Cancer discoveryPub Date : 2026-04-28DOI: 10.1158/2159-8290.cd-nw2026-0047
{"title":"NCI Director: \"Our Mission Remains Unchanged, and Funding is Strong\".","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0047","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0047","url":null,"abstract":"During his address and \"fireside chat\" at the American Association for Cancer Research Annual Meeting 2026 in San Diego, CA, on April 20, NCI Director Anthony Letai, MD, PhD, assured the cancer community that federal support for cancer research remains strong despite numerous challenges researchers encountered during fiscal year 2025, clarified approaches to funding, and offered encouragement to early-career investigators.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"21 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754599","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}
Cancer discoveryPub Date : 2026-04-28DOI: 10.1158/2159-8290.CD-NW2026-0046
{"title":"Daraxonrasib Continues Victory Lap.","authors":"","doi":"10.1158/2159-8290.CD-NW2026-0046","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-NW2026-0046","url":null,"abstract":"<p><p>Results from two separate phase I/II studies investigating the pan-RAS inhibitor daraxonrasib suggest it is safe and effective for patients with pancreatic ductal adenocarcinoma, building on recently announced data showcasing the drug's superior performance in a phase III study. Together, these new data are an exciting sign that daraxonrasib could become the first targeted pancreatic cancer therapy to spur sustained responses.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1"},"PeriodicalIF":33.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763295","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}
Cancer discoveryPub Date : 2026-04-22DOI: 10.1158/2159-8290.cd-25-1454
Brett A Schroeder,Chirayu Mohindroo,Anna-Lena Meinhardt,Nobuyuki Takahashi,Yang Zhang,Min-Jung Lee,Sarthak Sahoo,Renee N Donahue,Rajesh Kumar,Michael Nirula,Yuan Yang,Shraddha Rastogi,Nahoko Sato,Sunmin Lee,Yo-Ting Tsai,Sophie Zhuang,Amira Kazi,Yue Huang,Parth Desai,Samantha Nichols,Linda Sciuto,Danielle Pinkiert,George Chrisafis,Max Greenberg,D Nathan Biery,Rusul Al-Marayaty,Howard H Yang,Maxwell P Lee,Christopher W Schultz,Rajaa El Meskini,Devon Atkinson,Kristen Fousek,James L Gulley,Jeffrey Schlom,Masashi Sato,Roshan L Shrestha,Ajit Kumar Sharma,Mohit Kumar Jolly,Claudia Palena,Lalage M Wakefield,Anish Thomas
{"title":"BLOCKADE OF TUMOR-INTRINSIC TGF-Β SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER.","authors":"Brett A Schroeder,Chirayu Mohindroo,Anna-Lena Meinhardt,Nobuyuki Takahashi,Yang Zhang,Min-Jung Lee,Sarthak Sahoo,Renee N Donahue,Rajesh Kumar,Michael Nirula,Yuan Yang,Shraddha Rastogi,Nahoko Sato,Sunmin Lee,Yo-Ting Tsai,Sophie Zhuang,Amira Kazi,Yue Huang,Parth Desai,Samantha Nichols,Linda Sciuto,Danielle Pinkiert,George Chrisafis,Max Greenberg,D Nathan Biery,Rusul Al-Marayaty,Howard H Yang,Maxwell P Lee,Christopher W Schultz,Rajaa El Meskini,Devon Atkinson,Kristen Fousek,James L Gulley,Jeffrey Schlom,Masashi Sato,Roshan L Shrestha,Ajit Kumar Sharma,Mohit Kumar Jolly,Claudia Palena,Lalage M Wakefield,Anish Thomas","doi":"10.1158/2159-8290.cd-25-1454","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1454","url":null,"abstract":"Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but their tumor-intrinsic consequences remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGF-β inhibitor, in small cell lung cancer. Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n=450), in higher frequencies with bintrafusp than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGF-β signaling. Functional studies demonstrated that tumor-intrinsic TGF-β signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGF-β-high transcriptional state associated with inferior survival. Together, these findings identify a context-dependent, growth-constraining function of TGF-β and support tumor-intrinsic biomarker-guidance while targeting stromal immunosuppressive pathways.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"248 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731602","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-nw2026-0041
{"title":"Elisrasib Elicits Clinical Benefit in KRASG12C-mutant NSCLC","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0041","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0041","url":null,"abstract":": In a phase I/II clinical trial, patients with locally advanced or metastatic KRAS G12C-mutant non–small cell lung cancer treated with the next-generation KRASG12C inhibitor elisrasib showed robust and durable clinical responses. Patients naïve to KRASG12C inhibitors, as well as those refractory to other such drugs, experienced high rates of disease control—98.5% and 83.9%, respectively.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"85 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725839","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-nw2026-0042
{"title":"Wildfire Smoke Exposure Associated with Increased Cancer Risk.","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0042","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0042","url":null,"abstract":"According to a new study, exposure to smoke from wildfires is associated with lung, colorectal, breast, bladder, and blood cancers, highlighting the long-term health risks it poses.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"22 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731251","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-nw2026-0044
