Cancer research最新文献

{"title":"Abstract LB118: Machine learning-based tumor grading in pancreatic ductal adenocarcinoma: Exploring texture features for automated classification and clinical decision support","authors":"Miracle Thomas","doi":"10.1158/1538-7445.am2025-lb118","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb118","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and a leading cause of cancer-related death in the U.S. Due to late-onset symptoms, it often remains undiagnosed until advanced stages, resulting in poor prognosis. This study presents a machine learning approach to classify tumor grades based on texture features extracted from histological images, offering insights into prognosis and treatment decisions. A 2019 study by Qiu et al. demonstrated the effectiveness of machine learning-based CT texture analysis in predicting PDAC histopathological grades, achieving 86% accuracy, 78% sensitivity, and 95% specificity. Similarly, this work utilizes images from four tumor grades—Normal, Grade I, Grade II, and Grade III—obtained from Hematoxylin and Eosin and May-Grunwald-Giemsa staining. Texture features, including Gray-Level Co-occurrence Matrix (GLCM) properties, Local Binary Pattern (LBP) features, and Histogram of Oriented Gradients (HOG), were extracted to create a feature vector for each image. These vectors were used to train a Support Vector Machine (SVM) model with Error-Correcting Output Codes (ECOC) for multiclass classification, with hyperparameter optimization to improve model performance. Cross-validation was used to evaluate the model, yielding an accuracy of 53%. Although this accuracy is suboptimal, it represents a foundational step in automated PDAC tumor classification. The model could still serve as a useful tool in clinical practice, especially when used alongside other diagnostic methods or as a baseline for further improvements. Principal Component Analysis (PCA) was applied to visualize the feature distribution, and a confusion matrix was generated to assess classification performance. Results indicate that, despite the modest accuracy, the extracted texture features have potential for distinguishing between tumor grades, providing a starting point for automated classification and supporting clinical decision-making. The study introduces an innovative approach to PDAC tumor grading, addressing the urgent need for improved diagnostic tools. While further work is needed to optimize performance, this research sets the stage for future advancements that could impact clinical decision-making and patient outcomes. Citation Format: Miracle Thomas. Machine learning-based tumor grading in pancreatic ductal adenocarcinoma: Exploring texture features for automated classification and clinical decision support [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB118.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"34 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876037","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":"Abstract LB218: Early reduction in circulating tumor DNA (ctDNA) is associated with clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC)","authors":"Jia Luo, Salman R. Punekar, Kathryn C. Arbour, Melissa Johnson, Alex Spira, Ignacio Garrido-Laguna, Jonathan W. Goldman, Benjamin Herzberg, Sai-Hong Ignatius Ou, Dae Won Kim, Lijia Wang, Li Cheng, Vidya Seshadri, Sumit Kar, Minoti Hiremath, David S. Hong","doi":"10.1158/1538-7445.am2025-lb218","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb218","url":null,"abstract":"Background: Patients with previously treated NSCLC have a high unmet medical need, with a reported median overall survival (OS) of <1 year. RAS mutations are the most common driver mutation found in approximately 30% of patients with NSCLC. Daraxonrasib (RMC-6236) is an oral, RAS(ON), multi-selective, noncovalent, tri-complex inhibitor of GTP-bound mutant and wild-type RAS. As of a 30 Sep 2024 data cutoff, daraxonrasib monotherapy demonstrated manageable safety and tolerability at 120-220 mg QD with few ≥Grade (G) 3 treatment-related adverse events in ≥ 2 patients (rash [6.8%], vomiting and anemia [2.7% each]), and no G4 or 5 TRAEs. Encouraging clinical activity was seen at 120-220 mg (confirmed ORR=38%, median PFS=9.8 months, and median OS=17.7 months). Here, we present an exploratory analysis of ctDNA from patients with NSCLC treated with daraxonrasib. Methods: Patients with advanced RAS mutant tumors were treated in the Phase 1 study (NCT05379985). Dose optimization was performed at 120-300 mg. In NSCLC, 300 mg was not considered for further development due to a less