Clinical Cancer Research最新文献

{"title":"GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.","authors":"Silvia Stacchiotti, Silvia Martini, Sandro Pasquali, Anna M Frezza, Alessia Beretta, Stefano Percio, Mara Lecchi, Monica Tortoreto, Marta Barisella, Paola Collini, Gian Paolo Dagrada, Alessandra Merlini, Paul H Huang, Andrew Jenks, Robin L Jones, William D Tap, Matilde Ingrosso, Carlo Morosi, Silvia Brich, Claudia Giani, Paolo Verderio, Paolo G Casali, Hugh Leonard, Alessandro Gronchi, Valentina Zuco, Nadia Zaffaroni","doi":"10.1158/1078-0432.CCR-23-3991","DOIUrl":"10.1158/1078-0432.CCR-23-3991","url":null,"abstract":"<p><strong>Purpose: </strong>Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness.</p><p><strong>Experimental design: </strong>A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.</p><p><strong>Results: </strong>ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.</p><p><strong>Conclusions: </strong>This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5122-5137"},"PeriodicalIF":12.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11565171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281266","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":"Long-Term Follow-up of Levonorgestrel Intrauterine Device for Atypical Hyperplasia and Early Endometrial Cancer Reveals Relapse Characterized by Immune Exhaustion.","authors":"Mikayla B Bowen, Brenda Melendez, Qian Zhang, Richard K Yang, Bryan M Fellman, Barrett C Lawson, Naomi N Adjei, Joseph Celestino, Khalida M Wani, Bhavana Singh, Diana L Urbauer, Alexander J Lazar, Karen H Lu, Jennifer A Wargo, Shannon N Westin, Melinda S Yates","doi":"10.1158/1078-0432.CCR-24-0362","DOIUrl":"10.1158/1078-0432.CCR-24-0362","url":null,"abstract":"<p><strong>Purpose: </strong>Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited.</p><p><strong>Materials and methods: </strong>Follow-up data from patients in our prospective phase II trial of levonorgestrel intrauterine device (LIUD) for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse.</p><p><strong>Results: </strong>Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at 6 months, premenopausal status, and Hispanic ethnicity (P < 0.05), but only 6-month response status remained a significant predictor in a multivariate model (P = 0.023). LIUD increased abundance of NK cells (ΔMCP-counter score = 46.13, FDR = 0.004) and cytotoxic lymphocytes (ΔMCP-counter score = 277.67, FDR = 0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC = 1.62, FDR = 0.025) and GZMA (log2FC = 2.47, FDR = 0.008). NK cells were reduced at relapse (ΔMCP-counter score = -55.96, FDR = 0.02). Immune-related pathways (IFNα response and TGFβ signaling) were enriched at relapse (FDR < 0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR < 0.05).</p><p><strong>Conclusions: </strong>Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for nonsurgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion. See related commentary by Johannet and Friedman, p. 5001.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5073-5082"},"PeriodicalIF":12.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449864","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":"Divergent clinical and immunologic outcomes based on STK11 co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade.","authors":"Samuel Rosner, Sydney Connor, Khaled Sanber, Marianna Zahurak, Tianbei Zhang, Isha Gurumurthy, Zhen Zeng, Brad Presson, Dipika Singh, Roni Rayes, Lavanya Sivapalan, Gavin Pereira, Zhicheng Ji, Rohit Thummalapalli, Joshua E Reuss, Stephen R Broderick, David R Jones, Julie S Deutsch, Tricia R Cottrell, Jamie Chaft, Jonathan Spicer, Janis Taube, Valsamo Anagnostou, Julie R Brahmer, Drew M Pardoll, Hongkai Ji, Patrick M Forde, Kristen A Marrone, Kellie N Smith","doi":"10.1158/1078-0432.CCR-24-2983","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2983","url":null,"abstract":"<p><strong>Purpose: </strong>Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 co-mutations in this setting are unknown.</p><p><strong>Experimental design: </strong>We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors.</p><p><strong>Results: </strong>Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT).</p><p><strong>Conclusions: </strong>These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638585","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":"Predictive and Dynamic Signature for Antiangiogenics in Combination with a PD1 Inhibitor in Soft-Tissue Sarcoma: Correlative Studies Linked to the IMMUNOSARC Trial.","authors":"David S Moura, Jesus M Lopez-Marti, Iva Benesova, Carlos de Andrea, Davide di Lernia, Serena Lacerenza, Jose L Mondaza-Hernandez, Marta Martin-Ruiz, Marta Ramirez-Calvo, Giovanni Grignani, Javier Martinez-Trufero, Andres Redondo, Claudia Valverde, Silvia Stacchiotti, Antonio Lopez-Pousa, José A Lopez-Guerrero, Antonio Gutierrez, Victor Encinas-Tobajas, Nadia Hindi, Dario Sangiolo, Jose A Lopez-Martin, Zuzana Ozaniak Strizova, Javier Martin-Broto","doi":"10.1158/1078-0432.CCR-24-1782","DOIUrl":"10.1158/1078-0432.CCR-24-1782","url":null,"abstract":"<p><strong>Purpose: </strong>The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial.</p><p><strong>Experimental design: </strong>Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients.