Clinical Cancer Research最新文献

{"title":"Spatial heterogeneity, stromal phenotypes, and therapeutic vulnerabilities in colorectal cancer peritoneal metastasis","authors":"Johnny Chin-Ann. Ong, Joseph J. Zhao, Ying Liu, Supriya Srivastava, Daryl K. A. Chia, Ying En Quek, Xiaonan Fan, Haoran Ma, Kie Kyon Huang, Taotao Sheng, Qiu Xuan Tan, Gillian Ng, Joey W. S. Tan, Jia-Ying Joey. Lee, Lit-Hsin Loo, Li Yen Chong, Xue Wen. Ong, Su Ting Tay, Takeshi Hagihara, Angie Tan, Craig Ryan Cecil Joseph, Melissa C. C. Teo, Josephine Hendrikson, Clara Y. L. Chong, Wanyu Guo, Claramae S. Chia, Jolene S.M. Wong, Chin Jin Seo, Mingzhe Cai, Yvonne Tay, Kevin M. S. Sim, Ryan Y. K. Tay, Robert Walsh, Marcello Guaglio, Federica Morano, Ming Teh, Huey Yew Jeffrey Lum, Tony K. H. Lim, Louis Vermeulen, Maarten F. Bijlsma, Kristiaan Lenos, Samuel J. Klempner, Joe P. S. Yeong, Wei Peng Yong, Filippo Pietrantonio, Patrick Tan, Raghav Sundar","doi":"10.1158/1078-0432.ccr-24-3780","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3780","url":null,"abstract":"Purpose: Peritoneal metastases (PM) in colorectal cancer (CRC) portend a poor prognosis. We sought to elucidate molecular features differentiating primary tumors (PTs) from PMs and actionable targets facilitating transcoelomic dissemination and progression. Experimental Design: We performed multi-omic profiling of 227 samples from 136 patients, including 56 primary tumor (PT) and 120 synchronous PMs comprising 34 matched PT-PM pairs. Whole exome, and bulk RNA-seq analysis was conducted to identify underlying genomic aberrations and transcriptomic differences between primary and peritoneal lesions. We spatially characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. Results: Whole exome sequencing found genomic alterations and clonality patterns between PTs and PMs remain broadly similar. Transcriptomic profiles however, suggest a transition as tumors reach the peritoneum towards a more mesenchymal tumor profile and fibrotic tumor microenvironment. Applying spatial profiling, we identify a fibro-collagenous and immune-infiltrated stromal phenotype (stromal cluster [SC] 2) characterized by increased cancer-associated fibroblasts, memory B cells, M2 macrophages and T-cell exhaustion. These findings were orthogonally validated by multiplex immunohistochemistry. Patients with SC2 stroma had poorer survival and were characterized by high SERPINE-1 (PAI-1) expression. PM in patients with SC2 stroma were associated with enriched oncogenic pathways such as TGF-β. PAI-1 inhibition of CRC PM cell-lines with a novel biologic demonstrated reduced IL2-STAT5 and TGF-β pathways and cell death. Conclusions: Our findings unveil distinctive and actionable molecular signatures, offering deeper insights into the intricate crosstalk between tumor cells and stromal microenvironments enabling PM in CRC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"43 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889593","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":"Venetoclax plus modified-intensity Idarubicin and Cytarabine treatment as first-line treatment for newly diagnosed pediatric acute myeloid leukemia","authors":"Shiyuan Wang, Mingyan Jiang, Yaqin Wang, Lixian Chang, Beibei Zhao, Xiaoming Liu, Benquan Qi, Shuchun Wang, Tianfeng Liu, Xiaoyan Zhang, Yumei Chen, Fang Liu, Ye Guo, Xiaojuan Chen, Li Zhang, Yao Zou, Wenyu Yang, Ju Gao, Xiaofan Zhu, Min Ruan","doi":"10.1158/1078-0432.ccr-25-0479","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0479","url":null,"abstract":"Purpose: Venetoclax (VEN) has shown excellent activity in eliminating acute myeloid leukemia (AML) blasts in preclinical and clinical trials, but clinical data in pediatric newly diagnosed AML (ND-AML) remain limited. We evaluated VEN plus modified-intensity idarubicin and cytarabine chemotherapy (VIA) in childhood ND-AML. Experimental design: In an open-label, single-arm, multi-center prospective clinical trial, 65 ND-AML pediatric patients received VIA induction (VEN and modified-intensity cytarabine and idarubicin). Consolidation was guided on response to induction and individualized risk stratification. Primary end point was complete remission (CR) and measurable residual disease (MRD) response rates. Results: After induction cycle 1, CR and MRD negativity was 90.8% and 78.5%, increasing to 96.8% and 87.3% following induction cycle 2. 