favorable tolerability profile and reduced dose intensity; 200 mg daily is the proposed dose for NSCLC. The efficacy evaluable population (EE, N=40) was defined as patients with RAS G12X mutant (nonsynonymous mutations at codon 12 in K, H, or NRAS) NSCLC treated with 120-220 mg, receiving 1 or 2 prior lines of therapy, including prior immunotherapy and platinum chemotherapy, who have not received docetaxel previously. Responses were assessed per RECIST v1.1. Paired plasma samples (collected at baseline and day 1 of cycle 2 or 3) were analyzed, by Guardant Infinity, for changes in RAS mutant variant allele frequency (VAF) in ctDNA. Results: As of September 30, 2024, paired plasma samples were tested from 54 patients with RAS G12X mutant NSCLC who received 120-220 mg daily daraxonrasib as second line or later therapy. A RAS G12X mutant allele was detected in baseline ctDNA in 59% (32/54) of patients. In these patients, response or stable disease (SD) was observed across a wide range of baseline RAS mutant VAFs (0.04-52.05% VAF). Complete ctDNA clearance (i.e., 100% RAS VAF decrease from baseline) was seen in 89% (8/9) of responders, 70% (14/20) of patients with SD, and 0% (0/3) of patients with progressive disease (PD), across different RAS G12X mutations. In contrast, incomplete ctDNA clearance was seen in 11% (1/9) of responders, 30% (6/20) of patients with SD, and all patients with PD (p=0.018, Freeman-Halton Fisher exact test). In the EE, 23 patients were ctDNA evaluable; complete ctDNA clearance was seen in 86% (6/7) of responders and 63% (10/16) of patients with SD. Conclusions: These data demonstrate that clinical response to the multi-selective, RAS(ON) inhibitor, daraxonrasib, is associated with early on-treatment complete clearance of ctDNA for multiple RAS G12X mutations in NSCLC. Citation Format: Jia Luo, Salman R. Punekar, Kathryn C. Arbour, Melissa Johnson, Alex","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"7 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872965","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":"Abstract LB464: Identification of endothelial Ovol1 as a novel regulator of Slug-dependent angiogenic signaling in colorectal cancer","authors":"Kapil Thapa, Brandon Burow, Emma Bates, Jennifer Fang","doi":"10.1158/1538-7445.am2025-lb464","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb464","url":null,"abstract":"Cancer progression and metastasis depends upon tumor neovascularization to connect solid tumors to the systemic circulation. Endothelial cells that line the inner lumen of blood vessels critically support the pathological angiogenesis needed to form tumor blood vessels, and anti-angiogenics are frequently used as part of chemotherapy treatment for many cancer types. However, anti-angiogenics are often less effective than expected such as in colorectal cancer where the VEGF inhibitor bevacizumab improves outcomes in only a subset of patients. This suggests that new strategies targeting core angiogenic pathways may be more promising. We recently found that transcription factor Slug mediates a partial endothelial-to-mesenchymal transition (pEndoMT) in endothelial cells that is essential for sprouting angiogenesis and tumor neovascularization. However, an outstanding question remains: what regulates Slug during tumor angiogenesis? Sequence analysis of the Slug gene reveals two predicted DNA-binding sites for the transcription factor Ovol1. Here, we explore the hypothesis that Ovol1 regulates Slug to induce pEndoMT in angiogenesis. We show that Ovol1 is necessary and sufficient to drive angiogenesis in vitro in a Slug-dependent manner. Constitutive overexpression of Ovol1 increases Slug expression in cultured endothelial cells, and endothelial-specific Ovol1 knockout leads to suppression of colorectal cancer tumor xenograft growth in mice. In summary, we report that Ovol1 is a novel regulator of sprouting angiogenesis and tumor neovascularization via effects on Slug levels. This expanded understanding of Ovol-Slug regulation of the pEndoMT signaling axis in endothelial cells and in colorectal cancer is expected to help drive development of new and potentially more effective anti-angiogenic therapies that may one day help to better suppress tumor growth in cancer patients. (Funding: Louisiana Cancer Research Center New Investigator Award (CR1305A6), Louisiana Cancer Research Center Summer Undergraduate Cancer Research Experience Program, Tulane Carol Lavin Bernick Faculty Research Award, and Tulane Committee on Research Fellowship Award) Citation Format: Kapil Thapa, Brandon Burow, Emma Bates, Jennifer Fang. Identification of endothelial Ovol1 as a novel regulator of Slug-dependent angiogenic signaling in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB464.