nbsp;Yang Shao,&nbsp;Jun Guo,&nbsp;Yanfeng Xi,&nbsp;Jianming Ying,&nbsp;Lu Si","doi":"10.1111/cas.70062","DOIUrl":"10.1111/cas.70062","url":null,"abstract":"<p>Mucosal melanoma (MM) is an uncommon and aggressive malignant tumor, characterized by a scarcity of effective treatment options and novel biomarkers. To develop novel biomarkers, a total of 89 MM tumor samples (including 50 cases in the discovery cohort and 39 cases in the validation cohort) were collected from three medical centers. Targeted bisulfite sequencing and RNA sequencing were conducted in the discovery cohort, and Cox regression analysis was employed to evaluate DNA methylation (methyDNA) and RNA expression data. Our results revealed that, compared to control samples, MM tumor samples exhibited a hypomethylated status of the Carnosine dipeptidase 1 (<i>CNDP1</i>) promoter (<i>p</i> &lt; 0.001), which significantly up-regulated its gene expression (<i>R</i> = −0.815, <i>p</i> &lt; 0.001) and indicated a worse prognosis (<i>p</i> = 0.002, hazard ratio (HR) (95% confidence interval, CI) = 0.01 (6.78E-04 ~ 0.20)). Using immunohistochemical staining, we found that CNDP1 protein was expressed in 81.8% of MM cases (36/44, including 1+/2+/3+), and high expression (2+/3+) was associated with significantly decreased overall survival (<i>p</i> = 0.0120, HR (95% CI) = 2.693 (1.223–5.931)). This pattern is consistent across both discovery and validation cohorts. Moreover, among the 21 patients who received immunotherapy, those with hypomethylated <i>CNDP1</i> were associated with a ‘cold’ tumor immune microenvironment and suboptimal therapeutic outcomes (Objective Response Rate: 38% vs. 60%; Disease Control Rate: 75% vs. 100%). In conclusion, the overexpression of <i>CNDP1</i>, driven by promoter hypomethylation, may serve as a potential predictor of poor prognosis and diminished response to immunotherapy in MM.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1671-1678"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of KRAS Mutations Using Extracellular Vesicle DNA in Colorectal Cancer Patients","authors":"Sho Kuriyama,&nbsp;Takeshi Yamada,&nbsp;Toshimitsu Miyasaka,&nbsp;Kay Uehara,&nbsp;Ryo Ohta,&nbsp;Akihisa Matsuda,&nbsp;Goro Takahashi,&nbsp;Takuma Iwai,&nbsp;Kohki Takeda,&nbsp;Koji Ueda,&nbsp;Shintaro Kanaka,&nbsp;Yasuyuki Yokoyama,&nbsp;Seiichi Shinji,&nbsp;Hiromichi Sonoda,&nbsp;Takeshi Nagasaka,&nbsp;Hiroshi Yoshida","doi":"10.1111/cas.70059","DOIUrl":"10.1111/cas.70059","url":null,"abstract":"<p>Liquid biopsy using circulating tumor DNA (ctDNA) is useful for precision medicine and molecular-guided oncology; however, its sensitivity is insufficient. We focused on DNA in extracellular vesicles (evDNA) as a new target for liquid biopsy and investigated its sensitivity. This observational study included 334 Stage I–IV colorectal cancer patients. evDNAs and ctDNAs were extracted from plasma collected before surgery. <i>KRAS</i> mutation status was analyzed using droplet digital PCR. One hundred and forty-eight patients had <i>KRAS</i> mutations in tumor tissues, and 186 patients had no <i>KRAS</i> mutations. In Stage II (Stage II 37.8% vs. 13.3%, <i>p</i> = 0.015) or III (Stage III 43.1% vs. 13.6%, <i>p</i> = 0.001) patients, sensitivities to detect <i>KRAS</i> mutations using evDNA were higher than those using ctDNA. Surprisingly, evDNA identified <i>KRAS</i> mutations in 13.8% of patients who lacked them in tumor tissue samples. Among Stage III patients, those with higher concentrations of evDNA had significantly poorer relapse-free survival compared with those who had lower concentrations of evDNA (<i>p</i> = 0.043). The use of evDNA improved the identification rate of <i>KRAS</i> mutations. By using evDNA, <i>KRAS</i> mutations were identified in more than 10% of patients