28 (43.2%) patients underwent hematopoietic stem cell transplantation (HSCT) without engraftment failure. CBF AML [t(8;21) and inv(16)/t(16;16)] patients achieved a favorable response rate, but the median log10 reduction of transcript levels was suboptimal [-1.7 (cycle 1) and -2.6 (cycle 2) for RUNX1::RUNX1T1, -2.3 and -2.5 for CBFB::MYH11]. Disease relapse was frequently observed in KIT mutation, RUNX1::RUNX1T1 and CBFB::MYH11. The most common grade 3-4 toxicities were hematological toxicities and febrile neutropenia (FN). No treatment-related deaths occurred. With a median follow-up of 15.7 months, the estimated 12-month overall survival and event-free survival was 92.3% (95% CI 86.0-99.8) and 79.1% (95% CI 69.6-90.0). MRD negativity post cycle 1 correlated with superior long-term survival (P < 0.001). Conclusions: VIA regimen is highly effective and relatively safe in children with ND-AML, with deep remission and favorable survival outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"34 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884655","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":"Antibody Drug Conjugates in Non-Small Cell Lung Cancer: Where is the Target and the Biomarker?","authors":"Fred R. Hirsch","doi":"10.1158/1078-0432.ccr-25-0839","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0839","url":null,"abstract":"ADCs are an emerging treatment of NSCLC. Some do not require biomarkers, while others require mutations and/or protein expression. New diagnostic technologies give opportunities for better target identification and selection of patients. Combination therapies might broaden relevant patient populations but might call for combined biomarker selection paradigms.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884505","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":"Pretargeting: Bridging the two worlds of radiopharmaceutical probes","authors":"Yuriko Mori, Jens Cardinale, Frederik L. Giesel","doi":"10.1158/1078-0432.ccr-25-0568","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0568","url":null,"abstract":"The human trophoblast cell-surface antigen 2 (Trop-2) is expressed in a variety of malignant diseases. Using pretargeting methodology, a novel antibody against Trop-2 was radiolabeled and evaluated in a preclinical setting. This showed promising characteristics lending itself as potential basis for further clinical trials as imaging agent and potential theranostic.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"43 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884654","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 Effect of IGFBP-3 on Low-Dose Tamoxifen Efficacy in Noninvasive Breast Cancer in the Phase III Tam-01 Trial","authors":"Harriet Johansson, Debora Macis, Martino Oliva, Matteo Puntoni, Eva Blondeaux, Aliana Guerrieri-Gonzaga, Valentina Aristarco, Irene Maria Briata, Tania Buttiron-Webber, Luca Boni, Matteo Lazzeroni, Davide Serrano, Livia Giordano, Maria Digennaro, Laura Cortesi, Francesco Millo, Katia Cagossi, Giuseppe Aprile, Fabio Falcini, Elisa Gallerani, Bernardo Bonanni, Andrea DeCensi","doi":"10.1158/1078-0432.ccr-24-2987","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2987","url":null,"abstract":"Purpose: Low-dose tamoxifen 5 mg/day (babytam) for 3 years can decrease the incidence of new breast cancer events in women with breast intraepithelial neoplasia by 42% with limited toxicity, which provides a new treatment option for these disorders. However, predictive biomarkers of babytam efficacy are lacking. We studied whether baseline levels of insulin-like growth factor-1 (IGF-I), IGF-binding protein-3 (IGFBP-3), estradiol, and sex hormone–binding globulin (SHBG) and their ratios predict babytam efficacy on breast cancer events in a preplanned secondary analysis. Patients and Methods: Within a 1:1 placebo-controlled, multicenter randomized trial of babytam or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ, 406 of 500 participants consented to blood sampling at baseline and at 1 and 3 years. Serum IGF-I, IGFBP-3, estradiol, and SHBG levels and their ratios were measured using chemiluminescent immunoassays. Biomarker changes were estimated using mixed-effects models, and incidence rate ratios were calculated after 10 years of follow-up with Poisson regression. Subgroup analyses were performed using an interaction test and subpopulation treatment effect pattern plot. Results: Baseline levels of IGFBP-3 in the three top quartiles (≥3.44 µg/mL), but not in the lower quartile, predicted greater babytam efficacy compared with placebo (Pinteraction = 0.006). Baseline IGF-I, estradiol, or SHBG levels were not predictive of babytam efficacy, whereas the IGF-I/IGFBP-3 ratio was borderline significant (Pinteraction = 0.067). Conclusions: High baseline levels of IGFBP-3 (≥3.44 µg/mL) predicted babytam efficacy and may help differentiate which women benefit most from this treatment.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"43 1","pages":"OF1-OF6"},"PeriodicalIF":11.