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"140 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872969","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":"Abstract LB091: T cell targeted lentiviral gene delivery using the PACK-IT Platform generates CAR-T cells with superior potency compared to conventional lentivirus and enables in vivo generation of CD19-CAR T cells capable of controlling leukemia in preclinical models","authors":"Kylie A. Burdsall, Peng Xu, Daniela Castro-Martinez, Louai Labanieh, Katie Ho, Quanming Shi, Bingfei Yu, Elena Sotillo, Howard Y. Chang, Crystal L. Mackall","doi":"10.1158/1538-7445.am2025-lb091","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb091","url":null,"abstract":"Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized outcomes for patients with B cell and plasma cell malignancies; however, a sizable fraction of CAR-T cell recipients fail to experience long term disease control. In some cases, therapeutic failure may be attributed to inadequate T cell potency induced by prolonged activation and ex vivo proliferation during the traditional multiday CAR-T cell manufacturing process. Moreover, only a small fraction of eligible patients receive commercial CAR-T cell therapies due to access barriers such as cost and difficulty meeting supply demand equilibrium. With the goal of enhancing anti-tumor efficacy and patient access, we developed the Programmable Antibody-mediated Cellular Knock-In of T cells (PACK-IT) Platform. To direct genetic integration specifically into T cells, the PACK-IT Platform incorporates a mutated form of the lentiviral viral envelope protein, Vesicular Stomatitis Virus glycoprotein (VSV-G), that ablates binding to the natural cognate receptor. Mutant VSV-G is coupled with envelope expression of a T cell targeting scFv, leading to PACK-IT Platform cargo delivery specifically in T cells. Using an optimized anti-CD3.PACK-IT to deliver a CD19.28.z-CAR, we generated human CAR-T cells ex vivo via a rapid 4 day manufacturing process that eliminates the need for a T cell purification or activation step. When tested against Nalm-6 leukemia in NSG mice, ex vivo generated anti-CD3.PACK-IT.CD19.28.z-CAR T cells outperformed CD19.28.z-CAR T cells produced with a 4 day conventional lentiviral engineering process. The PACK-IT platform also enabled an ultra-rapid 4 hour manufacturing process, eliminating the need for T cell purification, activation, and ex-vivo CAR-T cell expansion. Notably, intravenous administration of anti-CD3.PACK-IT.CD19.28.z-CAR lentiviral particles (3.92e9 lentiviral particles/ mouse) to immunodeficient NSG mice inoculated with human T cells (5e6/mouse) generated CD19.28z CAR-T cells in vivo that mediated significant antitumor effects against Nalm-6 leukemia. These findings demonstrate the feasibility of using anti-CD3.PACK-IT, an envelope engineered lentivirus, to enable ultra-rapid ex vivo manufacturing of functionally superior CAR-T cells and to produce CAR-T cells in vivo capable of tumor control. This platform offers the potential to improve access by reducing costs and delays associated with CAR-T cell manufacturing and enhance outcomes by delivering products of greater potency. Citation Format: Kylie A. Burdsall, Peng Xu, Daniela Castro-Martinez, Louai Labanieh, Katie Ho, Quanming Shi, Bingfei Yu, Elena Sotillo, Howard Y. Chang, Crystal L. Mackall. T cell targeted lentiviral gene delivery using the PACK-IT Platform generates CAR-T cells with superior potency compared to conventional lentivirus and enables in vivo generation of CD19-CAR T cells capable of controlling leukemia in preclinical models [abstract]. In: Proceedings of the American Association for Cancer","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875714","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":"Abstract LB150: Metagenomics and metabolomics identify differential biomarkers in MASLD and hepatocellular carcinoma in South Texas Hispanics","authors":"Shweta Singh, Sierra Vidaurri, Anupam Dhasmana, Swati Dhasmana, Bablu Kumar, Jacob Galan, Natasha S. Garcia-Rodriguez, Murali Mohan Yallapu, Subhash Chauhan, Sheema Khan","doi":"10.1158/1538-7445.am2025-lb150","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb150","url":null,"abstract":"Background: The Rio Grande Valley (RGV) is a major hotspot for hepatocellular carcinoma (HCC) and liver diseases. HCC often develops from metabolic dysfunction-associated steatotic liver disease (MASLD), progressing through stages like simple steatosis, MASH, and cirrhosis. However, the mechanisms driving progression remain poorly understood. In this study, we examined liver microbiome signatures to identify those that differentiate MASLD patients at risk for HCC. We also explored microbiome-metabolome associations, uncovering microbe-metabolite links in RGV patients. These findings demonstrate microbiome's role in HCC progression, potentially guiding future diagnostic and therapeutic strategies. Methods: FFPE tissue blocks from MASLD, MASH, HCC, and cirrhosis samples were selected. DNA extraction was carried out using the QIAamp DNA FFPE Advanced Kit with protocol modifications, and quality was assessed with NanoDrop, Qubit, Bioanalyzer, and TapeStation. 16S rRNA metagenomics was performed on Illumina MiSeq, and raw sequences were processed using Trim Galore to ensure high-quality reads. Taxonomic classification was conducted with Kraken 2, comparing against the United Human Gastrointestinal Genome (UHGG) v2.0.2 reference database, retaining species-level classified reads for further analysis. Microbial community diversity and comparative analyses were carried out using R packages in Microbiome Analyst, employing Welch t-tests, Bray-Curtis ordination, and LEfSe to identify differential abundance. Additionally, metabolomics was performed using Bruker and Thermo instruments to explore the correlation between microbial populations and metabolites. Results: Proteobacteria was most abundant in the liver of MASLD patients, followed by Firmicutes, Actinobacteria, Bacteroidetes, and Fusobacteria, which decreased in MASH, Cirrhosis, and HCC. Elevated Beijerinckiaceae, Moraxellaceae, Streptococcaceae, and Enterobacteriaceae were found in MASLD compared to the other stages. Alpha and beta diversity analyses revealed significant microbial differences, particularly between MASLD and HCC (p = 0.001). MASH showed increased Ruminococcus, Enterobacter, and Enterococcus, while Cirrhosis had more Collinsella, Veillonella, and Prevotella. Linear discriminant analysis identified key taxa, including Ruminococcus, Enterobacter, and Staphylococcus in MASH, and Bifidobacterium_thermophilum, Lacticaseibacillus_rhamnosus, and Lactobacillus spp. in MASLD. Metabolomics revealed altered metabolic pathways linked to these microbial shifts. Combined microbiome and metabolomics analyses showed correlations with metabolic activity, and random forest models validated these taxa as potential biomarkers, with Spearman correlation confirming the link between microbiome diversity and liver disease progression. Conclusion: This study is crucial for identifying the etiology of HCC and developing microbial species-based diagnostic and prognostic biomarkers. It is particularly relevant f","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"75 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875702","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":"Abstract LB255: MCTarg: A plasma-based metabolic biomarker model for multi-cancer early detection","authors":"Yan Li, Xinping Xu, Chunyan Zeng, Bei Qing, Yun He, Yanlong Liu, Guodong Song, Jianhua Hu, Tianqi Shao, Li Liu, Qingyan Wei, Shuqi Yu, He Wen, Junyuan Hu, Wei Zhang, Youxiang Chen, Zhenkun Xia","doi":"10.1158/1538-7445.am2025-lb255","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb255","url":null,"abstract":"Introduction: Cancer remains a leading cause of mortality worldwide. The multi-cancer early detection (MCED) test complements current screening methods improving early detection and treatment outcomes. While most MCED tests focus on community populations, our MCTarg models were specifically designed to address both low-risk and high-risk populations (e.g., those with conditions such as ulcerative colitis, adenomatous polyps, chronic bronchitis, tuberculosis, atrophic gastritis, and H. pylori infection), tailoring the approach to the unique characteristics and needs of each group. Here, we present the performance of our Multiple Cancer Target (MCTarg), which utilizes a single plasma metabolite test combined with machine learning technology to screen for the most prevalent cancer types—specifically lung cancer (LC), gastric cancer (GC), and colorectal cancer (CRC). Methods: We enrolled 951 cancer patients (540 LC, 203 GC, 208 CRC) and 889 non-cancer individuals (healthy controls and those with benign diseases) across three centers. Plasma samples were analyzed using GC-MS and LC-MS multi-platforms. Participants were divided into a discovery cohort for identifying cancer signatures and optimizing models, and an internal