Clinical Cancer Research最新文献

{"title":"Immune and Growth Factor Signaling Pathways Are Associated with Pathologic Complete Response to an Anti-Type I Insulin-like Growth Factor Receptor Regimen in Patients with Breast Cancer.","authors":"Emmanuel F Petricoin,Denise M Wolf,Christina Yau,Julia D Wulfkuhle,Laura Van't Veer,Rosa I Gallagher,Laura J Esserman,Gillian L Hirst,Lamorna Brown-Swigart,Douglas Yee, ","doi":"10.1158/1078-0432.ccr-25-0553","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0553","url":null,"abstract":"PURPOSEPretreatment specimens from patients treated on the I-SPY2 neoadjuvant breast cancer trial were studied to identify prespecified biomarkers associated with response to the regimen of paclitaxel, the anti-type I insulin-like growth factor receptor (IGF-1R) antibody ganitumab, and metformin (PGM) followed by doxorubicin and cyclophosphamide (AC) compared with control therapy (paclitaxel followed by AC). The primary endpoint of this trial is pathologic complete response (pCR).EXPERIMENTAL DESIGNOne hundred six patients treated with PGM and 119 contemporary controls were evaluated using laser capture microdissection and reverse-phase protein array to evaluate 32 prespecified potential predictive biomarkers in the IGF-1R pathway and 109 additional exploratory endpoints.RESULTSTotal levels of IGF-1R were poorly correlated with phosphorylated IGF-1R/insulin receptor (IR). Higher levels of phosphorylated IGF-1R/IR were associated with an increased likelihood of obtaining pCR, especially in the hormone receptor (HR)-positive subgroup. Markers of immune response also showed an association with pCR but differed between HR+ and HR- subgroups. In HR- tumors, phospho-STAT1 Y701 and low levels of phospho-p27 associated with pCR. These relationships were not observed in patients treated with control chemotherapy.CONCLUSIONSActivation status of IGF-1R/IR associated with increased pCR to PGM in HR+ breast cancers. Immune activation markers were also associated with response in HR+ and HR- subgroups. Thus, IGF-1R may directly regulate tumor biology and associate with immune response to therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"41 1","pages":"OF1-OF11"},"PeriodicalIF":11.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognosis and biological characteristics of ER-low metastatic breast cancer: results from a multicenter cohort and the TONIC trial.","authors":"Federica Miglietta,Manon De Graaf,Claudio Vernieri,Federico Piacentini,Matilde Cacciatore,Andrea Botticelli,Andrea Vingiani,Giuseppe Fotia,Lorenzo Nicolè,Gaia Griguolo,Tommaso Giarratano,Davide Massa,Valerio Pellegrini,Francesca Schiavi,Francesca Porra,Matteo Fassan,Giancarlo Pruneri,Angelo Paolo Dei Tos,Valentina Guarneri,Marleen Kok,Maria Vittoria Dieci","doi":"10.1158/1078-0432.ccr-25-1796","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1796","url":null,"abstract":"PURPOSETo assess prognosis of ER-low expression and its dynamics in HER2- metastatic breast cancer (BC) and to compare sensitivity to nivolumab between ER-low and triple-negative (TN) BC.EXPERIMENTAL DESIGNTwo cohorts were analyzed: a multicenter cohort of 982 patients with HER2- metastatic BC, and one prospective cohort of 110 patients with ER<10%/HER2- metastatic BC enrolled in the TONIC trial (testing nivolumab). Endpoints were: overall survival (OS) and post-relapse survival (PRS) in the retrospective cohort; progression-free survival (PFS), OS, and clinical benefit rate (CBR) in the TONIC trial.RESULTSER-low BC were 7.3% of retrospective cases, 15/110 of the TONIC. In the retrospective cohort, patients with ER-low BC had significantly poorer OS (p<0.001) and numerically shorter PRS (p=0.230) compared to ER+/HER2- BC, and numerically longer OS (p=0.098) and significantly longer PRS (p=0.017) compared to TNBC. In the TONIC, patients with ER-low BC, compared to TN, showed similar response to nivolumab (CBR: 20.0% vs 22.1%, p=1), PFS (median 1.7 vs 2.0 months, p=0.5) and OS (median 5.3 vs 8.6 months, p=0.3). Among patients with primary ER+/HER2- BC (n=565), the conversion towards ER-low or TNBC at metastasis conferred independent negative prognostic impact both for OS (p=0.002 and 0.001, respectively) and PRS (p=0.018 and p=0.001, respectively).DISCUSSIONWe provided evidence of the prognostic role of ER-low expression and its dynamics in patients with HER2- metastatic