without <i>KRAS</i> mutations in their tumor tissues. The concentration of evDNA can be a prognostic factor for Stage III colorectal cancer patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1661-1670"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal PKM2: A Noninvasive Diagnostic Marker Linking Macrophage Metabolic Reprogramming to Gastric Cancer Pathogenesis","authors":"Mengyun Yuan,&nbsp;Xiaoxia Zheng,&nbsp;Shanshan Zheng,&nbsp;Huaizhi Li,&nbsp;Xingxing Zhang,&nbsp;Yuxuan Chen,&nbsp;Xiang Zhang,&nbsp;Bo Han,&nbsp;Wei Wei,&nbsp;Jian Wu,&nbsp;Qingmin Sun","doi":"10.1111/cas.70056","DOIUrl":"10.1111/cas.70056","url":null,"abstract":"<p>Tumor-derived exosomes (TDEs) have emerged as vital biomarkers of multiple cancers. However, the diagnostic and stage-predicting effects of exosomal pyruvate kinase isoenzyme type M2 (PKM2) in peripheral blood and its mechanism in promoting gastric cancer (GC) remain unclear. Here, we analyzed plasma exosomal PKM2 in 216 blood samples collected from GC patients and healthy donors (HD). The area under the curve (AUC) of plasma exosomal PKM2 demonstrated superior performance in early GC diagnosis compared with that of widely used clinical biomarkers. Kaplan–Meier analysis revealed that high exosomal PKM2 expression was associated with poor prognosis in patients with GC (HR = 1.623, <i>p</i> = 0.029). Single-cell transcriptome sequencing analysis showed that PKM2 was enriched in tumor-associated macrophages (TAM). We further confirmed that the polarization of TAM to the pro-tumoral M2 phenotype induced by exosomal PKM2 promoted the proliferation, migration, and invasion of GC cells. Mechanistically, exosomal PKM2 enhanced lipid synthesis in TAM by inhibiting SCAP polyubiquitination, which triggered the nuclear accumulation of SREBP1, thereby upregulating fatty acid synthesis enzymes, such as FASN, ACACA, and ACLY. In conclusion, plasma exosomal PKM2 is a promising novel biomarker for the clinical diagnosis of GC. Importantly, exosomal PKM2 shapes the tumor microenvironment by activating the SREBP1-related lipid synthesis pathway in macrophages, thereby contributing to GC development.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1537-1549"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opportunities to Modulate Tumor Ecosystem Toward Successful Glioblastoma Immunotherapy","authors":"Mariko Takahashi,&nbsp;Darina Mukhamejanova,&nbsp;Himani Jasewicz,&nbsp;Nandini Acharya,&nbsp;James J. Moon,&nbsp;Toshiro Hara","doi":"10.1111/cas.70052","DOIUrl":"10.1111/cas.70052","url":null,"abstract":"<p>Over the past decade, the failure of multiple clinical trials has confirmed the need for a systematic and comprehensive understanding of glioblastoma (GBM). Current immunotherapies aiming to harness the immune system to achieve anti-tumor effects remain largely ineffective, highlighting the complexities of the GBM microenvironment. However, our recent understanding of immune niches within the central nervous system provides both opportunities and challenges in translating these insights into successful immunotherapy implementation. We discuss these strategies, including targeting multiple antigens within the heterogeneous GBM microenvironment, identifying new druggable targets to abrogate immunosuppression, and understanding niche-specific immune cell functionality to modulate tumor-immune-stroma interactions.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1482-1499"},"PeriodicalIF":4.