Cancer research communications最新文献

{"title":"Novel Pretreatment Autoantibodies Correlate with Enfortumab Vedotin-Related Dermatologic Events in Patients with Advanced Urothelial Cancer.","authors":"Evangelia Vlachou, Burles A Johnson, David J McConkey, Noah M Hahn, Yuezhou Jing, Stephanie Russell, Daniel Stairiker, Antony Rosen, Livia A Casciola-Rosen, Jean Hoffman-Censits","doi":"10.1158/2767-9764.CRC-25-0039","DOIUrl":"10.1158/2767-9764.CRC-25-0039","url":null,"abstract":"<p><p>Enfortumab vedotin (EV) plus pembrolizumab (P) is the first-line treatment for patients with advanced urothelial cancer (aUC). No biomarker for EV toxicity or response has been prospectively validated. EV-related dermatologic events (EVDE) are common and correlate with improved outcomes in retrospective studies. Immune checkpoint inhibitor-related toxicity also correlates with improved outcomes, and the presence of autoantibodies correlates with improved responses. We hypothesized that EV unmasks preexisting subclinical autoimmune responses leading to EVDEs in the setting of EV or EV/P. Our goal was to determine whether novel autoantibodies, if detected, correlate with EVDEs. We screened for novel autoantibodies using an immunoprecipitation-based approach in a pilot retrospective cohort (A) and a prospective longitudinal cohort (B) of patients with aUC who were treated with EV or EV/P and experienced EVDEs. Incidence of EVDEs, radiographic response, and progression-free and overall survival were compared between patients with and without autoantibodies. Two of six cohort A patients had pretreatment autoantibodies [Rho-associated coiled-coil containing protein kinase 2 (one patient) and target of Myb1-like 1 membrane trafficking protein (one patient)]. Pretreatment autoantibodies were also identified in 6/23 cohort B patients [mitochondrial complex 3 - M2 antigen (four patients), NMD3 ribosome export adapter (two patients), and carnitine palmitoyltransferase (one patient)]. All six (100%) cohort B antibody-positive patients developed EVDEs during treatment. To our knowledge, this is the first study correlating EVDEs with novel pretreatment autoantibodies in patients with mUC. Further studies are needed to confirm that they are biomarkers of EV-related skin toxicity and/or response.</p><p><strong>Significance: </strong>EV is approved alone and with pembrolizumab (EV/P) for aUC. EV-related dermatologic events (EVDEs) have been correlated with improved outcomes. We identified novel pre- and on-treatment autoantibodies in sera of patients with mUC treated with EV or EV/P which correlated with EVDEs.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1674-1680"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Validity of FoundationOne Liquid CDx for Detection of BRAFV600E in Colorectal Cancer.","authors":"Rona Yaeger, Jean-François Martini, Lincoln Pasquina, Brian Tunquist, Xiaosong Zhang, Fatima Kaiser, Norberto Pantoja Galicia, Shibing Deng, Siliang Gong, Cui Guo, Jimmy Kiely, Ta-Chou Vincent Ng, Graham Ferrier, Josep Tabernero, Scott Kopetz","doi":"10.1158/2767-9764.CRC-25-0002","DOIUrl":"10.1158/2767-9764.CRC-25-0002","url":null,"abstract":"<p><strong>Purpose: </strong>The BRAF inhibitor encorafenib (Enco) plus the anti-EGFR antibody cetuximab (Cetux) improved overall survival, objective response rate, and progression-free survival in previously treated BRAFV600E-mutant metastatic colorectal cancer in BEACON, a phase III randomized trial, leading to regulatory approval for this indication. To support rapid, plasma-based testing for BRAFV600E identification, clinical validity of a ctDNA-based assay, FoundationOneLiquid CDx (F1LCDx), was assessed against the reference tumor-based clinical trial assay (CTA) in liquid biopsy-evaluable samples from BEACON and commercially obtained tissue-matched plasma samples.</p><p><strong>Patients and methods: </strong>Pretreatment tissue samples were collected in BEACON to confirm BRAF mutational status using the central single gene PCR assay. Concordance between the CTA and liquid biopsy tests was assessed, and clinical validity of liquid biopsy testing was examined using clinical outcomes from BEACON.</p><p><strong>Results: </strong>Of the 523 evaluable patients, 433 with matched tissue and plasma samples had CTA and F1LCDx results available (BEACON, n = 328; commercial, n = 105). A strong concordance in detecting BRAFV600E was found between F1LCDx and CTA, with a positive percent agreement of 87.2% and negative percent agreement of 97.1%. Among 42 F1LCDx-/CTA+ samples, 41 (97.6%) had ctDNA tumor fraction <1%. Among samples with ctDNA tumor fraction >1%, the positive percent agreement was 99.4% and negative percent agreement was 86.7%. Clinical outcomes with Enco plus Cetux were similar between those identified as F1LCDx+/CTA+ and CTA+ overall.