Cancer research communications最新文献

{"title":"Supermeres containing Discoidin Domain Receptor 1 extracellular domain promote collagen alignment and immune exclusion in microsatellite stable colorectal cancer.","authors":"Maxwell Stuart Hamilton, Samuel T Ellis, Zheng Cao, Oleg S Tutanov, Alan J Simmons, Radhika Aramandla, James N Higginbotham, Marisol Ramirez, Katherine W Schnee, Matthew E Bechard, Harsimran Kaur, Jeffrey L Franklin, Swastika Mandal, Ken S Lau, Qi Liu, Jeremy A Goettel, Ambra Pozzi, Robert J Coffey","doi":"10.1158/2767-9764.CRC-26-0105","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0105","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) is an effective treatment for microsatellite instability-high (MSI-H) colorectal cancers (CRCs) that are highly infiltrated by CD8+ T cells. Microsatellite stable (MSS) CRCs are unresponsive to ICB, at least in part, due to the paucity of intratumoral CD8+ T cells. We recently identified Discoidin Domain Receptor 1 (DDR1) as one of four genes associated with CD8+ T-cell exclusion in MSS CRC. There are conflicting reports about the presence and role of the cleaved ectodomain (cECD) of DDR1 in mouse models of breast and pancreatic cancer. To explore the role of the DDR1 cECD in human CRC, we developed Collagen Alignment and Spatial Transcriptomics Analysis (CASTA), which revealed that genes involved in fibroblast contractility were associated with both DDR1 tumor expression and collagen alignment as determined by label-free second harmonic generation (2HG) imaging of the tumor collagen. Using 3D collagen co-cultures of CRC spheroids and fibroblasts, we show that DDR1 promotes collagen alignment and CD8+ T-cell exclusion. We found large amounts of DDR1 cECD in MSS CRC supermeres, 25-35 nm secreted amembranous nanoparticles. Supermeres containing DDR1 cECD were sufficient to induce contraction of human colonic fibroblasts. We propose a model in which supermeres containing DDR1 cECD promote the contraction of stromal fibroblasts in MSS CRC, leading to collagen alignment and CD8+ T-cell exclusion. These results support DDR1 cECD as an attractive therapeutic target in MSS CRC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ribonucleotide Reductase Inhibition Triggers Ferroptosis in Genetically Defined Subsets of Non-Small Cell Lung Cancer.","authors":"Utsav Sen, Dalia Natour, Subhamoy Chakraborty, Elisa Gobbini, Chih-Wei Fan, Calvin Koelbel, Andrew Elliott, Ari M Vanderwalde, Hossein Borghaei, Balazs Halmos, Deniz Demircioglu, Dan Hasson, Nishant Gandhi, Triparna Sen","doi":"10.1158/2767-9764.CRC-25-0829","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0829","url":null,"abstract":"<p><p>Non-small-cell lung cancer (NSCLC) is responsible for the majority of cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common NSCLC subtype. Despite advances in targeted therapies, treatment resistance remains a critical challenge. Ribonucleotide reductase (RNR), a crucial enzyme in deoxyribonucleotide triphosphate (dNTP) biosynthesis, is frequently upregulated in cancer, contributing to genomic instability and poor prognosis in multiple malignancies. However, the role of the RNR complex in driving tumorigenesis is not fully understood in oncogenic-driven LUAD. Transcriptomic analysis of more than 27,000 real-world NSCLC patient samples revealed that RNR subunits (RRM1 and RRM2) are significantly upregulated in TP53 mutated NSCLC and correlated with significantly poor prognosis in multiple oncogene-driven LUAD. Using pharmacologic and genetic approaches to inhibit RNR in LUAD models, we assessed functional consequences through molecular, biochemical, and imaging techniques. RNR inhibition induced appreciable replication stress and triggered DNA damage, leading to cell death in LUAD cells. Notably, we uncovered that RNR suppression preferentially induced ferroptosis, an iron-dependent cell death driven by lipid peroxidation. This represents a previously unrecognized mechanism of RNR-mediated cell death by which mutant LUAD cells can be selectively targeted. Our study establishes RNR inhibition as a potent strategy to selectively induce ferroptosis in oncogenic addicted LUAD, offering a new therapeutic avenue for genetically defined patient subgroups. Targeting nucleotide metabolism could serve as an effective approach to overcome treatment resistance and improve clinical outcomes for patients with high-risk LUAD.