</p><p><strong>Results: </strong>The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples.</p><p><strong>Conclusions: </strong>Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5192-5206"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281268","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: Belzutifan for Patients with Advanced Renal Cell Carcinoma.","authors":"Jaleh Fallah, Brian L Heiss, Hee-Koung Joeng, Chana Weinstock, Xin Gao, William F Pierce, Benjamin Chukwurah, Vishal Bhatnagar, Mallorie H Fiero, Laleh Amiri-Kordestani, Richard Pazdur, Paul G Kluetz, Daniel L Suzman","doi":"10.1158/1078-0432.CCR-24-1199","DOIUrl":"10.1158/1078-0432.CCR-24-1199","url":null,"abstract":"<p><p>On December 14, 2023, the U.S. FDA approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following treatment with a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. The FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following treatment with both a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review and overall survival. A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [HR = 0.75; 95% confidence interval (CI), 0.63-0.90; one-sided P value = 0.0008]. Kaplan-Meier curves reflected nonproportional hazards with similar median PFS estimates of 5.6 months (95% CI, 3.9-7.0) in the belzutifan arm and 5.6 months (95% CI, 4.8-5.8) in the everolimus arm. Although not reaching full maturity, the overall survival results seemed to show a favorable trend in the belzutifan arm compared with the everolimus arm (HR, 0.88; 95% CI, 0.73-1.07). The confirmed objective response rate by blinded independent central review was 22% and 3.6% in the belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower in the belzutifan arm compared with the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared with everolimus.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5003-5008"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153268","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":"Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial.","authors":"Xin Wang, Xiaozheng Kang, Ruixiang Zhang, Liyan Xue, Jiaqi Xu, Xiaotian Zhao, Qiuxiang Ou, Nuo Yu, Guojie Feng, Jiao Li, Ziyu Zheng, Xiankai Chen, Zhen Wang, Qingfeng Zheng, Yong Li, Jianjun Qin, Nan Bi, Yin Li","doi":"10.1158/1078-0432.CCR-24-1236","DOIUrl":"10.1158/1078-0432.CCR-24-1236","url":null,"abstract":"<p><strong>Purpose: </strong>This phase II trial investigated the safety and efficacy of chemoradiotherapy (CRT) followed by immunochemotherapy (iCT) and surgery in unresectable locally advanced esophageal squamous cell carcinoma (ESCC).</p><p><strong>Patients and methods: </strong>Patients with unresectable locally advanced ESCC received radiotherapy (50 Gy/25f, 5 days/week) and nab-paclitaxel (100 mg on day 1/week) plus cisplatin (25 mg/m2 on day 1/week) for 5 weeks, followed by tislelizumab (200 mg on day 1/cycle) plus chemotherapy (nab-paclitaxel 150 mg/m2 and cisplatin 75 mg/m2 on day 2/cycle) for two 21-day cycles. Patients who converted to resectable underwent surgery 2 to 4 weeks afterward. The primary endpoint was a 1-year progression-free survival (PFS) rate.</p><p><strong>Results: </strong>Thirty patients were enrolled and underwent CRT (median follow-up: 21 months), of whom 24 received iCT. Twenty (66.7%) patients achieved resectability (R0: 95.2%; pathologic complete response: 65.0%; major pathologic response: 90.0%). One-year PFS and overall survival (OS) rates were 79.4% and 89.6%, respectively. The R0 resection group exhibited longer PFS (median, not reached vs. 8.4 months; HR = 0.28; 95% confidence interval, 0.08-0.84; P = 0.02) and OS (median, not reached vs. 19.2 months; HR = 0.18; 95% confidence interval, 0.04-0.73; P < 0.01) than the nonsurgery group. Grade 3 to 4 adverse events were observed in 11 (11/30, 36.7%) patients, and immune-related pneumonitis was observed in 5 (5/24, 20.8%) patients. Post-CRT minimal residual disease before surgery was associated with unfavorable PFS and OS.</p><p><strong>Conclusions: </strong>Our study met the primary endpoint. Conversion CRT and subsequent iCT followed by surgery was a promising treatment strategy for unresectable locally advanced ESCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 22","pages":"5061-5072"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616050","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":"High Mechanical Conditioning by Tumor Extracellular Matrix Stiffness Is a Predictive Biomarker for Antifibrotic Therapy in HER2-Negative Breast Cancer.","authors":"Miguel Quintela-Fandino, Begoña Bermejo, Esther Zamora, Fernando Moreno, José Ángel García-Saenz, Sonia Pernas, Noelia Martínez-Jañez, Desirée Jiménez, Encarna Adrover, Raquel de Andrés, Silvana Mourón, Maria J Bueno, Luis Manso, Gemma Viñas, Emilio Alba, Antonio Llombart-Cussac, Javier Cortés, Cristina Tebar, Denise J Roe, Adam Grant, Adam Watson, Ramon Colomer, Ghassan Mouneimne","doi":"10.1158/1078-0432.CCR-24-1518","DOIUrl":"10.1158/1078-0432.CCR-24-1518","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib's antifibrotic effect on breast cancer outcomes.</p><p><strong>Experimental design: </strong>We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib's impact on event-free survival based on MeCo scores.