Cancer research最新文献

{"title":"Abstract LB066: Cytokine and chemokine screening reveals altered NK-DC-T cell crosstalk in the aged tumor microenvironment","authors":"Alex C. Chen, Marijana Rucevic, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Simon Forsberg, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Nir Hacohen, Debattama R. Sen","doi":"10.1158/1538-7445.am2025-lb066","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb066","url":null,"abstract":"The etiology and effects of age-related immune dysfunction in cancer remain incompletely understood. We previously demonstrated that the limited priming and function of CD8+ T cells in aged tumor-bearing mice are linked to altered NK-DC-T cell crosstalk within the aged tumor microenvironment (TME). Given that cytokines and chemokines play critical roles in NK-DC-T cell crosstalk, we further investigated which cytokines and chemokines might drive these defects in the aged TME. Tumor-bearing mice aged between 10 and 68 weeks were used to collect serum and tumor interstitial fluid samples, as well as tumor interstitial fluid samples from mice receiving CD40 agonist therapy. The collected samples were processed and analyzed using the Olink Target 48 mouse cytokine and chemokine panel. Consistent with the observed limited CD8+ T cell function, age-related changes in key cytokines and chemokines were identified in tumor interstitial fluid. We specifically observed a decline in effector cytokines, such as IL-2, IFN-γ, and TNF, that correlates with aging. Moreover, chemokines like CXCL9, essential for recruiting T cells, along with CCL4 and CCL2, important for myeloid recruitment, also showed a significant progressive decrease as age increased within the mouse TME. However, the age-related decline of these chemokines was not observed in the serum samples, suggesting no systematic decrease in peripheral circulation and further confirming that the age-related defects seen in the TME were likely tumor-driven. Notably, we found elevated levels of IL-2, IFN-γ, TNF, CXCL9, CCL4, and CCL2 in aged mice after treatment with a CD40 agonist. Additionally, these aged mice exhibited improved tumor control after treatment, indicating the crucial roles of these cytokines and chemokines in the aged TME. While CD40 agonist therapy has seen limited clinical success, our presented data demonstrate a novel approach that considers aging's effect on anti-tumor immunity. Additionally, our findings suggest a promising strategy for utilizing cytokines and chemokines in cancer treatment for older patients. Citation Format: Alex C. Chen, Marijana Rucevic, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Simon Forsberg, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Nir Hacohen, Debattama R. Sen. Cytokine and chemokine screening reveals altered NK-DC-T cell crosstalk in the aged tumor microenvironment [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 LB066.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"78 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876038","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 LB058: Investigating the role of SIM2 and SIRT3 in mitochondrial dynamics and homeostasis in ER+ breast cancer","authors":"Hannah N. Carter, Steven W. Wall, Garhett L. Wyatt, Lilia Sanchez, Weston W. Porter","doi":"10.1158/1538-7445.am2025-lb058","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb058","url":null,"abstract":"Mitochondrial dynamics are essential for cellular energy regulation and homeostasis, processes crucial for normal development and breast cancer progression. Maintaining mitochondrial integrity requires a balance between fusion and fission events, which influence cellular metabolism and oxidative stress responses. Recent studies have identified Singleminded-2s (SIM2s), a tumor suppressor in mammary epithelial cells, as a regulator of mitochondrial morphology and dynamics. Our data suggest that the loss of SIM2s in estrogen receptor-positive (ER+) breast cancer cells leads to altered mitochondrial morphology, with decreased mitochondrial fusion (OPA1) and increased fission (DRP1). Additionally, SIM2 loss correlates with increased acetylation of Superoxide Dismutase 2 (SOD2) at lysine residues 68 and 122, indicating reduced SIRT3 activity. These findings suggest an interaction between SIM2 and SIRT3 in regulating mitochondrial dynamics and homeostasis. Furthermore, pharmacological inhibition of SIRT3 in SIM2-deficient cells induces synthetic lethality, highlighting SIRT3 as a potential therapeutic target for metastatic breast cancer. These results emphasize a potential relationship between SIM2 and SIRT3 and their crucial roles in mitochondrial integrity and homeostasis in ER+ breast cancer. Citation Format: Hannah N. Carter, Steven W. Wall, Garhett L. Wyatt, Lilia Sanchez, Weston W. Porter. Investigating the role of SIM2 and SIRT3 in mitochondrial dynamics and homeostasis in ER+ breast 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 LB058.