Cancer discovery最新文献_第10页

Immunogenicity and Efficacy of Personalized Adjuvant mRNA Cancer Vaccines. 个性化 mRNA 癌症疫苗的免疫原性和疗效。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-1196

Pedro Berraondo, Raquel Cuesta, Miguel F Sanmamed, Ignacio Melero

引用次数: 0

ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma. ROR2 调控胰腺肿瘤和腺癌的细胞可塑性

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0137

Simone Benitz, Alec Steep, Malak M Nasser, Jonathan Preall, Ujjwal Mukund Mahajan, Holly McQuithey, Ian Loveless, Erick T Davis, Hui-Ju Wen, Daniel W Long, Thomas Metzler, Samuel Zwernik, Michaela Louw, Donald Rempinski, Daniel J Salas-Escabillas, Sydney M Brender, Linghao Song, Ling Huang, Brian K Theisen, Zhenyu Zhang, Nina G Steele, Ivonne Regel, Filip Bednar, Howard C Crawford

{"title":"ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.","authors":"Simone Benitz, Alec Steep, Malak M Nasser, Jonathan Preall, Ujjwal Mukund Mahajan, Holly McQuithey, Ian Loveless, Erick T Davis, Hui-Ju Wen, Daniel W Long, Thomas Metzler, Samuel Zwernik, Michaela Louw, Donald Rempinski, Daniel J Salas-Escabillas, Sydney M Brender, Linghao Song, Ling Huang, Brian K Theisen, Zhenyu Zhang, Nina G Steele, Ivonne Regel, Filip Bednar, Howard C Crawford","doi":"10.1158/2159-8290.CD-24-0137","DOIUrl":"10.1158/2159-8290.CD-24-0137","url":null,"abstract":"Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor PDX1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in a mouse and human. We identified the receptor tyrosine kinase ROR2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. Significance: We discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to KRAS inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies. See related commentary by Marasco and Misale, p. 2018.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2162-2182"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554214","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}

引用次数: 0

T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study. 个体化新抗原疗法 mRNA-4157 (V940) 单独或与 Pembrolizumab 联用的 T 细胞反应在 KEYNOTE-603 1 期研究中。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0158

Justin F Gainor, Manish R Patel, Jeffrey S Weber, Martin Gutierrez, Julie E Bauman, Jeffrey M Clarke, Ricklie Julian, Aaron J Scott, Jessica L Geiger, Kedar Kirtane, Celine Robert-Tissot, Brandon Coder, Moomal Tasneem, Jing Sun, Wei Zheng, Lauren Gerbereux, Andressa Laino, Filippos Porichis, Jack Russella Pollard, Peijie Hou, Vasudha Sehgal, Xing Chen, Manju Morrissey, Hikmat N Daghestani, Igor Feldman, Lakshmi Srinivasan, Joshua P Frederick, Michelle Brown, Praveen Aanur, Robert Meehan, Howard A Burris

{"title":"T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study.","authors":"Justin F Gainor, Manish R Patel, Jeffrey S Weber, Martin Gutierrez, Julie E Bauman, Jeffrey M Clarke, Ricklie Julian, Aaron J Scott, Jessica L Geiger, Kedar Kirtane, Celine Robert-Tissot, Brandon Coder, Moomal Tasneem, Jing Sun, Wei Zheng, Lauren Gerbereux, Andressa Laino, Filippos Porichis, Jack Russella Pollard, Peijie Hou, Vasudha Sehgal, Xing Chen, Manju Morrissey, Hikmat N Daghestani, Igor Feldman, Lakshmi Srinivasan, Joshua P Frederick, Michelle Brown, Praveen Aanur, Robert Meehan, Howard A Burris","doi":"10.1158/2159-8290.CD-24-0158","DOIUrl":"10.1158/2159-8290.CD-24-0158","url":null,"abstract":"mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2209-2223"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901036","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}

引用次数: 0

Drugging p53: Barriers, Criteria, and Prospects. 给 p53 下药：障碍、标准和前景。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0837

