Clinical Cancer Research最新文献

{"title":"Pilot Study of Daily Exemestane in Women with Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer","authors":"Britt K. Erickson, Howard Bailey, Rebecca C. Arend, Dina El-Rayes, Mahmoud A. Khalifa, Amy Skubitz, Kristin Boylan, Andrew C. Nelson, Anna Burton, Bharat Thyagarajan, Thomas Havighurst, KyungMann Kim, Eileen Dimond, Katina DeShong, Brandy Heckman-Stoddard, Goli Samimi, Eva Szabo, Lisa Barroilhet","doi":"10.1158/1078-0432.ccr-25-1878","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1878","url":null,"abstract":"Objective: To evaluate exemestane, an aromatase inhibitor, as a preventive intervention for endometrial cancer. Methods: This is a multi-center, single-arm, ‘window of opportunity’ pilot study of exemestane (25 mg daily for 21-42 days) in postmenopausal individuals undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer (EC). The primary objective is to determine change in proliferation, measured by Ki-67 expression, in pre- and post-treatment endometrial tissues specimens. Secondary outcomes include measurement of circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety, and adverse effects. Results: Forty participants were accrued to the study. Preoperative diagnoses included EIN (n=11, 27.5%), grade 1 EC (n=26, 65%), and grade 2 EC (n=3, 7.5%). Median Ki-67 score decreased from 40.7% [IQR (33.9, 50.3)] at baseline to 18.1% [IQR (8.8, 31.8)] at surgery, representing a median absolute change of 20.4% [IQR (-29.9, -6.7), p<0.001]. In a matched historical control cohort, participants also had a decrease in Ki-67 score with a median absolute change from baseline of -6.7% [IQR (-12.7, -1.3), p 0.001]. However, the decrease in Ki-67 was greater in the study participants than the historic controls, with a median difference between the groups of -13.4% [IQR (-23.3, 6.9), p ]. Both tissue ER and PR expression declined significantly with exemestane treatment (p<0.001). However, serum estradiol levels did not change between baseline and post-treatment (p=0.16). Conclusion: In this pilot study, exemestane demonstrated anti-proliferative effects in endometrial intraepithelial neoplasia and low-grade endometrial cancer. This agent warrants further evaluation for the prevention of endometrial cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228973","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-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Selecting Dosages for First-In-Human Trials","authors":"Hao Zhu, Alex N. Phipps, Ying Yuan, Brad A. Davidson, Stacy S. Shord, Jiang Liu, Patricia M. LoRusso","doi":"10.1158/1078-0432.ccr-25-0095","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0095","url":null,"abstract":"Dosage optimization has become a focus in oncology drug development, as highlighted by recent U.S. Food and Drug Administration initiatives including Project Optimus. Traditionally, most oncology drug development programs identify a maximum tolerated dosage and advance this dose in subsequent clinical trials and premarket applications. This approach has been routinely applied for cytotoxic chemotherapeutics, where higher dosages generally yield more efficacy as well as toxicity. However, it is less suited for the more targeted pharmacology of modern oncology drugs, where excessive escalation may only add additional toxicity. Instead, paradigms that utilize the totality of data accumulated throughout drug development can better determine optimized dosages that minimize the risk of underdosing, leading to exposure to subtherapeutic dosages, and overdosing, leading to unnecessary toxicities. Appropriate selection of dosing in first-in-human (FIH) trials is crucial, as it facilitates the efficient identification of optimized doses for subsequent trials. Nonclinical research and clinical data from previous trials can inform both FIH dosage selection and trial design. When background data is lacking, modeling and simulation techniques have been developed to integrate information to determine rational starting dose. Additionally, innovative model-informed clinical trial designs allow for statistically guided dose escalation and recommendation, and can be updated in real time to maximize potential patient benefit within the FIH trial. Unfortunately, these techniques remain underutilized. Here, in this first paper in a series of three discussing innovative strategies for dosage optimization, we highlight expectations and provide suggestions for the future of dosage selection and optimization in FIH oncology trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202994","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-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Early