</p><p><strong>Conclusions: </strong>This study supports using liquid biopsies as a clinically valid assay for identifying BRAFV600E alterations in patients with metastatic colorectal cancer, particularly when ctDNA tumor fraction was >1%.</p><p><strong>Significance: </strong>In the phase III BEACON trial, which established Enco plus Cetux as a standard of care for previously treated BRAFV600E-mutant metastatic colorectal cancer, mutational status was confirmed through testing of tumor tissue. To support rapid, less invasive testing for BRAFV600E in plasma, this retrospective study assessed a ctDNA-based assay and found strong concordance between the liquid biopsy test and the tumor-based assay in detecting BRAFV600E.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1566-1573"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seclidemstat (SP-2577) Induces Transcriptomic Reprogramming and Cytotoxicity in Multiple Fusion-Positive Sarcomas.","authors":"Galen C Rask, Cenny Taslim, Ariunaa Bayanjargal, Rachel D Dreher, Matthew V Cannon, Julia Selich-Anderson, Jesse C Crow, Aundrietta Duncan, Emily R Theisen","doi":"10.1158/2767-9764.CRC-24-0296","DOIUrl":"10.1158/2767-9764.CRC-24-0296","url":null,"abstract":"<p><p>Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. The encoded fusion oncoproteins typically include a DNA-binding domain and function as oncogenic transcription factors. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. Oncogenic fusion transcription factors are challenging to target directly, and new therapies are needed. Treatment with the small molecule SP-2509 results in reversal of the transcriptional activity of the FET fusion that causes Ewing sarcoma, EWSR1::FLI1. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649), but its pharmacologic activity in FET fusion-positive sarcomas has not been demonstrated. We found potent seclidemstat cytotoxicity against both FET-rearranged and other fusion-positive sarcoma cell lines in vitro, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, myxoid liposarcoma, and fusion-positive rhabdomyosarcoma. We also define transcriptomic effects of seclidemstat with bulk RNA sequencing. Seclidemstat recapitulated much of SP-2509 transcriptional activity in Ewing sarcoma. Widespread transcriptional changes were seen in all tested cell lines after seclidemstat treatment, regardless of the fusion protein expressed. This included reversal of FET fusion transcriptional signatures for EWSR1::WT1, EWSR1::ATF1, and EWSR1::ERG. Though novel inhibitors are unlikely to display single-agent efficacy in the clinic, these data suggest that seclidemstat remains a promising new treatment strategy for patients with FET-rearranged and other fusion-positive sarcomas.</p><p><strong>Significance: </strong>In this study, we show seclidemstat has in vitro activity in multiple rare and aggressive sarcomas caused by FET fusion proteins. With 13 RNA sequencing experiments, including multiple FET-rearranged sarcoma cell lines, this dataset is a rich resource for those studying FET-rearranged sarcomas.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1584-1598"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Sorting Nexin 10 Accelerates KRAS-Induced Pancreatic Tumorigenesis.","authors":"Kohinoor Khan, Mohammad Shameem, Ashley N Sigafoos, Linda Kiey, Catherine E Hagen, Gopal Ramakrishnan, Leslie Morse, Martin E Fernandez-Zapico, Ricardo A Battaglino","doi":"10.1158/2767-9764.CRC-25-0168","DOIUrl":"10.1158/2767-9764.CRC-25-0168","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive forms of pancreatic cancer, is associated with poor survival outcomes and currently ranks as the third leading cause of cancer-related death in the United States. Despite its clinical significance, the mechanisms of PDAC development and progression remain, in part, poorly understood. In this study, we provide evidence of a novel role of sorting nexin 10 (SNX10), a member of the sorting nexin family, in the regulation of KRAS-induced pancreatic carcinogenesis. We demonstrate that SNX10 is downregulated in PDAC, especially in advanced cases. Furthermore, mutational analysis revealed SNX10 genetic alterations in PDAC cases. Functional studies demonstrated that SNX10 overexpression in human PDAC cells inhibited cell proliferation and colony formation. Moreover, SNX10 overexpression induced G1-phase cell-cycle arrest and decreased KRAS signaling activity. Using a novel Snx10 knockout mouse crossed with a Kras-driven PDAC model, we observed reduced survival, increased tumor cell proliferation, enhanced aggression, and heightened inflammation. Collectively, these findings highlight SNX10 as a tumor suppressor candidate in PDAC and underscore its promise as a foundation for new therapeutic approaches.