validation cohort for performance evaluation. External validation was conducted on an independent cohort (108 cancer patients, 125 non-cancer individuals) from two additional centers. Furthermore, the discriminatory ability of these metabolites between the non-cancer and multi-cancer groups was confirmed using targeted metabolomic analysis. Results: Two screening models, MCTarg-1 for low-risk populations and MCTarg-2 for high-risk populations, were established for various clinical scenarios. MCTarg-1 for low-risk populations exhibited 98.9% sensitivity at 98.0% specificity in the internal validation cohort and 93.5% sensitivity at 95.0% specificity in the external validation cohort. MCTarg-2 for high-risk populations yielded 59.9% sensitivity at 94.4% specificity internally, and 64.8% sensitivity at 85.6% specificity externally. For early-stage (I-II) patients in the external cohort, sensitivities were 79.1% for MCTarg-1 and 69.2% for MCTarg-2. With 66 metabolite biomarkers identified, MCTarg-1 exhibited 80.6% sensitivity at 98.0% specificity in the internal validation cohort, and 73.3% sensitivity at 86.7% specificity in the external validation cohort. MCTarg-2 also showed 69.4% sensitivity at 91.7% specificity, and 57.4% sensitivity at 84.0% specificity, respectively. Conclusions: Our MCTarg has demonstrated outstanding and competitive performance across various risk groups. With further large-scale validation and the inclusion of additional cancer types, MCTarg has the potential to become a universally applicable, simple, and cost-effective method, enabling early detection and localization of common cancers in large populations. Citation Format: Yan Li, Xinping Xu, Chunyan Zeng, Bei Qing, Yun He, Yanlong Liu, Guodong Song, Jianhua","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875720","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":"Abstract LB073: Characterizing the ovarian cancer immune microenvironment in a syngeneic murine model","authors":"Alexandra N. McMellen, Benjamin G. Bitler, Michael S. Leibowitz","doi":"10.1158/1538-7445.am2025-lb073","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb073","url":null,"abstract":"Ovarian cancer (OvCa) is the deadliest gynecologic malignancy and, unfortunately, there are no effective salvage therapies for patients with refractory or resistant (r/r) disease. This is due in part to a limited understanding of the tumor microenvironment (TME), the marked differences between tumors established in different metastatic niches, and how the TME may change in the context of therapy resistance. OvCa uniquely metastasizes through peritoneal spread, resulting in various tumor niches with distinct tumor mutational burdens within the same patient. These niches have not been well characterized in murine models of OvCa and contribute to continued ineffective therapeutic interventions for r/r OvCa. To better define the ovarian cancer TME, we are utilizing orthotopic syngeneic murine models sensitive and resistant to the FDA approved PARP inhibitor (PARPi), Olaparib, ID8 and ID8-OR respectively. This model has both a TP53 and BRCA2 deletion, recapitulating the mutational status of OvCa patients likely to receive a PARPi. After tumor establishment, ascites as well as solid tumors at distinct tumor sites were collected and dissociated for further analysis. Using flow cytometric assays, we characterized the T cell infiltrate within the TME at distinct niches and surface marker expression on the tumor cells. These data confirm the presence of tumor infiltrating T cells within the OvCa TME across different tumor niches. We observed that the tumor infiltrating T cell percentage as well as their phenotype varies across the different metastatic niches of this disease. We observe a greater percentage of T cells present in the ascites as compared to the other metastatic sites including the omentum, the ovaries, and the bowel wall. Additionally, we observe a greater percentage of T-regulatory cells in PARPi-resistant omental tumors. Interestingly, while we do observe CD4+ and CD8+ T cells in the collected tumors, we do not see consistent expression of markers associated with either activation or exhaustion. Further studies are required to better characterize the functionality of the tumor infiltrating T cells. The data generated from these studies will inform the development of successful salvage immunotherapies for relapsed and refractory patients with ovarian cancer. Citation Format: Alexandra N. McMellen, Benjamin G. Bitler, Michael S. Leibowitz. Characterizing the ovarian cancer immune microenvironment in a syngeneic murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB073.