BC. We offered insights into sensitivity to antiPD1 in metastatic BC, showing that patients with ER-low BC have comparable likelihood of responding to nivolumab as those with TNBC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"19 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARC028 Samples Reveal an Interplay between TGF-β, IFN Signaling, and Low HLA Class I Expression as Contributors to Ewing Sarcoma Checkpoint Blockade Resistance.","authors":"Jessica D Daley, Elina Mukherjee, David Ferraro, Shanthi Bhaskar, Anthony Green, Ernest M Meyer, Hussain Tawbi, Melissa Burgess, Tullia C Bruno, Anthony R Cillo, Kelly M Bailey","doi":"10.1158/1078-0432.CCR-24-3882","DOIUrl":"10.1158/1078-0432.CCR-24-3882","url":null,"abstract":"<p><strong>Purpose: </strong>Ewing sarcoma, in contrast to some adult sarcoma subtypes, generally does not respond to single-agent immunotherapy targeting PD1. The features of Ewing sarcoma that preclude the effectiveness of immunotherapy remain largely unknown. To address this question, we utilized biopsies from patients with Ewing sarcoma obtained before and after pembrolizumab (anti-PD1) therapy from the phase II clinical trial SARC028 to interrogate the Ewing tumor microenvironment and features associated with resistance to checkpoint inhibition.</p><p><strong>Experimental design: </strong>We utilized multiplexed immunofluorescence, spatial proteomics, and spatial transcriptomics to analyze paired pretreatment and 8-week posttreatment biopsy specimens from patients with Ewing sarcoma enrolled in SARC028.</p><p><strong>Results: </strong>Pembrolizumab therapy did not alter the quantity of immune cell infiltration in Ewing tumor biopsies. Analysis of tumor-associated protein markers revealed increased immunoregulatory markers after pembrolizumab. Spatial transcriptomics identified 10 cellular neighborhoods (CN) across patients consisting of specific cell subsets. CN10 was consistently observed across patients with a poor response. This CN was enriched for a tumor subpopulation with a high TGF-β response, low IFN response, and low HLA class I expression. IFN response, HLA class I expression, and overall immune infiltration were correlated.</p><p><strong>Conclusions: </strong>Analyses of paired Ewing sarcoma tumor samples from SARC028 reveal an immunosuppressive triad, the disruption of which should be pursued to improve antitumor immunity. This work highlights the unique insight that can be gained from the analysis of paired patient Ewing sarcoma tumor biopsy samples from clinical trials.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"3805-3816"},"PeriodicalIF":10.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I Dose Escalation Trial Combining Olaparib and Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer","authors":"Andreas Rimner, Benjamin H. Lok, Daphna Y. Gelblum, Rupesh R. Kotecha, Jacob Y. Shin, Quincey LaPlant, Annemarie F. Shepherd, Narek Shaverdian, Charles B. Simone, Vanessa J. Ng, Alexandru Ionescu, Helena A. Yu, Robert Daly, Michael D. Offin, Ellen D. Yorke, Michelle S. Ginsberg, Zhigang Zhang, Abraham J. Wu, Charles M. Rudin","doi":"10.1158/1078-0432.ccr-24-4342","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4342","url":null,"abstract":"Purpose: Patients with extensive-stage small cell lung cancer (ES-SCLC) are commonly treated with induction systemic therapy and consolidative thoracic radiation therapy (TRT). PARP inhibitors have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open label phase I study of concurrent olaparib with TRT. Patients and Methods: Patients without progression after induction platinum/etoposide +/- atezolizumab were treated with oral olaparib for 3 weeks and concurrent low-dose TRT (30 Gy/10 fractions) in weeks 2 and 3. Olaparib dose started at 50mg twice daily and escalated in 50mg/dose increments in cohorts of 3 patients each. Primary objectives were the safety and maximum tolerated dose (MTD) of olaparib + TRT. Secondary objectives included in-field local recurrence rate, progression-free survival (PFS), and overall survival (OS). Results: Between 10/2018 and 03/2022, 24 patients with a median age of 68 years were treated (median follow-up: 11.4 months) with platinum/etoposide and 30 Gy/10 fractions TRT; 10 patients also received atezolizumab. The MTD of olaparib with TRT was 200mg twice daily. There were 3 grade 3 (G3) dose-limiting adverse events (AEs), including pneumonitis/pneumonia, esophagitis, and abdominal pain. The most common G2-3 treatment-related AEs were esophagitis (n=12) and pneumonitis/pneumonia (n=2). There were no G4 or 5 AEs. The 12-month cumulative incidence of local recurrence was 27%, median PFS and OS were 3.6 months and 17.7 months, respectively. Conclusions: This study defined a MTD and recommended phase II dose of 200mg twice daily olaparib with concurrent low-dose TRT, and the combination appeared safe without unexpected toxicities.