</p><p><strong>Significance: </strong>SNX10 plays a crucial role in reducing pancreatic tumorigenesis. This discovery offers valuable insights into PDAC's biology and the development of new effective treatments.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1541-1551"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144857143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors.","authors":"Funda Meric-Bernstam, Martin Gutierrez, Enrique Sanz-Garcia, Diego Villa, Jun Zhang, Jennifer Friedmann, Fengting Yan, Mark A Socinski, John Sarantopoulos, Luis E Raez, Quincy S Chu, Maxime Chénard-Poirier, Manash S Chatterjee, Hong Ren, Qi Liu, Douglas A Levine, Komal L Jhaveri","doi":"10.1158/2767-9764.CRC-25-0019","DOIUrl":"10.1158/2767-9764.CRC-25-0019","url":null,"abstract":"<p><strong>Purpose: </strong>Zilovertamab vedotin, an antibody-drug conjugate targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), had manageable safety and promising antitumor activity in participants with relapsed or refractory non-Hodgkin lymphomas. We evaluated zilovertamab vedotin in participants with previously treated metastatic solid tumors.</p><p><strong>Patients and methods: </strong>This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor-positive breast cancer, nonsquamous non-small-cell lung cancer, platinum-resistant ovarian cancer, or pancreatic cancer. Participants received zilovertamab vedotin ≤2.5 mg/kg once every 3 weeks (Q1/3W) or <1.75 mg/kg twice every 3 weeks (Q2/3W). The primary endpoint was objective response rate per RECIST version 1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes.</p><p><strong>Results: </strong>A total of 102 participants were enrolled (Q1/3W, n = 70; Q2/3W, n = 32). The objective response rate was 1% [95% confidence interval (CI), 0%-8%] with Q1/3W dosing (one partial response, hormone receptor-positive/HER2-negative breast cancer cohort) and 0% with Q2/3W dosing. The median progression-free survival (95% CI) was 2.3 (2.0-4.1) and 1.9 (1.7-2.1) months, respectively; the median overall survival (95% CI) was 8.3 (5.2-10.3) and 5.5 (4.4-11.0) months, respectively. Across dosing regimens, treatment-related adverse events were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related adverse events led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 IHC was available on 17 participants, with only 3 (all nonresponders) showing ROR1 expression.</p><p><strong>Conclusions: </strong>Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously treated metastatic solid tumors.</p><p><strong>Significance: </strong>Zilovertamab vedotin had minimal antitumor activity and manageable safety in participants with previously treated metastatic solid tumors of various histologic subtypes. The results suggest that further development of zilovertamab vedotin in these solid tumors is not warranted.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1664-1673"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Antiangiogenic Therapy Is Associated with AIMP Protein Family Expression in Glioblastoma and Lower-Grade Gliomas.","authors":"Humaira Noor, Yuanning Zheng, Haruka Itakura, Olivier Gevaert","doi":"10.1158/2767-9764.CRC-25-0170","DOIUrl":"10.1158/2767-9764.CRC-25-0170","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly vascularized, heterogeneous tumor, yet antiangiogenic therapies have yielded limited survival benefits. The lack of validated predictive biomarkers for treatment response stratification remains a major challenge. Aminoacyl tRNA synthetase complex-interacting multicomplex proteins (AIMP) 1/2/3 have been implicated in central nervous system diseases, but their roles in gliomas remain unexplored. We investigated their association with angiogenesis and their significance as predictive biomarkers for antiangiogenic treatment response. In this multi-cohort retrospective study, we analyzed glioma samples from The Cancer Genome Atlas, Chinese Glioma Genome Atlas, REMBRANDT, Gravendeel, BELOB, and REGOMA trials, and four single-cell