British Journal of Cancer最新文献

{"title":"Temporal dynamics of immune cell patterns in bladder cancer patients receiving Bacillus Calmette-Guérin therapy","authors":"Jiang-Li Lu, Yun-Lin Ye, Dan-Dan Zheng, Xin-Yu Shi, Li-Ling Hu, Xiao-Yi Yuan, Tao-Nong Cai, Kun Meng, Neng-Qiao Wen, Yu-Ying Li, Ding-Kang Wang, Fu-Jin Shi, Dan-Ya Liu, Qing-Yu He, Zi-Ke Qin, Chris Zhiyi Zhang, Yun Cao","doi":"10.1038/s41416-024-02883-5","DOIUrl":"10.1038/s41416-024-02883-5","url":null,"abstract":"Bacillus Calmette-Guérin (BCG) is capable of enhancing the infiltration of immune cells into the tumour. However the temporal dynamics of immune cell patterns in patients receiving BCG instillation remains unclear. Ninety-six patients who underwent intravesical BCG therapy, comprising 46 responders and 50 non-responders, were retrospectively enroled to explore the evolving immune landscape. This study involved a detailed examination of sequential samples collected before, during, and after BCG treatment to assess BCG’s influence on the immune microenvironment, employing techniques such as immunohistochemistry, fluorescent multiplex immunohistochemistry, and mass spectrometry techniques. Our study found that initial BCG instillation leads to enhanced immune cell infiltration, correlating with treatment efficacy, with responders exhibiting more pronounced increases. Non-responders experience a rise in immune cell infiltration and PD-L1 expression during the first instillation, which returns to baseline after treatment. In non-responders, BCG re-challenge fail to further increase immune cell infiltration into the tumour or improve patient outcomes. Strikingly, proteomics data revealed that GBP1 expression was induced by BCG treatment in non-responders. Our findings demonstrated the induction of tumour PD-L1 expression by BCG in non-responders, and therefore provide insights for the combination of BCG and anti-PD1/anti-PD-L1 therapy.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 12","pages":"1901-1912"},"PeriodicalIF":6.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma","authors":"Matteo Villa, Geeta G. Sharma, Federica Malighetti, Mario Mauri, Giulia Arosio, Nicoletta Cordani, Cosimo Lobello, Hugo Larose, Alessandra Pirola, Deborah D’Aliberti, Luca Massimino, Lucrezia Criscuolo, Lisa Pagani, Clizia Chinello, Cristina Mastini, Diletta Fontana, Silvia Bombelli, Raffaella Meneveri, Federica Lovisa, Lara Mussolin, Andrea Janikova, Šárka Pospíšilová, Suzanne D. Turner, Giorgio Inghirami, Fulvio Magni, Mario Urso, Fabio Pagni, Daniele Ramazzotti, Rocco Piazza, Roberto Chiarle, Carlo Gambacorti-Passerini, Luca Mologni","doi":"10.1038/s41416-024-02881-7","DOIUrl":"10.1038/s41416-024-02881-7","url":null,"abstract":"Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory. We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models. Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients. These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1781-1795"},"PeriodicalIF":6.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02881-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential clinical utility of Whole Genome Sequencing for patients with cancer: evaluation of a regional implementation of the 100,000 Genomes Project","authors":"Elaine Y. L. Leung, Helen L. Robbins, Shafquat Zaman, Neeraj Lal, Dion Morton, Lisa Dew, Anthony P. Williams, Yvonne Wallis, Jennie Bell, Manoj Raghavan, Gary Middleton, Andrew D. Beggs","doi":"10.1038/s41416-024-02890-6","DOIUrl":"10.1038/s41416-024-02890-6","url":null,"abstract":"The 100,000 Genomes Project established infrastructure for Whole Genome Sequencing (WGS) in the United Kingdom. A retrospective study of cancer patients recruited to the 100,000 Genomes Project by the West Midlands Genomics Medicine Centre, evaluating clinical relevance of results. After excluding samples with no sequencing data (1678/4851; 34.6%), 3166 sample sets (germline and somatic) from 3067 participants were sequenced. Results of 1256 participants (41.0%) were interpreted (excluding participants who died (308/3067; 10.0%) or were clinically excluded (1503/3067; 49.0%)). Of these, 323 (25.7%) had no variants in genes which may alter management (Domain 1 genes). Of the remaining 