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The GENIE Data Model: A Solid Tumor, Person-Centric Framework for Scalable, Harmonized Precision Oncology Data Collection.","authors":"Jennifer N Hoppe, Jocelyn Lee, Tomi F Akinyemiju, Danielle S Bitterman, Michael Brudno, Michelle F Green, Vojtech Huser, Jafi A Lipson, Sanjay Mishra, Daniel P Nussbaum, Jai N Patel, Valentina I Petkov, Kelli M Rasmussen, Sahussapont Joseph Sirintrapun, Patricia A Spears, Sebastiaan Van Sandijk, Anne-Marie Meyer, Umit Topaloglu, Jeremy L Warner","doi":"10.1158/2767-9764.CRC-26-0148","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0148","url":null,"abstract":"<p><p>Adequately powered analyses in precision oncology often require combining cohorts across institutions. Yet integration is constrained by the least granular source and may become infeasible when data elements are too heterogeneous to harmonize and map to a common data model. This challenge is acute in multi-institutional precision oncology research, where real-world evidence requires harmonized clinico-omic data integration. Existing models often lack sufficient treatment patterns, outcomes, and genomic data, limiting interoperability and scalability. To address these gaps, AACR Project GENIE™ (Genomics Evidence Neoplasia Information Exchange) developed the GENIE Data Model (GDM), a comprehensive, open-source, oncology data model for scalable, consistent, and interoperable data collection across solid tumors designed to effectively capture the patient's journey with cancer. Through iterative consensus-building, four working groups comprising 13 subject matter experts defined data elements across multiple clinical domains: patient characteristics, imaging, diagnosis, surgery, histopathology, biomarkers, systemic therapy, radiation, clinical trial history, disease response and outcomes, and social determinants of health. Elements were defined using standardized terminologies and permissible values to support mapping to HL7 FHIR, OMOP, and other existing oncology standards. The model architecture distinguishes manually abstracted elements from computationally collected elements, enabling parallel workflows. The GDM provides an extensible framework that addresses critical gaps and enables scalable, harmonized data collection essential for precision oncology and real-world evidence generation.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1b/2 Study of Atezolizumab in Combination with Thiopurine Therapy in Patients with Metastatic Solid Tumors and Intermediate Tumor Mutational Burden.","authors":"Christine Federspiel Secher, Martin Højgaard, Iben Spanggaard, Ane Yde Schmidt, Yuliu Guo, Luca Robinson, Daniela De Zio, Linea N Toksvang, Frederik Otzen Bagger, Kjeld Schmiegelow, Kristoffer S Rohrberg","doi":"10.1158/2767-9764.CRC-26-0210","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0210","url":null,"abstract":"<p><strong>Purpose: </strong>The TEMPLE study was a phase 1b/2 trial evaluating the safety, tolerability, and efficacy of atezolizumab combined with thiopurine therapy in patients with metastatic solid tumors, aim-ing to increase tumor mutational burden (TMB) through single-nucleotide mismatching and neoepitope generation.</p><p><strong>Patients and methods: </strong>Phase 1b was an open-label, single-arm dose de-escalation trial conducted to determine the recommended phase 2 dose (RP2D) of 6-mercaptopurine and 6-thioguanine combined with atezolizumab in adult patients with metastatic solid tumors harboring intermediate TMB (5-10 mut/Mb). Phase 2 used Simon's two-stage design to assess objective response per RECIST v1.1. Secondary endpoints included overall survival and progression-free survival.