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884690","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":"p-AKT protein expression predicts response to AKT inhibitor combined with docetaxel therapy in adenocarcinoma and neuroendocrine prostate cancer.","authors":"Hipacia Werneck Gomes, Natalie L Lister, Shivakumar Keerthikumar, Birunthi Niranjan, Michelle G Richards, Andrew Ryan, Edmond M Kwan, Gail P Risbridger, Renea A Taylor","doi":"10.1158/1078-0432.CCR-24-3848","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3848","url":null,"abstract":"<p><strong>Purpose: </strong>AKT inhibitors, such as capivasertib, have shown activity in specific patients with metastatic castration-resistant prostate cancer when combined with docetaxel, although none have been approved. While PTEN loss is often linked to AKT pathway activation and response to AKT inhibitors, clinical trials show no consistent association. This study uses patient-tumor models to identify biomarkers associated with an effective response to AKT inhibitor plus docetaxel.</p><p><strong>Experimental design: </strong>Targeted DNA sequencing and immunostaining for PTEN and p-AKT(Ser473) was assessed in 39 prostate cancer patient-derived xenografts (PDXs), including adenocarcinoma and neuroendocrine phenotypes. Matching PDX-derived organoids were used to evaluate the functional effects of capivasertib and docetaxel on in vitro tumor growth.</p><p><strong>Results: </strong>p-AKT protein expression varied widely across PDX models and showed no correlation with PTEN/PI3K/AKT mutations or PTEN protein levels. Neuroendocrine tumors displayed higher p-AKT expression than adenocarcinomas. Knockdown of AKT1 in neuroendocrine organoids increased sensitivity to docetaxel, while AKT1 overexpression decreased it. In three out of seven organoids tested, the combination of capivasertib and docetaxel produced a synergistic effect, resulting in greater growth inhibition than either agent alone. These responsive organoids exhibited a neuroendocrine phenotype and high p-AKT expression, consistent with a predictive response.</p><p><strong>Conclusions: </strong>Our preclinical findings indicate that p-AKT protein expression, rather than PTEN, may be a more reliable predictor of response to AKT inhibition combined with docetaxel. Using p-AKT as a parameter, we uncovered the efficacy of this combination in neuroendocrine prostate cancer, highlighting the potential to refine patient selection criteria for future clinical trials.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986153","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":"CHIP'ing Signal from Noise in Liquid Biopsy.","authors":"Elsa Bernard,Jean-Baptiste Micol","doi":"10.1158/1078-0432.ccr-25-0569","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0569","url":null,"abstract":"The presence of clonal hematopoiesis (CH) in cell-free DNA (cfDNA) analysis can distort the interpretation of results and impact cancer treatment decisions. This CCR Translations discusses the importance of distinguishing the origin of cfDNA variants as tumoral or hematopoietic and its potential clinical implications.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"258 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871976","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":"Leveraging Longitudinal Patient-Reported Outcomes Trajectories to Predict Survival in Non-Small-Cell Lung Cancer","authors":"Jiawei Zhou, Benyam Muluneh, Zhaoyang Wang, Huaxiu Yao, Jim H. Hughes","doi":"10.1158/1078-0432.ccr-25-0292","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0292","url":null,"abstract":"Purpose: Despite their potential, patient-reported outcomes (PRO) are often underutilized in clinical decision-making, especially when improvements in PRO do not align with clinical outcomes. This misalignment may result from insufficient analytical methods that overlook the temporal dynamics and substantial variability of PRO data. To address these gaps, we developed a novel approach to investigate the prognostic value of longitudinal PRO dynamics in non-small-cell lung cancer (NSCLC) using Lung Cancer Symptom Scale (LCSS) data. Methods: Longitudinal patient-reported LCSS data from 481 NSCLC participants in the placebo arm of a Phase III trial were analyzed. A population modeling approach was applied to describe PRO progression trajectories while accounting for substantial variability in the data. Associations between PRO model parameters and survival outcomes were assessed using Cox proportional hazards models. Model-informed PRO parameters were used to predict survival via machine learning. Results: A PRO progression model described LCSS dynamics and predicted a median time to symptom progression of 229 days (95% confidence interval [CI]: 15-583). Faster PRO progression