933 participants, 552 (59.2%) had clinical recommendations made (718 recommendations in total). These included therapeutic recommendations (377/933; 40.4%), such as clinical trial, unlicensed or licensed therapies or high TMB recommendations, and germline variants warranting clinical genetics review (85/933; 9.1%). At the last follow up, 20.2% of all recommendations were followed (145/718). However, only a small proportion of therapeutic recommendations were followed (5.1%, 25/491). The 100,000 Genomes Project has established infrastructure and regional experience to support personalised cancer care. The majority of those with successful sequencing had actionable variants. Ensuring GTAB recommendations are followed will maximise benefits for patients.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1805-1813"},"PeriodicalIF":6.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02890-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crucial immunological roles of the invasion front in innate and adaptive immunity in cervical cancer","authors":"Yuhya Hirahara, Kanako Shimizu, Satoru Yamasaki, Tomonori Iyoda, Shogo Ueda, Shinya Sato, Jotaro Harada, Haruya Saji, Satoshi Fujii, Yohei Miyagi, Etsuko Miyagi, Shin-ichiro Fujii","doi":"10.1038/s41416-024-02877-3","DOIUrl":"10.1038/s41416-024-02877-3","url":null,"abstract":"The immunostimulatory actions of innate and adaptive immune responses play a crucial role in the cancer-immunity cycle. Although cervical cancer (CC) exhibits a high recurrence rate, the relation with lymphocytes in the tumor tissue have not been analyzed. We analyzed NKT, NK, and T cells, not only in peripheral blood (PB), but also tumor tissue through histological analysis from 23 patients with CC collected before treatment. A correlation of them between PB and the tumor tissue were assessed. We detected functional NKT and NKG2Dhi NK cells and effector CD4+ Tregs in PB. In the tumor, we detected the infiltration of LAG-3+ TIM-3+ CD4+ and CD8+ T cells rather than NK cells particularly in the invasion front (IF) by fluorescent multiplex immunohistochemistry. The heatmap and correlation analysis revealed that LAG-3+ TIM-3+ CD8+ T cells are highly associated with CD69+ CD103− exhausted CD8+ T cells. We identified the statistical relationship between CD4+Tregs in PB and the number of LAG-3+ TIM-3+ CD4+ T cells in the IF, which may be related to recurrence in patients with CC. LAG-3+ TIM-3+ T cells located in the IF may play a key role in regulation of the tumor immune microenvironment.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1762-1774"},"PeriodicalIF":6.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A proteome-wide association study identifies putative causal proteins for breast cancer risk","authors":"Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Jill E. Henry, Bing Zhang, Xingyi Guo, Michele L. Cote, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long","doi":"10.1038/s41416-024-02879-1","DOIUrl":"10.1038/s41416-024-02879-1","url":null,"abstract":"Genome-wide association studies (GWAS) have identified more than 200 breast cancer risk-associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue related to breast cancer risk. We profiled the proteome in fresh frozen breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank (KTB). Protein expression levels were log2-transformed then normalized via quantile and inverse-rank transformations. GWAS data were also generated for these 120 samples. These data were used to build statistical models to predict protein expression levels via cis-genetic variants using the elastic net method. The prediction models were then applied to the GWAS summary statistics data of 133,384 breast cancer cases and 113,789 controls to assess the associations of genetically predicted protein expression levels with breast cancer risk overall and its subtypes using the S-PrediXcan method. A total of 6388 proteins were detected in the normal breast tissue samples from 120 women with a high detection false discovery rate (FDR) p value < 0.01. Among the 5820 proteins detected in more than 80% of participants, prediction models were successfully built for 2060 proteins with R > 0.1 and P < 0.05. Among these 2060 