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876099","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":"Abstract LB209: Dynamic STING repression orchestrates immune cell functionality across development and maturation","authors":"Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan","doi":"10.1158/1538-7445.am2025-lb209","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb209","url":null,"abstract":"Stimulator of Interferon Genes (STING) is a critical component of the innate immune system. Mechanisms of STING-mediated type I interferon (IFN-I) signaling during infection are well studied in myeloid cells. However, homeostatic STING expression patterns and their regulation, particularly in lymphoid cells, are unknown. We established a Sting1IRES-EGFP reporter mouse to systematically characterize STING expression spatially in tissues and temporally along development of immune cells. Using this reporter and conditional Sting1 transgenic mouse models, we show that STING expression is repressed in neutrophils and forced STING signaling and expression drives systemic inflammatory disease due to secretion of cytokines and chemokines by neutrophils. Additionally, we show that STING expression is temporally restricted during T lymphocyte development at the double positive stage. Forced STING expression and signaling severely impairs T lymphocyte development and reduces thymopoiesis independent of the type I IFN receptor (IFNAR1). Mechanistically, STING expression in the thymus is controlled via epigenetic silencing by DNA methyltransferase 1 (DNMT1). Forced STING signaling in the thymus favors lineage commitment to innate-like γδ T cells rather than adaptive αβ T cells, revealing a previously unanticipated role of STING in T lymphocyte fate choice. Using two syngeneic tumor models and a cohort of human colorectal cancer patients, we found that tumor-infiltrating CD8+ T lymphocytes gradually repress STING expression as a tumor grows and loss of STING expression strongly correlates with CD8+ T cell exhaustion. Together, our data demonstrates the physiological importance of controlled, rather than ubiquitous STING expression and uncovers STING expression dynamics as an important new dimension of STING pathobiology. Citation Format: Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan. Dynamic STING repression orchestrates immune cell functionality across development and maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB209.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872964","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":"Abstract LB205: Myeloid cell targeted immune modulation in solid tumor and brain tumor patients: An analysis of nct05388487 phase 1 study data","authors":"Anjie Zheng, Ruofan Huang, Yuhong Xu, Jinsong Wu","doi":"10.1158/1538-7445.am2025-lb205","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb205","url":null,"abstract":"Background: T-cell-based immunotherapy has proven effective in many solid tumors, but its wider application remains challenging, especially for gliomas. MDSCs in the peripheral blood mononuclear cells (PBMCs) and tumor microenvironment were considered to be a major factor affecting the response rate of ICB. All-trans retinoic acid (ATRA) is a natural vitamin A metabolite, and evidence suggests that ATRA can induce MDSC maturation and differentiation for the benefit of cancer treatment. The NCT05388487 trial was designed to test the safety and preliminary efficacy of ATRA liposomes (HF1K16) in last-stage solid tumor patients. This study aimed to analyze the dynamic change of immune cells and tumor microenvironment during the treatment. Methods: HF1K16 was administered in 21-day cycles (every other day on days 1-14) until the end of treatment (EOT). PBMC samples were collected during the treatment. Flow cytometry was used to evaluate changes in myeloid cell phenotypes and T-cell composition. In certain cases, surgically removed tumor tissue from patients who had been treated multiple cycles were obtained and analyzed. Results: All the patients with non-glioma solid tumors had received extensive prior treatment including surgery, target therapy, chemotherapy, and cancer metastasis. 