{"title":"QLS5132 Goes after CLDN6 in Ovarian Cancer.","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0044","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0044","url":null,"abstract":"For patients with advanced platinum-resistant ovarian cancer, treatment options remain limited, but new agents are emerging. One is QLS5132, an antibody-drug conjugate targeting CLDN6; early data from a phase I trial indicates that it has a favorable safety profile and appears active in this disease.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"46 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731611","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-25-1551
Salah-Eddine Bentebibel, Daniel J. McGrail, Veena Kochat, Emre Arslan, Reham Abdel-Wahab, Barbara Pazdrak, Ravi Murthy, Nourel Hoda M. Tahon, Sung-Nam Cho, Dzifa Y. Duose, Khalida Wani, Jingjing Liu, Cara Haymaker, Javier A. Gomez, Heather Sonnemann, Arjun S. Katailiha, Barbara Nassif-Rausseo, Maha Rahim, Irene Li, Aaron T. Mayer, Xiaodong Yang, Frank J. Hsu, Jianhua Zhang, Daniel H. Johnson, Rodabe N. Amaria, Isabella C. Glitza Oliva, Sapna P. Patel, Patrick Hwu, Khaled M. Elsayes, Hussein A. Tawbi, Jared K. Burks, Chantale Bernatchez, Michael A. Davies, Kunal Rai, Gregory Lizee, Suhendan Ekmekcioglu, Adi Diab
{"title":"Intratumoral sotigalimab with pembrolizumab induces rapid activation of antigen presenting cells and drives anti-tumor responses in non-injected tumors in metastatic melanoma: A phase I/II study","authors":"Salah-Eddine Bentebibel, Daniel J. McGrail, Veena Kochat, Emre Arslan, Reham Abdel-Wahab, Barbara Pazdrak, Ravi Murthy, Nourel Hoda M. Tahon, Sung-Nam Cho, Dzifa Y. Duose, Khalida Wani, Jingjing Liu, Cara Haymaker, Javier A. Gomez, Heather Sonnemann, Arjun S. Katailiha, Barbara Nassif-Rausseo, Maha Rahim, Irene Li, Aaron T. Mayer, Xiaodong Yang, Frank J. Hsu, Jianhua Zhang, Daniel H. Johnson, Rodabe N. Amaria, Isabella C. Glitza Oliva, Sapna P. Patel, Patrick Hwu, Khaled M. Elsayes, Hussein A. Tawbi, Jared K. Burks, Chantale Bernatchez, Michael A. Davies, Kunal Rai, Gregory Lizee, Suhendan Ekmekcioglu, Adi Diab","doi":"10.1158/2159-8290.cd-25-1551","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1551","url":null,"abstract":"Immune checkpoint blockers (ICBs) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab in 32 ICB-naïve MM patients. Primary endpoints were safety, and objective response rate (ORR). Sotigalimab was well tolerated. At the recommended phase 2 dose (RP2D), the ORR was 50% and the disease control rate (DCR) was 92%, with ORR of 67% in injected and 50% in non-injected tumors. Multiomic analyses of tumor and blood showed sotigalimab effectively engaged the CD40 pathway, boosting infiltration and activation of myeloid cells, including CD11c+DC-LAMP+ dendritic cells (DCs) and macrophages. The combination therapy activated innate and adaptive immunity in injected tumors and cytotoxic responses in non-injected tumors. TCR sequencing showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes, but not with baseline features associated with response to anti-PD1 monotherapy.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"246 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147733658","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-25-1458
Benedikt Pelzer, Cem Meydan, Isaac M. Spiegel, Ioannis Karagiannidis, Min Xia, Matt Teater, Emma M. Welter, Zowie E. Searcy, Laura K. Hilton, Darko Barisic, Amos Fong, Pengyan Fa, Shenon Sethi, Irem S. Isgor, Jessie J. Fielding, Alireza Karbalayghareh, Colin S. Burdette, Sravya Tumuluru, Sonia M. Debek, Sunjae Lee, Ramon Massoni-Badosa, Ceyda Durmaz, Eralda Salataj, Prasath Pararajalingam, Zhengming Chen, Richard J. Pelzl, Sanket Shah, Martin A. Rivas, Kenneth B. Hoehn, Coraline Mlynarczyk, Hannah M. Isles, Xiang Wang, Ahmet Dogan, Kojo S.J. Elenitoba-Johnson, David W. Scott, Kostiantyn Dreval, Ryan D. Morin, Christina S. Leslie, Rishi Puri, Jacob B. Geri, Christopher R. Chin, Amy Chadburn, Christopher E. Mason, Hans Christian. Reinhardt, Montserrat C. Anguera, Wendy Béguelin, Leandro Venturutti, Ari M. Melnick
{"title":"SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities","authors":"Benedikt Pelzer, Cem Meydan, Isaac M. Spiegel, Ioannis Karagiannidis, Min Xia, Matt Teater, Emma M. Welter, Zowie E. Searcy, Laura K. Hilton, Darko Barisic, Amos Fong, Pengyan Fa, Shenon Sethi, Irem S. Isgor, Jessie J. Fielding, Alireza Karbalayghareh, Colin S. Burdette, Sravya Tumuluru, Sonia M. Debek, Sunjae Lee, Ramon Massoni-Badosa, Ceyda Durmaz, Eralda Salataj, Prasath Pararajalingam, Zhengming Chen, Richard J. Pelzl, Sanket Shah, Martin A. Rivas, Kenneth B. Hoehn, Coraline Mlynarczyk, Hannah M. Isles, Xiang Wang, Ahmet Dogan, Kojo S.J. Elenitoba-Johnson, David W. Scott, Kostiantyn Dreval, Ryan D. Morin, Christina S. Leslie, Rishi Puri, Jacob B. Geri, Christopher R. Chin, Amy Chadburn, Christopher E. Mason, Hans Christian. Reinhardt, Montserrat C. Anguera, Wendy Béguelin, Leandro Venturutti, Ari M. Melnick","doi":"10.1158/2159-8290.cd-25-1458","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1458","url":null,"abstract":"Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCL derive from follicular B cells engaged in adaptive immune responses. By studying co-occurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extra-follicular trajectory. Using animal models and human specimens, we find this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory and a distinct, autoimmune B-cell-like state. This trajectory is associated with sex-biased outcomes: female patients and mice exhibit reduced survival compared to males in our cohorts. Further analysis links this disparity to enhanced X-chromosome-linked expression and functionality of toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"143 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147733655","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}
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