</p><p><strong>Results: </strong>In phase 1b, the initial dose level proved too toxic in this heavily pretreated population. The subsequent dose level (6MP 37.5 mg/m² QD + 6TG 10.0 mg/m² QD + atezolizumab 1200 mg Q3W) was well tolerated and defined as the RP2D. The most common treatment-related ad-verse events were anorexia, nausea, and fatigue. In phase 2 stage 1, 3 of 13 patients achieved stable disease, while the remaining 10 patients experienced progressive disease. No objective responses were observed, and the trial was ter-minated after stage 1. Translational analyses of serial tumor biopsies using whole-genome and RNA sequencing revealed no definitive shifts in tumor mutational burden or neoepitope gen-eration.</p><p><strong>Conclusions: </strong>A safe and tolerable dose of 6-mercaptopurine and 6-thioguanine combined with atezolizumab was identified in patients with metastatic solid tumors. Although clinical benefit was limited, the TEMPLE study informs future investigations in patients with less advanced disease.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer.","authors":"Chiori Tabe, Rajesh Kumar, Yue Huang, Michael J Kruhlak, Ajit Kumar Sharma, Roshan L Shrestha, Anish Thomas","doi":"10.1158/2767-9764.CRC-26-0560","DOIUrl":"10.1158/2767-9764.CRC-26-0560","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is characterized by pervasive chromosomal instability (CIN) and remains largely refractory to targeted therapies. KIF18A, a motor protein that regulates chromosome alignment during mitosis, has emerged as a selective dependency in CIN-high tumors. Whether this dependency extends to SCLC, a prototypical CIN-high cancer, has not been established, and biomarkers predicting response to KIF18A inhibition, currently in clinical trials, are lacking. We integrated analyses of patient tumor datasets, neuroendocrine (NE) and non- NE SCLC cell lines, and functional perturbation models to define the determinants of response to KIF18A inhibition. Chromosomal instability metrics, transcriptional programs, mitotic dynamics, and spindle assembly checkpoint (SAC) function were assessed using genomic profiling, live-cell imaging, genetic perturbation, and pharmacologic inhibition. KIF18A expression was elevated in SCLC tumors and correlated with CIN-associated transcriptional programs, proliferative markers, and NE status; however, these features did not predict sensitivity to KIF18A inhibition. Instead, response was determined by the functional integrity of the SAC. SAC-proficient SCLC cells underwent sustained mitotic arrest followed by apoptotic cell death upon KIF18A inhibition, whereas SAC-defective cells failed to maintain checkpoint activation and survived. Mechanistically, resistant cells exhibited impaired kinetochore recruitment of core SAC components, including MAD1 and BUBR1. Importantly, transient induction of acute CIN through MPS1 inhibition partially restored sensitivity to KIF18A inhibition in resistant models. This study provides the first mechanistic characterization of KIF18A dependency in SCLC, identifying SAC competency as the primary determinant of response. These findings establish a biologically informed framework for patient stratification and rational combination strategies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Community-Based Hereditary Breast and Ovarian Cancer Family History Assessment and Genetic Testing among Spanish-Speaking Hispanic/Latina Women in California.","authors":"Daisy M Montoya, Amanda F Corpuz, Karla E Gonzalez, Kaylee Santos, Alyssa Reed, Julie H T Dang, Helen K Chew, Guadalupe Polanco-Echeverry, Lizeth I Tamayo, Miriam T Hernandez, Alejandra Martinez, Elad Ziv, Susan L Neuhausen, Luis G Carvajal-Carmona, Ysabel Duron, Laura Fejerman","doi":"10.1158/2767-9764.CRC-26-0046","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0046","url":null,"abstract":"<p><p>Breast cancer is the most common cancer among women in the United States, and the leading cause of cancer incidence and mortality among Hispanic/Latina (H/L) women. For women with a genetic predisposition to hereditary breast and ovarian cancer (HBOC), genetic counseling has been shown to aid in the decision-making process and engagement in risk-reducing strategies for cancer prevention and early detection. However, H/L women are less likely to receive genetic testing and undergo genetic counseling than Non-Hispanic White women. We developed a Promotores-led virtual HBOC outreach, education, and risk assessment program (\"Tu Historia Cuenta (THC)\") for Spanish-speaking H/L women in California. In this study we describe genetic testing uptake, testing results, and participants' experiences. Participants (N=1286) responded to a demographic and HBOC family history survey. Those identified as high-risk based on the family history survey were offered free genetic testing with a hereditary cancer panel. Of the 111 women identified as high-risk, 18 had been previously tested and 33 received genetic testing through THC, resulting in a 35.5% completion rate for those offered testing. Among the 51 women with test results, six had a positive result, three were carriers of a variant of unknown significance, 38 had a negative result, and four participants tested before recruitment did not know their results. Participants who tested through THC indicated satisfaction with the genetic testing process. These findings underscore the importance of simplifying access and exploring additional factors influencing H/L women's decision to receive testing beyond previously established cost, awareness, and knowledge barriers.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-Level KRAS G12C Prevalence Among Hispanic/Latino and Non-Hispanic White Patients in Real-World Clinicogenomic Cohorts.","authors":"Daniel F Pilco-Janeta, Myriam De la Cruz-Puebla, Daisy R Guamán-Pilco, Diego Montenegro, William Miranda","doi":"10.1158/2767-9764.CRC-26-0322","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0322","url":null,"abstract":"<p><p>KRAS G12C is a treatment-defining biomarker in non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD). Hispanic/Latino (H/L) patients remain undercharacterized in precision oncology datasets, and patient-level KRAS G12C prevalence has not been consistently quantified using strict ethnicity definitions. We analyzed MSK-CHORD and AACR GENIE after excluding the MSK contributing center. H/L required explicit Hispanic/Latino-origin annotation; non-Hispanic White (NH-W) required White race with explicit non-Hispanic ethnicity. Primary analyses compared patient-level KRAS G12C prevalence in mutually exclusive LUAD and non-LUAD NSCLC. In LUAD, KRAS G12C prevalence was lower in H/L than NH-W patients in MSK-CHORD (7.9% vs 15.4%; OR, 0.47; 95% CI, 0.30-0.74; P<0.001) and GENIE (7.2% vs 15.1%; OR, 0.44; 95% CI, 0.33-0.58; P<0.0001). In non-LUAD NSCLC, differences were smaller and not significant in MSK-CHORD (4.8% vs 5.1%; OR, 0.94; P=1.000) or GENIE (4.9% vs 6.7%; OR, 0.73; P=0.461). In MSK-CHORD LUAD, adjustment for smoking moved the OR from 0.50 to 0.68. H/L patients had lower patient-level KRAS G12C prevalence than NH-W patients in LUAD across two real-world clinicogenomic cohorts. The finding was histology-specific and attenuated after smoking adjustment, supporting a biomarker-yield interpretation.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 2 Study of Berzosertib in Combination with Carboplatin compared to Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer.","authors":"Atish D Choudhury, Caiwei Zhong, Wanling Xie, Bose S Kochupurakkal, Peter I-Fan Wu, Irbaz Bin Riaz, Ruolin Liu, David D Yang, Edmund Folefac, Daniel Lee, Mamta Parikh, David J Einstein, Elizabeth R Kessler, Tina Mayer, Rana R McKay, Amanda Pace, Kent W Mouw, Li Chen, Viktor A Adalsteinsson, Eliezer M Van Allen, Charles A Kunos, Steven D Gore, Biswajit Das, Alan D'Andrea, Mary-Ellen Taplin, Geoffrey I Shapiro","doi":"10.1158/2767-9764.CRC-26-0488","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0488","url":null,"abstract":"<p><strong>Purpose: </strong>Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer.</p><p><strong>Patients and methods: </strong>Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response).</p><p><strong>Results: </strong>Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial.</p><p><strong>Conclusions: </strong>Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148815112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRB-701: a Second-Generation Nectin-4 Targeted Antibody-Drug Conjugate with Optimized Stability and Pharmacokinetics for the Treatment of Solid Tumors.","authors":"Zhaopeng Sun, Mo Dan, Lu Lv, Mingyue Shen, Can Yuan, Congcong Niu, Yang Zhang, Xixin Hu, Xiwu Hui, Andrew Kolodziej","doi":"10.1158/2767-9764.CRC-25-0799","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0799","url":null,"abstract":"<p><p>The adhesion protein nectin-4 is a clinically validated tumor-selective antigen that is overexpressed across multiple cancer types and has been successfully exploited as a target for antibody-drug conjugates (ADCs), most notably enfortumab vedotin (EV), which is approved for treatment of urothelial carcinoma. Here, we report the design and preclinical characterization of a second-generation nectin-4 targeted ADC, CRB-701 (also identified as SYS6002). CRB-701 was synthesized using microbial transglutaminase (mTGase) technology to conjugate two molecules of monomethyl auristatin E (MMAE) via a cleavable linker to a highly selective, high-affinity anti-nectin-4 monoclonal antibody. CRB-701 exhibited potent in vitro cytotoxicity in nectin-4 expressing cell lines and in vivo antitumor activity in cell line-derived and patient-derived murine xenograft models of human cancer (cell line-derived models: PC-3-NECTIN4 prostate cancer, MDA-MB-468 breast cancer, and HT1376 bladder cancer; patient-derived model: BL0597 bladder cancer), exhibiting efficacy similar to or great than to EV across tumors with varying levels of nectin-4 expression. CRB-701 delivered high levels of MMAE upon internalization in tumor cells and was markedly more stable in circulation than EV, with lower systemic MMAE release, an approximately two-fold longer half-life, and at least two-fold higher safety margin in monkeys. These results suggest that CRB-701 may be a promising alternative therapeutic for the treatment of nectin-4 expressing tumors, providing a more favorable therapeutic window and potentially enabling regimens with higher doses and less frequent dosing than are required for EV, the only currently approved nectin-4 targeting ADC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148815160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of proton versus photon (chemo)radiation on circulating immune cells in head and neck cancer.","authors":"Anneke L Eerkens, Nienke van Rooij, Annechien Plat, Annegé Vledder, Koen Brummel, Sjoukje F Oosting, Bert van der Vegt, Gyorgy B Halmos, Johannes A Langendijk, Marco de Bruyn, Hans W Nijman, Tineke W H Meijer","doi":"10.1158/2767-9764.CRC-26-0496","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-26-0496","url":null,"abstract":"<p><strong>Purpose: </strong>Proton therapy delivers more precise radiation with less toxicity than photons. Yet, its impact on circulating immune cells in head and neck squamous cell carcinoma (HNSCC) remains poorly understood. We compared the impact of proton versus photon radiation on circulating immune cells in patients with locally advanced HNSCC undergoing definitive (chemo)radiation.</p><p><strong>Patients and methods: </strong>Stage III-IV HNSCC patients receiving definitive radiation (70 Gy) with or without weekly cisplatin using proton or photon therapy were enrolled. Peripheral blood was collected at baseline, during treatment, and up to one-year post-treatment. White blood cell differentiation, lymphocyte subsets, and lymphocyte function were evaluated using high-dimensional flow cytometry and functional assays.</p><p><strong>Results: </strong>Twenty-seven patients were enrolled: 10 received chemoradiation (CRT) with protons, 8 radiation (RT) alone with protons, and 9 RT alone with photons. Absolute lymphocyte counts and naïve CD4+ T cells declined in all groups, while NK cells increased and memory T-cell populations remained largely unaffected, with no additional effect of concurrent cisplatin. Lymphocyte suppression persisted for up to 6 months in the CRT proton group, 3 months in the RT proton group, and 12 months in the RT photon group. Greater low-dose body irradiation (2Gy) was correlated to lower lymphocyte counts at 5 weeks and 6 months after treatment and was more common in photon-treated patients.</p><p><strong>Conclusions: </strong>Both proton and photon radiation markedly suppress circulating lymphocytes, particularly naïve CD4+ T cells, for at least three months after treatment in locally advanced HNSCC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}