transcriptomic datasets. Multiomic analyses incorporated transcriptomic, epigenetic, and proteomic data. Kaplan-Meier and Cox proportional hazards models were used to assess the potential prognostic value of AIMPs in heterogeneous and homogeneous treatment groups. Using single-cell transcriptomics, we explored spatial and cell type-specific AIMP2 expression in GBM. AIMP1/2/3 expressions correlated significantly with angiogenesis across The Cancer Genome Atlas cancers. In gliomas, AIMPs were upregulated in tumor versus normal tissues, higher- versus lower-grade gliomas, and recurrent versus primary tumors (P < 0.05). Upon retrospective analysis of two clinical trials assessing different antiangiogenic drugs, we found that high-AIMP2 subgroups had improved response to therapies in GBM [REGOMA: HR, 4.75 (1.96-11.5), P < 0.001; BELOB: HR, 2.3 (1.17-4.49), P = 0.015]. AIMP2-cg04317940methylation emerged as a clinically applicable stratification marker. Single-cell analysis revealed homogeneous AIMP2 expression in tumor tissues, particularly in astrocyte-like cells, suggesting a mechanistic link to tumor angiogenesis. These findings provide novel insights into the role of AIMPs in angiogenesis, offering improved patient stratification and therapeutic outcomes in recurrent GBM.</p><p><strong>Significance: </strong>This study identifies AIMP2 as a novel biomarker predictive of antiangiogenic treatment response in recurrent GBM. Through multiomic and single-cell analyses, AIMP2 is shown to be upregulated in aggressive gliomas and linked to angiogenesis. Its expression and methylation status offer a clinically applicable stratification tool, enabling more personalized therapeutic approaches and improved outcomes in patients receiving antiangiogenic therapies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1651-1663"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12438089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase IB Study of Binimetinib and Palbociclib in Molecularly Selected Advanced Triple-Negative Breast Cancer.","authors":"Luis Manso, Rodrigo Sánchez-Bayona, Juan Antonio Guerra, Alfonso Cortés-Salgado, Juan Miguel Cejalvo, José A García-Saenz, Serafín Morales, Lucía González-Cortijo, Silvana Mourón, María J Bueno, Leonardo D Garma, Miguel Quintela-Fandino","doi":"10.1158/2767-9764.CRC-25-0428","DOIUrl":"10.1158/2767-9764.CRC-25-0428","url":null,"abstract":"<p><strong>Purpose: </strong>Advanced, pretreated triple-negative breast cancer (TNBC) has a dismal prognosis and lacks effective options beyond standard cytotoxics. We previously showed, via phosphoproteomic screening, that cyclin-dependent kinase 6 (CDK6) and ERK hyperactivation are linked to adverse outcomes and represent actionable targets. This prompted us to evaluate palbociclib and binimetinib in advanced TNBC after one or two prior therapies.</p><p><strong>Patients and methods: </strong>Patients with increased ERK and/or CDK6 activity were eligible. Treatment consisted in daily binimetinib (45 mg twice a day) plus palbociclib (100 mg daily, days 1-21) in 28-day cycles. Palbociclib escalation to 125 mg was allowed in cycle 2. The primary objective was to demonstrate a 2.5 month-long progression-free survival (PFS), a 50% increase over the reference PFS for cytotoxics (1.7 months). Whole-exome sequencing was performed in tumor samples of the efficacy population.</p><p><strong>Results: </strong>Fifty-one patients were screened, of whom 50 were biomarker-positive. Twenty-four initiated treatment between June 2021 and July 2022. Toxicity was frequent, consisting mainly in fatigue, diarrhea, neutropenia, and ocular effects, requiring frequent dose interruptions or reductions. The primary objective was not met (median PFS 50 days). However, a bimodal PFS pattern emerged, with 13% of the patients achieving disease control lasting 4 to 13 months. Whole-exome sequencing revealed a distinct mutational landscape among long-term responders compared with early progressors.</p><p><strong>Conclusions: </strong>In this biomarker-enriched TNBC population, the combination of palbociclib and binimetinib showed limited activity and notable toxicity. Whereas CDK6 and ERK hyperactivation confirmed their prognostic role, they did not predict treatment benefit. Exploratory genomic findings suggest the existence of a biologically distinct subset of patients with prolonged benefit, encouraging further investigation.