</p><p><strong>Results: </strong>Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P < 0.01). Patients with low MeCo after run-in had the best long-term prognosis (HR = 0.087; P = 0.03).</p><p><strong>Conclusions: </strong>High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5094-5104"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281267","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":"Aberrant activation of wound healing programs within the metastatic niche facilitates lung colonization by osteosarcoma cells","authors":"James B. Reinecke, Leyre Jimenez Garcia, Amy C. Gross, Maren Cam, Matthew V. Cannon, Matthew J. Gust, Jeffrey P. Sheridan, Berkley E. Gryder, Ruben Dries, Ryan D. Roberts","doi":"10.1158/1078-0432.ccr-24-0049","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0049","url":null,"abstract":"Purpose: Lung metastasis is responsible for most deaths caused by osteosarcoma. How malignant bone cells coerce the lung microenvironment to support metastatic growth remains unclear. We sought to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms essential to metastatic niche formation in the lung. Experimental design: We used single-cell transcriptomics (scRNA-seq) to characterize molecular changes induced within lung tissues by disseminated osteosarcoma cells. We then evaluated the ability of nintedanib to reverse metastasis-specific changes in both immunocompetent mouse and immunodeficient xenograft models. Molecular pharmacodynamic studies used single-nucleus and spatial transcriptomics to define the tumor-intrinsic and -extrinsic changes induced by the drug. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to diseases associated with lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data suggested that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. Conclusions: Fibrosis is essential to osteosarcoma lung metastasis and represents a targetable vulnerability. Our data support a model where interactions between osteosarcoma and epithelial cells induce the deposition of extracellular matrix proteins—a reaction disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKIs on metastases in animal models.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"6 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610297","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":"CD40 agonist on patient-derived xenograft mice for the treatment of B-cell acute lymphoblastic leukemia","authors":"Pierre-Simon Bellaye, Aleksandra Georgievski, Paola Ballerini, Boutheina Bouslama, Corentin Richard, Romain Boidot, Guillaume Chevreux, Véronique Legros, Julien Guy, Jessica Racine, Bertrand Collin, Carmen Garrido, Ronan Quéré","doi":"10.1158/1078-0432.ccr-24-1391","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1391","url":null,"abstract":"Purpose: Cluster of differentiation 40 (CD40) is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases. However, the effect of CD40 activation on B-ALL cells has never been tested in vivo. Experimental Design: The aim of our preclinical study was to investigate the therapeutic potential of a CD40 agonist in the treatment of B-ALL using patient-derived xenograft (PDX) mouse models. Results: Intravenous administration of the CD40 agonist significantly impeded B-ALL cell proliferation and growth in vivo, accompanied by rapid activation of the extracellular signal-regulated kinase (ERK) pathway, leading to the induction of apoptosis and disruption of cell cycle progression. Co-treatment with a specific inhibitor of ERK further demonstrated that CD40 stimulation induced the pro-apoptosis of B-ALL cells in an ERK-dependent manner. Proteomic analysis revealed alterations in key signaling pathways associated with B-ALL expansion and maintenance. Moreover, the CD40 agonist markedly reduced the frequency of leukemia-initiating cells and leukemia development in PDX mice. Our study showed that the CD40 agonist can be associated with chemotherapeutic agents such as vincristine and dexamethasone, and this combination showed improved effectiveness. Additionally, the CD40 agonist was more effective on pre-B-ALL (EGIL B-III) that expressed CD40, than on common B-ALL (EGIL B-II) that lacked CD40 expression. Conclusion: These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"216 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610294","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 Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial","authors":"Francesca Sarno, Jair Tenorio, Sofia Perea, Laura Medina, Roberto Pazo-Cid, Ignacio Juez, Rocio Garcia-Carbonero, Jaime Feliu, Carmen Guillen-Ponce, Pedro P. Lopez-Casas, Carmen Guerra, Yolanda Duran, Jose Francisco López-Acosta, Carolina Alonso, Estrella Esquivel, Ana Dopazo, Dipikaa Akshinthala, Senthil K. Muthuswamy, Pablo Lapunzina, Bruno Bockorny, Manuel Hidalgo","doi":"10.1158/1078-0432.ccr-23-4026","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-23-4026","url":null,"abstract":"Purpose: Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC. Methods: Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician’s discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS). Results: 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months. Conclusions: Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610295","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}