rates were significantly associated with poorer survival (Hazard ratio [HR] 1.13, 95% CI: 1.076-1.18), while greater improved PRO effects by placebo/prior treatment correlated with improved survival (HR 0.93, 95% CI: 0.883-0.99). A machine learning model using PRO parameters achieved an AUC-ROC of 0.78, demonstrating their potential to predict overall survival. Conclusions: This study demonstrates that longitudinal PRO data can provide prognostic insights into survival in NSCLC. The findings support the use of PRO dynamics to improve clinical decision-making and optimize patient-centered treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"69 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867022","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":"ctDNA Clearance as an Early Indicator of Improved Clinical Outcomes in Advanced NSCLC Treated with TKI: Findings from an Aggregate Analysis of Eight Clinical Trials.","authors":"Hillary S Andrews, Nevine Zariffa, Katherine K Nishimura, Stephanie H Choi, Shibing Deng, Megan Eisele, Carin R Espenschied, Emily M Goren, Minakshi Guha, Samuel Hong, Dilafruz Juraeva, Nicole Krämer, Li Liu, Jean-Francois Martini, Brittany A McKelvey, Geoffrey R Oxnard, Gary A Pestano, Lynne Poole, Adam Rosenthal, Anna M Szpurka, Diana Merino Vega, Christine Ward, Sameera R Wijayawardana, Antje Hoering, Mark D Stewart, Jeff D Allen","doi":"10.1158/1078-0432.CCR-24-3612","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3612","url":null,"abstract":"<p><strong>Purpose: </strong>Circulating tumor DNA (ctDNA) holds promise as an early endpoint to predict overall survival (OS). The creation and structured interrogation of aggregated datasets inform the hypothesis that ctDNA is reasonably likely to predict treatment benefit. Friends of Cancer Research convened a diverse working group to establish and implement an analysis plan assessing patient-level associations between changes in ctDNA levels with OS and progression-free survival (PFS).</p><p><strong>Experimental design: </strong>The aggregate dataset included eight clinical trials representing 940 patients with biomarker-positive advanced non-small cell lung cancer treated with tyrosine kinase inhibitors. Detection of baseline and on-treatment ctDNA was assessed for associations with OS and PFS. Additionally, combinations of ctDNA detection and RECIST measurements up to 10 weeks on treatment were considered.</p><p><strong>Results: </strong>Patients with detected ctDNA at baseline that became nondetected on treatment (\"clearance\") experienced improved OS compared with patients with persistently detected ctDNA (adjusted HR = 2.12, P < 0.001). This pattern was also seen in the subset of patients with stable disease as measured by RECIST within 10 weeks of treatment initiation (adjusted HR = 4.15, P < 0.001). Results were similar for PFS.</p><p><strong>Conclusions: </strong>In patients with oncogene-driven advanced non-small cell lung cancer treated with tyrosine kinase inhibitors, ctDNA clearance within 10 weeks of treatment initiation was associated with improved OS and PFS. These patient-level results support the growing evidence that demonstrates a change in ctDNA levels during treatment is associated with clinical benefit. Future prospective trials should include predefined thresholds of molecular response to advance the utility of ctDNA as an early endpoint.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":10.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984974","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":"Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy.","authors":"Mamta Gupta, Hoon Choi, Samantha B Kemp, Emma E Furth, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Mark Rosen, Fang Liu, Quy Cao, Ben Z Stanger, Rong Zhou","doi":"10.1158/1078-0432.CCR-24-4049","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4049","url":null,"abstract":"<p><strong>Purpose: </strong>In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a promising new treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment.</p><p><strong>Experimental design: </strong>Multiple preclinical PDAC models including a genetically engineered mouse model (KPC) received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with immunohistochemistry (IHC) analyses.</p><p><strong>Results: </strong>Significant increase of tumor apparent diffusion coefficient (a DWI metric) was detected as early as 48h and persisted to Day7 after initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a DCE metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors.</p><p><strong>Conclusions: </strong>Multiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985824","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}