Phase Trials Using Innovative Trial Designs and Biomarkers","authors":"Olanrewaju O. Okusanya, Gabriela I. Patilea-Vrana, Anthony Sireci, Alexia Iasonos, Brad A. Davidson, Jiang Liu, Stacy S. Shord, Patricia M. LoRusso, Timothy A. Yap","doi":"10.1158/1078-0432.ccr-25-1918","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1918","url":null,"abstract":"Dosage selection for oncology drugs has traditionally relied on initial dose-finding trials to determine a maximum tolerated dose (MTD), which is then further evaluated in approval-supporting registrational trials. While this approach may have established optimized dosages for cytotoxic chemotherapeutics, many modern oncology drugs developed through this approach have been poorly optimized, requiring additional dosage optimization efforts in the post-market setting. Recent initiatives of the U.S. Food and Drug Administration outline the unsustainability of this approach, instead recommending the identification of a potentially optimized dosage at earlier stages through direct comparison of multiple dosages before marketing application submission. The selection of dosages for further investigation outside of the MTD requires fit-for-purpose techniques that address the specific promises and concerns of the drug under investigation. Although such strategies have been developed, they are currently rarely applied in favor of the MTD paradigm. Innovative trial elements, including various integral, integrated, and exploratory biomarkers as well as backfill and randomized dose expansion cohorts represent potential avenues to create and leverage additional data, and thereby make more informed dosing decisions. Additionally, modeling approaches such as clinical utility index can integrate these disparate datatypes into a single metric, facilitating more quantitative selection. This article, the second in a series of three articles addressing different stages of dose optimization, outlines best practices and areas for further development regarding innovative techniques for the selection of dosages for further evaluation prior to final dosage selection for registrational trials in oncology.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203654","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":"Radiogenomic profiling of prostate tumors prior to external beam radiotherapy converges on a transcriptomic signature of TGF-β activity driving tumor recurrence","authors":"Anson T. Ku, Uma Shankavaram, Shana Y. Trostel, Hong Zhang, Sumeyra Kartal, Houssein A. Sater, Stephanie A. Harmon, Nicole V. Carrabba, Yang Liu, Hyunnam Ryu, James A. Proudfoot, Boon Hao Hong, Bradford J. Wood, Peter A. Pinto, Peter L. Choyke, Mack Roach, Howard M. Sandler, Stephanie L. Pugh, Kenneth L. Zeitzer, Lucas C. Mendez, Nirav S. Kapadia, William A. Hall, Anand B. Desai, Radka S. Stoyanova, Alan Pollack, Elai Davicioni, Melvin L.K. Chua, Baris Turkbey, Adam G. Sowalsky, Deborah E. Citrin","doi":"10.1158/1078-0432.ccr-25-2186","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2186","url":null,"abstract":"Purpose: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies. Experimental Design: We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n=60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI (mpMRI) at baseline and 6 months post-treatment, with median follow-up of 6 years. Gene expression differences between patients with and without BCR were analyzed using pathway tools and validated in external datasets. A novel TGF-β gene signature was derived and tested across multiple cohorts (median follow-up: 5–11 years). Results: TGF-β activity was significantly associated with BCR in the discovery cohort (P = 0.0081), and correlated with PTEN/TP53 alterations (P = 0.0246) and baseline mpMRI tumor volume (P = 0.026). TGF-β activity also predicted metastasis-free survival (P = 0.037), and in an independent cohort (n=265) was prognostic for BCR-free (P = 0.05), metastasis-free (P < 0.001), and overall survival (P < 0.001). Conclusions: TGF-β activity is a dominant feature of intermediate-to-unfavorable risk prostate tumors prone to biochemical failure after EBRT with ADT and may serve as an independent prognostic biomarker beyond existing clinical criteria.