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"112 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A First-in-Human Study of ATM Inhibitor Lartesertib as Monotherapy in Patients with Advanced Solid Tumors","authors":"Lillian L. Siu, Timothy A. Yap, Sofia Genta, Gregory Pennock, Christine Hicking, Deepthi S. Vagge, Jatinder Kaur. Mukker, Giuseppe Locatelli, Anthony W. Tolcher","doi":"10.1158/1078-0432.ccr-25-1648","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1648","url":null,"abstract":"Purpose: This first-in-human Phase 1, open-label study (NCT04882917) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of the highly potent and selective oral ataxia‑telangiectasia mutated (ATM) kinase inhibitor lartesertib. Patients and methods: Patients with advanced solid tumors received oral doses of lartesertib for a dose range of 100–400 mg once daily (QD). Dose-escalation was based on PK, PD, and safety data guided by a Bayesian 2-parameter logistic regression model. Molecular responses (MRs) were assessed in circulating tumor DNA samples. Results: Twenty-two patients received lartesertib at doses of 100 mg (n = 2), 200 mg (n = 7), 300 mg (n = 9) and 400 mg (n = 4) QD. Maculopapular rash was the most common dose-limiting toxicity (4 events in 4 patients). The MTD was 300 mg QD. Most common Grade ≥3 treatment-emergent adverse event was anemia (4 patients). Five patients experienced ≥1 treatment‑related adverse event of Grade ≥3 (including one Grade 4 event of hypersensitivity). Exposure increased in a dose-related manner, with median time to maximum plasma concentration ranging from 1–2 hours and mean elimination half‑life from 5–7 hours across the dose range. PD analysis showed a trend of reduction of γ-H2AX levels, with highest target inhibition of 80%–100%. Best overall response was stable disease in 2 patients. MRs were observed in four patients of 21 evaluable patients. Conclusions: Lartesertib achieved target exposure and engagement without significant hematological toxicity. Further clinical evaluation of lartesertib in combination therapy is ongoing.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA Approval Summary: Datopotamab deruxtecan-dlnk for treatment of patients with unresectable or metastatic, HR-positive, HER2-negative breast cancer","authors":"Melanie Royce, Mirat Shah, Lijun Zhang, Joyce Cheng, Mary Kate Bonner, Melissa Pegues, Claudia P. Miller, Lily Leu, Lauren S. L. Price, Junshan Qiu, Jingyu Yu, Tien M. Truong, Sarah E. Dorff, Yuching Yang, Nailing Zhang, Maria Gutierrez-Lugo, Tiffany K. Ricks, William F. Pierce, Zhongjun Luo, Dana Kappel, Kirsten B. Goldberg, Stacy S. Shord, Shenghui Tang, Vishal Bhatnagar, Richard Pazdur, Paul G. Kluetz, Laleh Amiri-Kordestani","doi":"10.1158/1078-0432.ccr-25-1388","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1388","url":null,"abstract":"On January 17, 2025, the FDA approved datopotamab deruxtecan-dlnk (DATROWAY, Dato-DXd), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for the treatment of adults with unresectable or metastatic, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Approval was based on results from TROPION-Breast01 (TB01), a multicenter, randomized, open-label trial comparing Dato-DXd to investigator’s choice of chemotherapy (ICC). The trial was designed with dual primary endpoints: progression-free survival (PFS) assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and overall survival (OS). TB01 demonstrated a 2-month improvement in median PFS for Dato-DXd compared to ICC (6.9 months vs. 4.9 months, respectively; stratified hazard ratio (HR) 0.63 (95% CI: 0.52, 0.76; p&amp;lt;0.0001). The OS endpoint was not met; at the final analysis (FA) of OS, the median OS was 18.6 months in the Dato-DXd arm and 18.3 months in the ICC arm (HR: 1.01, 95% CI: 0.83, 1.22). Although there was no OS improvement, Dato-DXd was also not associated with a clear trend toward potential detriment compared to ICC. The most commonly reported adverse reactions (≥20%) with Dato-DXd were stomatitis, nausea, fatigue, alopecia, constipation, dry eye, keratitis, and vomiting. Overall, the favorable benefit-risk profile for Dato-DXd supported its approval for the intended indication.