</p><p><strong>Significance: </strong>Previous studies showed that patients with early TNBC with increased CDK4/6 and ERK activity are at high risk of relapse. Preclinical data also suggest the benefit of combined inhibition of CDK4/6 and MEK, and novel therapies are needed for TNBC in the advanced disease setting. Despite the rationale and a biomarker-driven design, this combination was toxic and showed limited efficacy. This combination should not be further developed in this disease.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1728-1737"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GALNT7 Stratifies dMMR/MSI Colorectal Cancer into Distinct Molecular Subsets Associated with Prognosis and PD-L1 Expression.","authors":"Hiroya Suzuki, Hirokazu Okayama, Shotaro Nakajima, Katsuharu Saito, Ryo Kanoda, Yuya Maruyama, Akira Matsuishi, Takuro Matsumoto, Misato Ito, Shun Chida, Wataru Sakamoto, Motonobu Saito, Zenichiro Saze, Tomoyuki Momma, Kosaku Mimura, Koji Kono","doi":"10.1158/2767-9764.CRC-25-0270","DOIUrl":"10.1158/2767-9764.CRC-25-0270","url":null,"abstract":"<p><p>Colorectal cancer with deficient mismatch repair (dMMR)/microsatellite instability (MSI) constitutes a distinct clinicopathologic and immunologic subtype, characterized by high sensitivity to immune checkpoint inhibitors. However, prognosis and therapeutic response vary considerably among dMMR/MSI colorectal cancers, underscoring the need for molecular markers to refine patient stratification. In this study, we systematically investigated cancer cell-intrinsic expression profiles of 188 glycosyltransferase genes by integrating single-cell, bulk, and cell line RNA sequencing datasets. This approach identified five glycosyltransferases, including GALNT7, expression of which differed consistently according to MSI status. The clinical and prognostic relevance of these glycosyltransferases was further analyzed across large-scale transcriptomic, proteomic, and IHC cohorts, comprising 662 dMMR/MSI and 3,483 proficient mismatch-repair (pMMR)/microsatellite-stable (MSS) colorectal cancers. A five-gene glycosyltransferase signature effectively distinguished MSI from MSS colorectal cancers across 18 datasets. Among the five genes, GALNT7 expression was robustly associated with favorable prognosis in four independent transcriptomic and IHC cohorts of dMMR/MSI colorectal cancers while showing little or no prognostic impact in pMMR/MSS colorectal cancers. Notably, GALNT7 expression was inversely correlated with PD-L1 expression at both the mRNA and protein levels in multiple datasets exclusively within dMMR/MSI colorectal cancers, but not in pMMR/MSS CRCs. Functional assays and lectin microarray analysis using MSI colorectal cancer cell lines revealed that GALNT7 knockdown enhanced IFNγ-induced PD-L1 expression without altering cell-surface glycosylation. In conclusion, GALNT7 expression stratified dMMR/MSI colorectal cancers into distinct subsets with differential tumor cell PD-L1 expression and diverse survival outcomes, highlighting its potential as a prognostic biomarker to guide treatment strategies.</p><p><strong>Significance: </strong>We identified glycosyltransferases with altered expression depending on MMR/MSI status. Our findings indicate the existence of two molecularly defined subtypes within dMMR/MSI colorectal cancers based on GALNT7 expression, characterized by differential tumor cell PD-L1 levels and distinct survival outcomes.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1530-1540"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Impact of Immune-Related Adverse Events on Combination Immune Checkpoint/Tyrosine Kinase Inhibition for Metastatic Renal Cancer.","authors":"Bunpei Isoda, Masanobu Shiga, Shuya Kandori, Shota Takahashi, Akifumi Omiya, Tomoki Ishida, Kotoe Matsuda, Hiromichi Sakurai, Bryan J Mathis, Ken Tanaka, Manabu Komine, Masahiro Iinuma, Akira Joraku, Hiromitsu Negoro, Masakazu Tsutsumi, Takamitsu Inoue, Jun Miyazaki, Hiroyuki Nishiyama","doi":"10.1158/2767-9764.CRC-25-0337","DOIUrl":"10.1158/2767-9764.CRC-25-0337","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI) combinations and tyrosine kinase inhibitor (TKI) use are standard for metastatic renal cell carcinoma (mRCC), leading to improved outcomes. However, due to a lack of predictive biomarkers, the presence or absence of immune-related adverse events (irAE) is currently used as a predictive factor in clinical practice. To elucidate the impact of irAEs on efficacy, a cohort of patients with mRCC who received ICI-based combination therapy as initial treatment was analyzed. Patients were divided into two groups: those who received