Huaxin Song, Shujun Xiao, Jiaqi Wu, Min Lu

引用次数: 0

Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors. 通过合理的蛋白质工程来增强不依赖于 MHC 的 T 细胞受体。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-1393

Ju-Fang Chang, Jack H Landmann, Tien-Ching Chang, Mehmet Emrah Selli, Yangdon Tenzin, John M Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar Gupta, John F DiPersio, Alex S Holehouse, Nathan Singh

{"title":"Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors.","authors":"Ju-Fang Chang, Jack H Landmann, Tien-Ching Chang, Mehmet Emrah Selli, Yangdon Tenzin, John M Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar Gupta, John F DiPersio, Alex S Holehouse, Nathan Singh","doi":"10.1158/2159-8290.CD-23-1393","DOIUrl":"10.1158/2159-8290.CD-23-1393","url":null,"abstract":"Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T-cell activation causes T-cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T-cell response, we designed MHC-independent T-cell receptors (miTCR) by linking antibody variable domains to T-cell receptor constant chains. Using predictive modeling, we observed that this standard \"cut and paste\" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications, we developed structure-enhanced miTCRs which significantly improved receptor-driven T-cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T-cell persistence and enabled improved leukemic control in vivo compared with classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function. Significance: Improving the durability of engineered T-cell immunotherapies is critical to enhancing efficacy. We used a structure-informed design to evolve improved miTCR function across several models. This work underscores the central role of synthetic receptor structure in T-cell function and provides a framework for improved receptor engineering.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2109-2121"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562643","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}

引用次数: 0

The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. 肺腺癌的 N6-甲基腺苷表转录组图谱

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-1212

Shiyan Wang, Yong Zeng, Lin Zhu, Min Zhang, Lei Zhou, Weixiong Yang, Weishan Luo, Lina Wang, Yanming Liu, Helen Zhu, Xin Xu, Peiran Su, Xinyue Zhang, Musaddeque Ahmed, Wei Chen, Moliang Chen, Sujun Chen, Mykhaylo Slobodyanyuk, Zhongpeng Xie, Jiansheng Guan, Wen Zhang, Aafaque Ahmad Khan, Shingo Sakashita, Ni Liu, Nhu-An Pham, Paul C Boutros, Zunfu Ke, Michael F Moran, Zongwei Cai, Chao Cheng, Jun Yu, Ming S Tsao, Housheng H He

{"title":"The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma.","authors":"Shiyan Wang, Yong Zeng, Lin Zhu, Min Zhang, Lei Zhou, Weixiong Yang, Weishan Luo, Lina Wang, Yanming Liu, Helen Zhu, Xin Xu, Peiran Su, Xinyue Zhang, Musaddeque Ahmed, Wei Chen, Moliang Chen, Sujun Chen, Mykhaylo Slobodyanyuk, Zhongpeng Xie, Jiansheng Guan, Wen Zhang, Aafaque Ahmad Khan, Shingo Sakashita, Ni Liu, Nhu-An Pham, Paul C Boutros, Zunfu Ke, Michael F Moran, Zongwei Cai, Chao Cheng, Jun Yu, Ming S Tsao, Housheng H He","doi":"10.1158/2159-8290.CD-23-1212","DOIUrl":"10.1158/2159-8290.CD-23-1212","url":null,"abstract":"Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo. Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2279-2299"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449754","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}

引用次数: 0

Targeting Noncoding cis-Regulatory Elements for Cancer Therapy in the Context of the 3D Genome. 在三维基因组背景下瞄准非编码顺式调控元件治疗癌症

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0836

Kailong Li, Gong-Hong Wei, Yuxin Yin, Jiawen Feng

引用次数: 0

Combination Diagnostics: Adding Blood-Based ctDNA Screening to Low-Dose CT Imaging for Early Detection of Lung Cancer. 联合诊断：在低剂量 CT 成像中加入基于血液的 ctDNA 筛查以早期检测肺癌。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-1195

Daniel A Haber, Steven J Skates

引用次数: 0

Early Cancer Detection Through Comprehensive Mapping of Dynamic Tumorigenesis. 通过全面绘制动态肿瘤发生图早期发现癌症