6 out of the 10 patients had prior ICB. The levels of MDSCs were in general much higher than those in healthy donors. When analyzed at C1D1, C1D7, C1D13, and C1D21 during the 1st cycle of treatment, a decline of MDSC level was observed in 9 out of the 10 patients. Concurrently, an increase of NK cells was observed in 7 out of 10 patients. In particular, the HF1K16 single-agent treatment had significant efficacy in refractory and recurrent glioma patients. Notably, one patient had a complete response (CR) after 10 cycles of dosing. This patient received continuous treatment for 24 months and has been cancer-free for exceeding 20 months. Out of the 8 patients who were first diagnosed with grade 2∼3 glioma, the median progression-free survival (PFS) is 90d. The mOS has not been reached but is estimated to be longer than 272d. Especially for patients with T naïve cells≥20% in CD3 T cells before treatment, the PFSTn≥20% is 202.5d (n=4), with HR=0.13. Cl95%= 0.018 to 0.858. For the treatment of rrGBM patients, The mOS is 317d. The median PFS for them is 64d. Most importantly, we collected the surgical removed tumor tissue from one patient who achieved SD for 5 cycles of treatment but progressed. For the treatment of rrGBM patients, The median mOS is 317d. The median PFS for them is 64d. Most importantly, we collected the surgical removed tumor tissue from one patient who achieved SD for 5 cycles of treatment but progressed. A notable finding was the increased presence of CD8+CTL cells and HLA-DR-expressing cells as compared to tissue samples obtained during the initial surgical. Notably, this patient has maintained a tumor-free status post-surgery, with no intervention required","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"7 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872967","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":"Abstract LB156: Early mutation-mediated detection of cancers via biomarker production","authors":"Shengyue Piao, Miller Harris, Kevin McHugh","doi":"10.1158/1538-7445.am2025-lb156","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb156","url":null,"abstract":"Background: Cancer remains one of the leading causes of mortality worldwide, with early detection pivotal to improving patient outcomes. Current diagnostic methods often lack the sensitivity and specificity to identify cancers at their earliest stages, especially for KRAS-driven cancers such as pancreatic cancer and non-small cell lung cancer (NSCLC). This challenge is further exacerbated for high-risk populations, where invasive biopsies, imaging, or endogenous biomarkers fail to meet clinical needs. There is a critical need for non-invasive, reliable, and continuous cancer detection methods capable of diagnosing tumors at nascent stages. To address this, we developed a mutation-mediated synthetic biomarker-based blood test specifically targeting early-stage cancers with KRAS G12 mutations. This study evaluates its performance in detecting KRAS-driven cancers using synthetic biomarkers and controls. Methods: A CRISPR-based gene editing system was designed to insert synthetic biomarker genes, such as Gaussia luciferase (GLuc), into cancer cells harboring KRAS G12 mutations. Using Gibson assembly, we constructed a donor plasmid carrying the GLuc gene alongside a plasmid encoding Cas9 VQR and sgRNA targeting the KRAS G12V locus. These plasmids were co-transfected into NCI-H727 human lung tumor cells. Single-cell sorting yielded 29 clonal lines with stable GLuc expression. Sequencing confirmed precise knock-in at the KRAS G12V target in 21 lines, with qPCR verifying exclusive insertion. GLuc secretion was measured via luciferase assays, and limits of detection (LOD) were assessed in vitro. To test biomarker detection in vivo, GLuc-expressing tumor cells were inoculated into SCID/NOD mice at varying numbers. Serum GLuc levels were measured using luciferase assays at defined time points. Results: In vitro, the LOD for GLuc-expressing cancer cells was 5,775 cells/mL. In vivo, SCID/NOD mice injected with GLuc-expressing tumor cells showed time-dependent increases in serum luminescence. Two weeks post-inoculation with 106 cells, serum luminescence in the experimental group was 8.24-fold higher than controls (8.24 ± 0.32), with a tumor lesion size of 29.86 ± 7.26 mm3. Conclusion: This mutation-mediated synthetic biomarker platform detected tumor lesions as small as millimeter-scale in vivo with high sensitivity and specificity after a single injection. Its non-invasive, scalable design offers the potential to transform early detection and monitoring of KRAS-driven cancers, addressing critical unmet needs for high-risk populations. Citation Format: Shengyue Piao, Miller Harris, Kevin McHugh. Early mutation-mediated detection of cancers via biomarker production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB156.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876103","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}