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"58 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-line MET tyrosine kinase inhibitors versus immunotherapy ± chemotherapy for patients with MET exon 14 skipping mutant metastatic NSCLC","authors":"Federica Pecci, Hui Li, Alessandro Di Federico, Jia Wu, Hong Chen, Eleonora Gariazzo, Francesco Mantuano, Edoardo Garbo, Mihaela Aldea, Valentina Santo, Don Gibbons, Hai Tran, Francesco Paoloni, Guilherme Rossato de Almeida, Giulio Metro, Andrea De Giglio, Francesco Gelsomino, Xinan Wang, Marcello Tiseo, Julia Rotow, Andrea Ardizzoni, J. Jack Lee, Mark M. Awad, Alfredo Addeo, Lingzhi Hong, Marcelo V. Negrao, Pasi A. Janne, John V. Heymach, Jianjun Zhang, Biagio Ricciuti, Xiuning Le","doi":"10.1158/1078-0432.ccr-25-1735","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1735","url":null,"abstract":"Purpose: First-line treatment options for MET exon 14 skipping (METex14) mutant metastatic non-small cell lung cancer (NSCLC) vary due to differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI)±chemotherapy. Experimental Design: Clinicopathologic data were collected from patients with metastatic METex14 mutant NSCLC receiving first-line MET TKI or ICI±chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI±chemotherapy. Subgroup analyses by clinicopathological characteristics were performed. Results: Among 158 patients, 80 received MET TKI and 78 ICI±chemotherapy as first-line. Baseline clinicopathologic features were balanced except for higher proportion of patients with a history of smoking in the ICI±chemotherapy group (p=0.03). With a median follow-up of 37.9 months, no difference was observed in rwPFS (HR 0.85, p=0.4) or OS (HR 0.97, p=0.9) with first-line MET TKI versus ICI±chemotherapy. In subgroup analyses, first-line ICI±chemotherapy improved rwPFS in PD-L1≥80% (HR 0.50, p=0.03), while MET TKI improved rwPFS (HR 0.40, p=0.005) and OS (HR 0.49, p=0.03) in PD-L1&amp;lt;50%, as well as rwPFS (HR 0.39, p=0.02) and OS (HR 0.36, p=0.03) in brain metastases, and rwPFS in bone metastases (HR 0.55, p=0.01). No differences were observed in the incidence of high-grade toxicity (p=0.9) or rates of permanent discontinuation (p=0.2) between first-line MET TKI and ICI±chemotherapy. Conclusions: First-line MET TKI improved outcomes in PD-L1&amp;lt;50% and brain/bone metastases, while ICI±chemotherapy prolonged PFS only in PD-L1≥80%, emphasizing the need for personalized treatment selection.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"7 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRI-based mathematical modeling to predict the response of I-SPY 2 breast cancer patients to neoadjuvant therapy","authors":"Reshmi J. S. Patel, Chengyue Wu, Casey E. Stowers, Rania M. Mohamed, Jingfei Ma, Gaiane M. Rauch, Thomas E. Yankeelov","doi":"10.1158/1078-0432.ccr-25-0668","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0668","url":null,"abstract":"Purpose: We seek to establish the generalizability of our biology-based mathematical model in accurately predicting the response of locally advanced breast cancer (LABC) patients to neoadjuvant therapy (NAT). Patients and Methods: 91 patients (representing three subtypes of LABC) from 10 I-SPY 2 clinical trial sites received quantitative MRI before (V1), three weeks into (V2), and after completion of (V3) the first 12-week standard-of-care or experimental NAT course. We used these data to calibrate, on a patient-specific basis, our previously developed biology-based mathematical model describing the spatiotemporal change in the number of tumor cells. After calibrating the mathematical model to the V1 and V2 MRI data, the calibrated model predicted the patient-specific tumor status at V3 by explicitly accounting for tumor cell movement (constrained by the mechanical properties of the surrounding tissue), proliferation, and death due to treatment. Results: The concordance correlation coefficient between the observed and predicted tumor change from V1 to V3 was 0.94 for total cellularity and 0.91 for volume. A logistic regression model of predicted tumor volume metrics from V1 to V3 differentiated pCR from non-pCR patients with an area under the receiver operating characteristic curve of 0.78. Conclusions: Our tumor forecasting pipeline can accurately predict tumor status after an NAT course—on a patient-specific basis, without a training dataset—using “real-world” MRI data obtained from a multi-subtype, multi-site clinical trial.