proteins, five proteins were significantly associated with overall breast cancer risk at an FDR p value < 0.1. Among these five proteins, the corresponding genes for proteins COPG1, DCTN3, and DDX6 were located at least 1 Megabase away from the GWAS-identified breast cancer risk variants. COPG1 was associated with an increased risk of breast cancer with a p value of 8.54 × 10–4. Both DCTN3 and DDX6 were associated with a decreased risk of breast cancer with p values of 1.01 × 10–3 and 3.25 × 10–4, respectively. The corresponding genes for the remaining two proteins, LSP1 and DNAJA3, were located in previously GWAS-identified breast cancer risk loci. After adjusting for GWAS-identified risk variants, the association for DNAJA3 was still significant (p value of 9.15 × 10–5 and adjusted p value of 1.94 × 10–4). However, the significance for LSP1 became weaker with a p value of 0.62. Stratification analyses by breast cancer subtypes identified three proteins, SMARCC1, LSP1, and NCKAP1L, associated with luminal A, luminal B, and ER-positive breast cancer. NCKAP1L was located at least 1Mb away from the GWAS-identified breast cancer risk variants. After adjusting for GWAS-identified breast cancer risk variants, the association for protein LSP1 was still significant (adjusted p value of 6.43 × 10–3 for luminal B subtype). We conducted the first breast-tissue-based PWAS and identified seven proteins associated with breast cancer, including five proteins not previously implicated. These findings help improve o","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1796-1804"},"PeriodicalIF":6.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02879-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune therapeutic strategies for the senescent tumor microenvironment","authors":"Tadahito Yasuda, Y. Alan Wang","doi":"10.1038/s41416-024-02865-7","DOIUrl":"10.1038/s41416-024-02865-7","url":null,"abstract":"Senescent cells can either to promote immunosuppressive tumor microenvironment or facilitate immune surveillance. Despite the revolutionary impact of cancer immunotherapy, durable responses in solid tumors, particularly in advanced stages, remain limited. Recent studies have shed light on the influence of senescent status within the tumor microenvironment (TME) on therapy resistance and major efforts are needed to overcome these challenges. This review summarizes recent advancements in targeting cellular senescence, with a particular focus on immunomodulatory approaches on the hallmarks of cellular senescence.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 3","pages":"237-244"},"PeriodicalIF":6.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning analysis of histopathological images predicts immunotherapy prognosis and reveals tumour microenvironment features in non-small cell lung cancer","authors":"Youyu Wang, Xueming Ju, Rong Hua, Ji Chen, Xiaoqin Dai, Lunxu Liu, Guifang Wang, Yifeng Bai, Honglin Hu, Xiaohua Li","doi":"10.1038/s41416-024-02856-8","DOIUrl":"10.1038/s41416-024-02856-8","url":null,"abstract":"Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a crucial treatment option for patients with advanced NSCLC. However, only a subset of patients experience clinical benefit from ICIs. Therefore, identifying biomarkers that can predict response to ICIs is imperative for optimising patient selection. Hematoxylin and eosin (H&E) images of NSCLC patients were obtained from the local cohort (n = 106) and The Cancer Genome Atlas (TCGA) (n = 899). We developed an ICI-related pathological prognostic signature (ir-PPS) based on H&E stained histopathology images to predict prognosis in NSCLC patients treated with ICIs using deep learning. To accomplish this, we employed a modified ResNet model (ResNet18-PG), a widely-used deep learning architecture well-known for its effectiveness in handling complex image recognition tasks. Our modifications include a progressive growing strategy to improve the stability of model training and the use of the AdamW optimiser, which enhances the optimisation process by adjusting the learning rate based on training dynamics. The deep learning model, ResNet18-PG, achieved an area under the receiver operating characteristic curve (AUC) of 0.918 