dual-ICI therapy (ICI-ICI, N = 55) or ICI and TKI therapy (ICI-TKI, N = 55). Subsequent to this initial categorization, each group was further subdivided based on the presence or absence of irAEs. In the ICI-ICI group, patients with irAEs exhibited significantly prolonged overall survival (OS) and progression-free survival [PFS; OS (median): not reached vs. 17.9 months, P = 0.03/PFS (median): 51.4 vs. 5.8 months, P < 0.01]. Conversely, no such correlation was observed between irAEs and OS/PFS in the ICI-TKI group. [OS (median): 26.3 months vs. not reached, P = 0.73/PFS (median): 16.8 months vs. 11.9 months, P = 0.38] Furthermore, treatment discontinuation due to AEs accounted for 65% (N = 32) in the ICI-ICI group and 57% (N = 24) in the ICI-TKI group, with a slightly higher tendency observed in the ICI-ICI group. These findings suggest that the prognostic impact of irAEs may differ depending on the treatment combination, and further basic research is needed to elucidate the underlying mechanisms.</p><p><strong>Significance: </strong>In patients with mRCC who received ICI-ICI, the occurrence of irAEs was associated with improved survival outcomes, whereas no such association was observed in patients who received ICI-TKI. This suggests that irAEs may reflect the favorable immune response specific to ICI-ICI therapy, whereas differences in the tumor microenvironment, particularly involving neutrophils, in ICI-TKI patients may influence treatment response.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1681-1689"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPSai: A Clinically Validated AI Tool for Tissue of Origin Prediction during Routine Tumor Profiling.","authors":"Hassan Ghani, Anthony Helmstetter, Jennifer R Ribeiro, Todd Maney, Stephanie Rock, Rebecca A Feldman, Jeff Swensen, Farah Abdulla, David B Spetzler, Elena Florento, Ari M Vanderwalde, Patricia Pittman, Milan Radovich, Jaclyn Hechtman, Casey Bales, George W Sledge, Myra M George, David Bryant, Jim P Abraham, Matthew J Oberley","doi":"10.1158/2767-9764.CRC-25-0171","DOIUrl":"10.1158/2767-9764.CRC-25-0171","url":null,"abstract":"<p><p>A subset of cancers present with unclear or potentially incorrect primary histopathologic diagnoses, including cancers of unknown primary (CUP). We aimed to develop and validate an artificial intelligence (AI) tool, Genomic Probability Score AI (GPSai™), which predicts tumor tissue of origin in CUP and flags potential misdiagnoses for additional workup during routine molecular testing. The GPSai model was trained on whole exome and whole transcriptome data from 201,612 cases submitted for tumor profiling at Caris Life Sciences. Retrospective (N = 21,549) and prospective (N = 76,271) validations were performed. The clinical impact was evaluated over 8 months of live testing and through physician surveys. GPSai demonstrated 95.0% accuracy in non-CUP cases and reported on tumor tissue of origin in 84.0% of CUP and 96.3% of non-CUP cases. During the initial 8 months of implementation, GPSai changed the diagnosis on 704 patients (0.88% of all profiled cases), which were supported by orthogonal evidence including imaging, IHC, mutational signatures, hallmark fusions, or viral reads. Diagnosis changes prompted changes in targeted therapy eligibility based on level 1 clinical evidence in 86.1% of cases (n = 606/704). A majority (89.7%; n = 87/97) of physician responses indicated acceptance of the GPSai results, and 53.6% (n = 52/97) of responses stated that the results prompted a change in treatment plan. GPSai accurately identifies tumor tissue of origin and has the potential for clinical impact in a small but meaningful subset of patients with CUP or pathologically ambiguous tumors. Our results support the integration of this AI tool into routine molecular testing to improve diagnostic accuracy and guide subsequent therapeutic decisions.</p><p><strong>Significance: </strong>Our findings show that GPSai, a deep learning-based tool, can support the identification of primary tumor sites with high accuracy in conjunction with orthogonal evidence. Its integration into routine tumor profiling furthermore allows simultaneous biomarker identification. Analysis of real-world implementation of GPSai shows that it enhances diagnostic accuracy, including resolution of CUP cases, and prompts clinically relevant therapeutic recommendation changes without requiring additional specimen.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1477-1489"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}