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203137","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":"Supplementation of Tamoxifen with low-dose Endoxifen in breast cancer patients with impaired tamoxifen metabolism (TAMENDOX): a randomized controlled phase 1/2 trial","authors":"Thomas E. Mürdter, Werner Schroth, Matthew P. Goetz, Roman Tremmel, Svitlana Igel, Elke Schaeffeler, Simon Jäger, Sibylle Loibl, Andreas Gerteis, Lena Pfaff, Christina Bechtner, Denise Wrobel, Ilka Bernhöft, Imma Fischer, Christoph Meisner, Michael Block, Hiltrud Brauch, Matthias Schwab","doi":"10.1158/1078-0432.ccr-25-2103","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2103","url":null,"abstract":"Purpose: Tamoxifen undergoes bioactivation to its active metabolite (Z)-endoxifen, which blocks estrogen-dependent breast tumor growth at high potency. We tested the feasibility and safety of supplementing standard tamoxifen therapy with low-dose (Z)-endoxifen in breast cancer patients with compromised tamoxifen bioactivation. Patients and Methods: We conducted a prospective, interventional, three group randomized trial including 235 hormone receptor-positive breast cancer patients who received standard tamoxifen therapy (20mg/day). Patients were stratified by CYP2D6 genotype (n=78), defining poor (PM), intermediate (IM) and normal metabolizers (NM), or by baseline (Z)-endoxifen plasma concentration (n=78), defining ≤15 nM, 15-25 nM and ≥25 nM. Co-treatment with (Z)-endoxifen 3, 1.5 mg/day or placebo was performed, respectively. A control group (n=79) received placebo regardless of metabolizer phenotype. The primary endpoint was the number of patients with (Z)-endoxifen levels >32 nM after six weeks treatment. Adverse events were continuously monitored. Results: A higher proportion of patients in both intervention groups achieved target concentrations >32 nM compared to control (P < 0.0001). At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 PM patients and all patients with baseline (Z)-endoxifen ≤15 nM achieved the target concentration. At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 IM patients and 95% of patients with 15-25 nM baseline (Z)-endoxifen levels achieved the target concentration. Similar proportions of patients receiving (Z)-endoxifen (6/80, 7.5%) or placebo (8/155, 5.2%) experienced Grade 3 adverse events. Conclusion: Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized anti-estrogen treatment for patients with low endoxifen plasma levels.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202996","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-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Selecting Optimized Dosages for Registrational Trials","authors":"Stacy S. Shord, Cong Chen, Jin Y. Jin, Scott Van Wart, Sarah K. Martin, Brad A. Davidson, Jiang Liu, Patricia M. LoRusso, Geoffrey R. Oxnard","doi":"10.1158/1078-0432.ccr-25-0098","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0098","url":null,"abstract":"The maximum tolerated dose has historically been the recommended phase two dose, and this dosage has typically been evaluated in registrational clinical trials for oncology drugs. With the emergence of targeted therapies, this approach may lead to the investigation of unnecessarily high dosages that elicit additional toxicity without added benefit. The utilization of innovative trial designs and model-informed approaches during clinical development can potentially lead to more informed dosage selection. Exposure-response analyses, clinical utility index, and other model-informed approaches have been successfully applied to understand preliminary activity and safety data for various classes of modern oncology drugs, providing insight to support the proposed dosage(s) for the registrational trial. Seamless trial designs have also played an important role in dosage selection by leveraging pre-planned flexibilities and statistical procedures to increase efficiency during the conduct of trials. Critically, both approaches can be fit for purpose, allowing for adaptation and the usage of the totality of relevant clinical and nonclinical data. Despite this, the evaluation of maximum tolerated dose remains prevalent in registrational trials. This article, the third in a series of three describing best-practice approaches to dosage optimization in oncology drug development, highlights successful applications of and relevant considerations for innovative trial designs and model-based approaches to aid the selection of better optimized dosages for evaluation in registrational clinical trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203656","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":"Checkpoint Blockade Combinations in High Tumor Mutational Burden/Load Tumors: Insights from the Atezolizumab + Bevacizumab and Nivolumab + Ipilimumab Cohorts in DRUP.","authors":"Karlijn Verkerk,Soemeya F Haj Mohammad,Laurien J Zeverijn,Birgit S Geurts,Ilse A C Spiekman,Florentine A J Verbeek,Hans Timmer,Maud A van Maren,V van der Noort,Miguel Parra Martinez,Paul Roepman,Anne M L Jansen,Wendy W J de Leng,Serena Marchetti,Kim Monkhorst,Henk M W Verheul,Hans Gelderblom,Emile E