and a recall of 0.995 on the local cohort. The ir-PPS effectively risk-stratified NSCLC patients. Patients in the low-risk group (n = 40) had significantly improved progression-free survival (PFS) after ICI treatment compared to those in the high-risk group (n = 66, log-rank P = 0.004, hazard ratio (HR) = 3.65, 95%CI: 1.75–7.60). The ir-PPS demonstrated good discriminatory power for predicting 6-month PFS (AUC = 0.750), 12-month PFS (AUC = 0.677), and 18-month PFS (AUC = 0.662). The low-risk group exhibited increased expression of immune checkpoint molecules, cytotoxicity-related genes, an elevated abundance of tumour-infiltrating lymphocytes, and enhanced activity in immune stimulatory pathways. The ir-PPS signature derived from H&E images using deep learning could predict ICIs prognosis in NSCLC patients. The ir-PPS provides a novel imaging biomarker that may help select optimal candidates for ICIs therapy in NSCLC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1833-1845"},"PeriodicalIF":6.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Study of Irinotecan, Trifluridine/tipiracil (TAS-102) plus Bevacizumab as a Later-line Therapy for Patients with Metastatic Colorectal Cancer (mCRC): a prospective single-center explorative study","authors":"Baoqi Li, Wenwei Yang, Na Liu, Deying Bi, Tingting Yang, Guifu Wu, Yongkun Sun","doi":"10.1038/s41416-024-02885-3","DOIUrl":"10.1038/s41416-024-02885-3","url":null,"abstract":"To explore the efficacy and safety of the combination of irinotecan, trifluridine/tipiracil (TAS-102), and bevacizumab in a later‐line setting for metastatic colorectal cancer (mCRC) patients. This was a single-center, phase II trial. The mCRC patients who are refractory to standard first-line and second-line treatment are eligible. Patients who previously received irinotecan while progressing during maintenance therapy are also eligible. The primary endpoint was the objective response rate (ORR). Between August 1, 2022, and September 30, 2023, 35 patients were enrolled, and 31 of them were evaluable for efficacy. The ORR was 25.8% (8/31), and the disease control rate (DCR) was 93.5% (29/31). As of April 30, 2024, the median progression-free survival (PFS) was 9.2 months (95% CI 6.285-12.115), whereas the median overall survival (OS) was not reached with the 1-year OS rate of 73.5%. The most common grade 3/4 treatment-related adverse events were neutropenia (34.3%), anemia (17.1%), and thrombocytopenia (8.6%). Irinotecan, TAS-102 plus bevacizumab regimen preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as later‐line treatment. This regimen warrants further exploration in refractory mCRC patients.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1775-1780"},"PeriodicalIF":6.4,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02885-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: CDK9 inhibition constrains multiple oncogenic transcriptional and epigenetic pathways in prostate cancer","authors":"Razia Rahman, Muhammed H. Rahaman, Adrienne R. Hanson, Nicholas Choo, Jianling Xie, Scott L. Townley, Raj Shrestha, Ramin Hassankhani, Saiful Islam, Susanne Ramm, Kaylene J. Simpson, Gail P. Risbridger, Giles Best, Margaret M. Centenera, Steven P. Balk, Ganessan Kichenadasse, Renea A. Taylor, Lisa M. Butler, Wayne D. Tilley, Simon J. Conn, Mitchell G. Lawrence, Shudong Wang, Luke A. Selth","doi":"10.1038/s41416-024-02862-w","DOIUrl":"10.1038/s41416-024-02862-w","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 10","pages":"1719-1719"},"PeriodicalIF":6.4,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02862-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma","authors":"Riccardo Serra, Stuart J. Smith, Jonathan Rowlinson, Noah Gorelick, Cara Moloney, Phoebe McCrorie, Gareth J. Veal, Philip Berry, Anthony J. Chalmers, Ian Suk, Kevin M. Shakesheff, Cameron Alexander, Richard G. Grundy, Henry Brem, Betty M. Tyler, Ruman Rahman","doi":"10.1038/s41416-024-02878-2","DOIUrl":"10.1038/s41416-024-02878-2","url":null,"abstract":"There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"131 11","pages":"1858-1868"},"PeriodicalIF":6.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02878-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}