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel immunocompetent Eµ-SOX11CCND1 mouse model phenotypically and molecularly resembles human mantle cell lymphoma","authors":"Hedieh Jafari, Fiona Brown-Burke, Betsy Pray, Shelby Sloan, JoBeth Helmig-Mason, Ian Hout, Sydney Leon, Mackenzie Long, Wing Keung Chan, Walter Hanel, Kara Corps, Violetta V. Leshchenko, Donna Edwards, Ravi Prakash Shukla, Sidorela Reci, Kris Vaddi, Peggy Scherle, Paul Collier, Alessandro La Ferlita, Satishkumar Singh, Rosario Distefano, Rosa Lapalombella, Lalit Sehgal, Robert B. Faryabi, Cem Meydan, Christopher E. Mason, Robert A. Baiocchi, Samir Parekh, Lapo Alinari","doi":"10.1158/1078-0432.ccr-25-0534","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0534","url":null,"abstract":"Purpose: Mantle cell lymphoma (MCL) remains incurable despite therapeutic advances, highlighting the need for improved preclinical models. Existing transgenic MCL mouse models have significant limitations, restricting their translational value. Experimental Design: We generated an immunocompetent MCL model by overexpressing the key oncogenic drivers SOX11 and CCND1 under the Eµ enhancer in C57BL/6 mice, aiming to replicate human MCL’s biological and pathological features. Results: Eµ-SOX11CCND1 mice developed lymphoma marked by clonal B1a cell expansion in lymphatic and extranodal tissues. Morphologic, immunophenotypic, and transcriptional profiling revealed strong similarity to human MCL, with pathway analysis confirming significant molecular overlap. Importantly, lymphoma cells could be adoptively transferred into wild-type recipients, enabling therapeutic testing within an intact immune system. Conclusions: The Eµ-SOX11CCND1 mouse represents a robust and biologically relevant model that faithfully recapitulates human MCL. Its immunocompetent nature and adoptive transfer capability make it a valuable model for studying disease mechanisms and evaluating novel therapeutic approaches for MCL patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"66 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal approach predicts relapse upon cessation of immune checkpoint inhibitors in advanced melanoma","authors":"Ka-Won Noh, Yuri Tolkach, Doris Helbig, Vincenzo Mitchell Barroso, Yannick Foerster, Max Schlaak, Tilo Biedermann, Reinhard Buettner, Oana-Diana Persa","doi":"10.1158/1078-0432.ccr-25-0889","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0889","url":null,"abstract":"Purpose: Treatment with immune checkpoint inhibitors (ICI) in advanced melanoma can result in durable responses, yet an algorithm to decide which patients can safely discontinue ICI is still lacking. Experimental Design: We used a multimodal approach combining clinical data, AI-based analysis of H&amp;E-stained whole-slide images of melanoma before ICI start, and gene expression signatures to identify biomarkers for relapse after discontinuing ICI in the absence of treatment progression. Results: Univariable Cox regression analysis identified best overall response, mRNA expression of six genes, tumor cell density (TCD), and the lymphocyte to plasma cell ratio (LYM/PC) as factors predictive of relapse upon cessation of ICI. Multivariable Cox regression analysis showed that both TGFBR1 expression and the integral digital pathology parameter-based prognostic system were independently associated with relapse after ICI discontinuation. Training a Multivariate Adaptive Regression Spline (MARS) model achieved the highest overall predictive accuracy of 84.6% for relapse after ICI discontinuation. Conclusions: The identified prognostic markers are fully explainable and easily implementable in routine practice and facilitate risk stratification upon cessation of ICI therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"26 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899115","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}