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VCP Promotes Cholangiocarcinoma Development by Mediating BAP1 Ubiquitination-Dependent Degradation","authors":"Peiying Zhang,&nbsp;Xiangning Liu,&nbsp;Yue Liu,&nbsp;Hongdao Zhu,&nbsp;Churun Zheng,&nbsp;Qi Ling,&nbsp;Fangjie Yan,&nbsp;Qiaojun He,&nbsp;Hong Zhu,&nbsp;Tao Yuan,&nbsp;Bo Yang","doi":"10.1111/cas.70061","DOIUrl":"10.1111/cas.70061","url":null,"abstract":"<p>Cholangiocarcinoma (CCA), recognized for its high malignancy, has been an enormous challenge due to lacking effective treatment therapy over the past decades. Recently, the targeted therapies, such as Pemigatinib and Ivosidenib, have provided new treatment options for patients carrying fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations, but only ~30% of patients harbor these mutants; it is urgent to explore novel targets and therapeutic therapies. The frequent downregulation of BAP1 has been observed in CCA, and the low expression of BAP1 is closely related to the poor prognosis of CCA. However, there are no effective interventions to re-activate BAP1 protein; blocking its degradation may provide a feasible strategy for BAP1-downregulation CCA treatment. In this study, we demonstrated the tumor-suppressive roles of BAP1 in CCA and identified VCP functions as the key upstream regulator mediated by BAP1 protein homeostasis. Mechanistically, VCP binds to BAP1 and promotes the latter's ubiquitination degradation via the ubiquitin-proteasome pathway, thus promoting cell proliferation and inhibiting cell apoptosis. Moreover, we found that VCP inhibitors inhibited CCA cell growth and promoted cell apoptosis by blocking BAP1 ubiquitination degradation. Collectively, our findings not only provided a novel mechanism underlying the aberrant low expression of BAP1 in CCA but also verified the anti-tumor effect of VCP inhibitors in CCA, offering a novel therapeutic target for CCA treatment.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1579-1591"},"PeriodicalIF":4.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting IDO-Mediated Tryptophan Metabolism","authors":"Yimin Zhou,&nbsp;Qiongyan Tao,&nbsp;Chubin Luo,&nbsp;Jinsong Chen,&nbsp;Genwen Chen,&nbsp;Jianyong Sun","doi":"10.1111/cas.70057","DOIUrl":"10.1111/cas.70057","url":null,"abstract":"<p>Primary or acquired mutations in RAS/RAF genes resulting in cetuximab resistance have limited its clinical application in colorectal cancer (CRC) patients. The mechanism of this resistance remains unclear. RNA sequencing from cetuximab-sensitive and -resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab-resistant CRC patients. In vitro, in vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab-resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti-tumor effect. Furthermore, in vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN-γ pathway in cetuximab-resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN-γ then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8⁺ T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti-tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab-resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1715-1729"},"PeriodicalIF":4.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Heterogeneity of PD-L1 Expression as a Biomarker for Third-Generation EGFR-TKI Response in Advanced EGFR-Mutant NSCLC","authors":"Yidan Zhang,&nbsp;Yingqi Xu,&nbsp;Hongping Jin,&nbsp;Tengfei Liu,&nbsp;Hua Zhong,&nbsp;Jianlin Xu,&nbsp;Yuqing Lou,&nbsp;Runbo Zhong","doi":"10.1111/cas.70060","DOIUrl":"10.1111/cas.70060","url":null,"abstract":"<p>The association between the spatial heterogeneity of programmed cell death ligand 1 (PD-L1) expression and the efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) remains elusive. This retrospective study analyzed data from 4171 NSCLC patients with EGFR-sensitive mutations treated at Shanghai Chest Hospital from August 2019 to September 2023. Among them, 182 patients receiving third-generation EGFR-TKIs monotherapy as a first-line treatment were enrolled. Patients were categorized by biopsy sites into primary lung lesions (<i>n</i> = 112) and