Voest","doi":"10.1158/1078-0432.ccr-25-2260","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2260","url":null,"abstract":"PURPOSETo evaluate the efficacy of atezolizumab plus bevacizumab (atezo+beva) in tumors with high tumor mutational burden (TMB; number of mutations per megabase), and nivolumab plus ipilimumab (nivo+ipi) in tumors with high TMB or tumor mutational load (TML; total number of non-synonymous mutations across the genome).PATIENTS AND METHODSPatients with treatment-refractory, solid tumors were treated in the Drug Rediscovery Protocol (2023-509152-33-00). Patients with microsatellite stable tumors harboring a TML of 200-1000, or TMB of 11-24 (Oncomine) or 15-39 (TSO500) were eligible for nivo+ipi. Similar patients with a panel-independent TMB ≥16 received atezo+beva. Clinical benefit (CB; confirmed objective response or stable disease ≥16 weeks) was the primary endpoint. Whole-genome and RNA-sequencing were performed on pre-treatment tumor biopsies.RESULTSAmong 25 evaluable patients with 14 different tumor types treated with atezo+beva, the CB-rate (CBR) was 60% (95% confidence interval [CI], 39-79), with an objective response rate (ORR) of 24% (95% CI, 9-45) and median duration of response (mDoR) of 25.0 months (95% CI, 13.8-NA). In the nivo+ipi cohort the CBR was 50% (95% CI, 29-71) and ORR 37.5% (95% CI, 19-59) among 24 evaluable patients with 13 distinct tumor types. The mDoR was not reached after a median follow-up of 36 months. In both cohorts, responses were only observed in patients with TMB >20, and TMB and (clonal) TML were significantly correlated with response. Various markers of adaptive immune infiltration were associated with longer progression-free survival.CONCLUSIONSAtezo+beva and nivo+ipi showed durable responses in patients with TMB >20, underscoring their tumor-agnostic efficacy in this patient population.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194703","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":"Increased Peripheral T Stem Cell-like Memory Features in Patients with Advanced Solid Tumors Treated with Tumor-Targeting IL-12 Immunocytokine Therapy.","authors":"Meghali Goswami, Carolina Celades, Christine M Minnar, Asma S Khelifa, Lisa K Poppe, Dara Bracken-Clarke, Nicole J Toney, Megan T Lynch, Jennifer L Marté, Sofia R Gameiro, James L Gulley, Jeffrey Schlom, Renee N Donahue","doi":"10.1158/1078-0432.CCR-25-1490","DOIUrl":"10.1158/1078-0432.CCR-25-1490","url":null,"abstract":"<p><strong>Purpose: </strong>T-cell stemness is important for antitumor immunity. The presence in tumor-draining lymph nodes and tumor of stem-like memory T (TSCM) cells and T cells expressing the transcription factor T-cell factor 1 (TCF1), critical in T-cell self-renewal, is associated with improved response to immune checkpoint inhibitors.</p><p><strong>Experimental design: </strong>We studied the effects of the tumor-targeting immunocytokine PDS01ADC (NHS-IL12) on peripheral T-cell stemness in murine hosts and in patients with advanced solid tumors. TSCM and expression of the murine T-cell stemness markers stem cell antigen 1 (Ly6a) and Tcf7 were evaluated in naïve and tumor-bearing mice receiving murine PDS01ADC (NHS-muIL12). Peripheral blood from patients treated in a clinical trial with PDS01ADC was analyzed for TSCM and expression of TCF1 on T-cell subsets.</p><p><strong>Results: </strong>NHS-muIL12 treatment in naïve mice increased stem cell antigen 1-positive peripheral T cells with stem-like phenotypes and promoted tumor infiltration of CD8+ T cells displaying increased stemness. In patients with advanced solid tumors, PDS01ADC treatment increased peripheral CD8+ and CD4+ TSCM frequencies and effector memory T cells expressing TCF1, with greater increases associated with disease control. Most peripheral TSCM cells were negative for PD-1 and TIGIT throughout treatment, suggesting their quiescence and self-renewal capacity. Expanded TCF1-negative effector memory CD8+ T cells expressed PD-1 with increased intensity of granzyme B, indicating an activated, cytotoxic state.</p><p><strong>Conclusions: </strong>PDS01ADC treatment in patients with advanced solid tumors boosts peripheral T cells with stem-like characteristics, correlating with disease stabilization. Further studies combining PDS01ADC with other immunotherapies to synergize with this peripheral burst of T-cell stemness are warranted.