metastatic lymph nodes (<i>n</i> = 70). PD-L1 expression was stratified based on tumor cell proportion score (TPS): &lt; 1%, 1%–49%, and ≥ 50%. The median progression-free survival (PFS) for the entire cohort was 18.33 months. In the PD-L1 TPS group, PFS was 18.87 months for TPS &lt; 1%, 17.6 months for TPS 1%–49%, and 13.6 months for TPS ≥ 50%, with significant differences across groups (<i>p</i> = 0.026). Moreover, multivariate analysis identified smoking history [HR = 1.653, 95% CI (1.132–2.414), <i>p</i> = 0.009] and TPS ≥ 50% [HR = 2.069, 95% CI (1.183–3.618), <i>p</i> = 0.011] as independent risk factors. In primary lesions, the median PFS was 21.93 months for TPS &lt; 1%, 18.57 months for TPS 1%–49%, and 10.17 months for TPS ≥ 50%, with significant differences (<i>p</i> &lt; 0.001). However, PD-L1 expression in metastatic lymph nodes was not associated with PFS (<i>p</i> = 0.973). In advanced EGFR-mutant NSCLC, high PD-L1 expression may suggest reduced efficacy of third-generation EGFR-TKIs. The spatial heterogeneity of PD-L1 expression could influence its predictive accuracy for third-generation EGFR-TKI efficacy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1648-1660"},"PeriodicalIF":4.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olaparib Plus Abiraterone in Asian Patients With Metastatic Castration-Resistant Prostate Cancer: PROpel Subset Analysis","authors":"Mototsugu Oya,&nbsp;Jae Young Joung,&nbsp;Ji Youl Lee,&nbsp;Mikio Sugimoto,&nbsp;Young Deuk Choi,&nbsp;Jun Hyuk Hong,&nbsp;Hiroji Uemura,&nbsp;Kazuo Nishimura,&nbsp;Hideyasu Tsumura,&nbsp;Satoru Kawakami,&nbsp;Yukiyoshi Hirayama,&nbsp;Tae Gyun Kwon,&nbsp;Cheol Kwak,&nbsp;Hiroyoshi Suzuki,&nbsp;Tomoko Fujita,&nbsp;Masahiro Nii,&nbsp;David McGuinness,&nbsp;Melanie Dujka,&nbsp;Christian Poehlein,&nbsp;Fred Saad,&nbsp;Noel Clarke","doi":"10.1111/cas.16459","DOIUrl":"10.1111/cas.16459","url":null,"abstract":"<p>In the phase 3 PROpel trial (NCT03732820) patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib plus abiraterone in the first-line setting showed significantly prolonged radiographic progression-free survival (rPFS; primary data cutoff [DCO]: 30 July 2021; hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.54–0.81; <i>p</i> &lt; 0.001), and at prespecified final OS analysis DCO (12 October 2022) numerically prolonged overall survival (OS; HR 0.81, 95% CI, 0.67–1.00; <i>p</i> = 0.054), versus placebo plus abiraterone for the global population. Here, we report efficacy, safety, and patient-reported outcome data for the Asian subset in PROpel. Eligible patients were randomly assigned (1:1) to either olaparib (300 mg twice daily) or placebo in combination with abiraterone (1000 mg once daily). The primary endpoint was investigator-assessed rPFS, and a key secondary endpoint was OS. In the Asian subset (<i>n</i> = 133) at primary analysis, median rPFS was 27.6 months in the olaparib plus abiraterone arm (<i>n</i> = 63), compared with 19.3 months in the placebo plus abiraterone arm (<i>n</i> = 70; HR 0.55, 95% CI, 0.32–0.95). Median OS at the final analysis was not reached in the olaparib plus abiraterone arm versus 43.7 months in the placebo plus abiraterone arm (HR 0.59, 95% CI, 0.32–1.06). The safety profile was generally similar in the Asian subset and the global population. Efficacy and safety results for olaparib plus abiraterone in the Asian subset were generally consistent with the global PROpel population supporting the combination of olaparib plus abiraterone as an important first-line treatment for consideration in Asian patients with mCRPC.</p><p><b>Trial Registration:</b> Clinicaltrials.gov identifier: NCT03732820</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1638-1647"},"PeriodicalIF":4.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}