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4159-4173"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759302","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":"Polyamine Depletion by D,L-α-Difluoromethylornithine Inhibits Ewing Sarcoma Metastasis by Inducing Ferroptosis.","authors":"Rachel Offenbacher, Kyle W Jackson, Masanori Hayashi, Jinghang Zhang, Da Peng, Yuqi Tan, Tracy Murray Stewart, Paul Ciero, Jackson Foley, Robert A Casero, Patrick Cahan, David M Loeb","doi":"10.1158/1078-0432.CCR-24-1778","DOIUrl":"10.1158/1078-0432.CCR-24-1778","url":null,"abstract":"<p><strong>Purpose: </strong>Despite decades of clinical trials, no progress has been made in improving the survival of patients with Ewing sarcoma who either present with metastatic disease or suffer a metastatic relapse. In our preclinical models, we found differential levels of polyamines in tumors that metastasize compared with tumors that do not, leading us to investigate the potential for D,L-α-difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, to prevent Ewing sarcoma metastasis.</p><p><strong>Experimental design: </strong>The effect of DFMO on Ewing sarcoma cell lines in vitro was studied by measuring proliferation, sphere formation, and clonogenic growth in soft agar. The effect in vivo was investigated using our orthotopic implantation/amputation model of metastasis. Transcriptomic changes were evaluated by RNA sequencing.</p><p><strong>Results: </strong>DFMO causes a cell cycle arrest and inhibits both sarcosphere formation and clonogenic growth in soft agar. In vivo, DFMO slows primary tumor growth and inhibits metastasis. RNA sequencing demonstrated gene expression patterns consistent with induction of ferroptosis caused by polyamine depletion, which was validated in vitro by demonstrating that DFMO treatment induces lipid peroxidation, and ferrostatin-1 and liproxstatin-1 allow sphere formation even in the presence of DFMO.</p><p><strong>Conclusions: </strong>DFMO slows the growth of Ewing sarcoma cells in vitro, with a profound impact on sphere formation and clonogenic growth, and affects all aspects of Ewing sarcoma tumorigenesis, including tumor initiation, tumor growth, and metastasis, probably through induction of ferroptosis mediated by polyamine depletion. Our results provide preclinical justification to test the ability of DFMO to prevent metastatic recurrence in patients with Ewing sarcoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4196-4210"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697786","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":"Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities.","authors":"Anne Knisely, Yibo Dai, Graham L Barlow, Sanghoon Lee, Barrett Lawson, Helen Clark, Bryan Fellman, Ying Yuan, Wei Lu, Idania Carolina Lubo Julio, Rossana N Lazcano, Manoj Chelvanambi, Brenda Melendez, Bharat Singh, Bhavana Singh, Khalida Wani, Jianfeng Chen, Chih-Chen Yeh, Jianjun Gao, Sean Barnes, Ou Shi, Khaja B Khan, Alejandra G Serrano, Lorena I Gomez-Bolanos, Carly Bess Scalise, Samantha K Cheung, Punashi Dutta, Sharlene Velichko, Adam C ElNaggar, Minetta C Liu, Roni N Wilke, Jeffrey How, Lois M Ramondetta, David M Boruta, Gwyn Richardson, Aaron Shafer, Shannon N Westin, Travis Sims, Anil K Sood, Pedro T Ramirez, Alexander J Lazar, Pamela T Soliman, Karen Lu, Cara L Haymaker, Luisa M Solis Soto, Jennifer A Wargo, Rachel Grisham, Kai W Wucherpfennig, Linghua Wang, Amir A Jazaeri","doi":"10.1158/1078-0432.CCR-25-0512","DOIUrl":"10.1158/1078-0432.CCR-25-0512","url":null,"abstract":"<p><strong>Purpose: </strong>Minimal residual disease (MRD) after first-line treatment of advanced-stage ovarian cancer remains a long-standing barrier to cure. We investigated the prognostic and translational value of MRD detection by second-look laparoscopy (SLL) and ctDNA at the completion of first-line therapy.</p><p><strong>Experimental design: </strong>Patients with high-grade epithelial ovarian cancer who had a complete clinical response to first-line therapy and underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients.</p><p><strong>Results: </strong>Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs. 23.8 months; P < 0.001) and OS (median OS 33.9 vs. not reached; P < 0.001). SLL positivity was an independent negative prognostic factor for OS (HR, 4.40; 95% confidence interval, 1.37-14.21; P = 0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs. 28.1 months; P < 0.001) and OS (32.4 months vs. not reached; P = 0.008). We demonstrated the feasibility of spatial multiomics in studying MRD and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2), and immune exclusion in MRD lesions.</p><p><strong>Conclusions: </strong>Approximately half of patients in clinical remission after first-line therapy have assessable MRD, which can inform prognosis, therapeutic target discovery, and clinical trials.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4122-4135"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759303","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}