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875711","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 CT263: Efficacy and multiomic analysis of Niraparib in relapsed mesothelioma: NERO a randomized phase II trial","authors":"Dean Fennell, Kayleigh Hill, Zina Eminton, Daniel Griffiths, Abigail Morgan-Fox, Charlotte Poile, Aleksandra Bzura, Jake Spicer, Min Zhang, Joanna Dzialo, Daniel Faulkner, Jinli Luo, Apostolos Nakas, Kudzayi Kutywayo, Geoff Saunders, Theodora Nearchou, Andrea Corkhill, Katie Mansell, Zoë Konn, Oli Dewane, Mavis Nye, Kathryn Murphy, Julia Tabreham, Liz Darlison, Judith Cave, Sarah Danson, Liz Toy, Pooja Bhatnagar, Nicola Steele, Paul Shaw, Paul Taylor, Peter Szlosarek, Dionysis Papadatos-Pastos, Michael Lind, Harman Saman, Shagufta Mirza, Lynn Campbell, Peter-Wells Jordan, Amrita Bajaj, Sean Duloo, Maurice Dungey, Gareth Griffiths","doi":"10.1158/1538-7445.am2025-ct263","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct263","url":null,"abstract":"Background: Mesothelioma is a lethal cancer caused by asbestos. Effective therapy in the relapsed setting, following standard of care treatments is lacking [1]. Inhibition of Poly-ADP ribose polymerase (PARPi) mediates synthetic lethality in cancers harboring DNA damage response gene (DDR) inactivation, notably BRCA1/2 resulting in homologous recombination deficiency (HRD), and transcription replication conflicts (TRCs). In relapsed mesothelioma PARPi was clinically active in the MIST1 phase II trial [2], warranting interrogation of underlying mechanisms and further randomized evaluation. Methods: NERO, NCT05455424 a multi-center, two-arm, open-label UK 2:1 randomized phase II trial compared active symptom control (ASC) with or without Niraparib (Nir). Eligibility: Relapsed mesothelioma with prior platinum doublet therapy (any line). The ASC+Nir arm received 200 or 300 mg daily in a 3-weekly cycle up to 24 weeks, with the option to continue if there was ongoing disease control. Primary endpoint: progression-free survival (PFS), one-sided α=0.1 with 80% power. In parallel, whole exome and transcriptomic analyses of the NERO, MIST1 cohort [2], primary patient derived explants (PDEs) and cell lines were conducted to understand correlates of PARPi sensitivity. Results: Between 11th July 2022 and 21st December 2023, 88 patients were enrolled. Characteristics: male: n = 62 (70.5%), median age: 72 (range 33-84) years, disease site: 77 (87.5%) had pleural mesothelioma. 83 (94.3%) PFS events were observed. Median (95% CI) PFS was 4.14 months (m) (2.76, 4.73) in the ASC + Nir arm versus 2.76m (1.41, 3.02) corresponding to an unadjusted PFS HR of 0.73 (one sided 90% CI 0.99, p-value 0.091). 6m PFS rate (95% CI) was 24.6% (14.4%, 36.2%) for ASC+Nir versus 13.8% (4.4%, 28.6%) for ASC. Most common Adverse Events (>20%) in the ASC+Nir arm: Fatigue (52.6%), Constipation (45.6%) & Nausea (43.9%). Interferon (IFN) α transcription (9p21.3) but not HRD or DDR gene burden was correlated with sensitivity to PARPi in MIST1, two PDE cohorts (Niraparib and Rucaparib), and in mesothelioma cell lines treated with multiple PARPi’s. Pattern recognition receptor signaling (Toll and RIG-I) positively correlated with IFNα, which in turn was associated with R-loops, a surrogate of TRCs across all models. MTAP/IFNA deletion at 9p21.3 inhibited PARPi activity in patients. Conclusions: NERO met its primary endpoint of longer PFS in patients with relapsed mesothelioma. PARPi response is predicted by IFNα transcription and 9p21.3 deletion status. Multiomic analysis of NERO is ongoing and will be presented. NERO is funded by Asthma and Lung UK (MCTA20F2) with drug supplied by GSK. [1] Janes, Alrifai, Fennell N Engl J Med 2021 (385) p1207-1218 [2] Fennell et al, Lancet Respir Med 2021 (9) p593-600 Citation Format: Dean Fennell, Kayleigh Hill, Zina Eminton, Daniel Griffiths, Abigail Morgan-Fox, Charlotte Poile, Aleksandra Bzura, Jake Spicer, Min Zhang, Joanna Dzialo, Daniel F","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875934","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 LB069: An agrin mechanotransduction for EGFR-addicted cancers","authors":"Sayan Chakraborty","doi":"10.1158/1538-7445.am2025-lb069","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb069","url":null,"abstract":"Epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), where it senses extracellular matrix (ECM) rigidity. Despite our understanding of the increasing role of tissue rigidity on various hallmarks of cancer development, how the ECM-driven mechanotransductive network impacts EGFR-dependent tumorigenesis remains uncharacterized. Here we show that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. The agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin-EGFR rigidity response to YAP-TEAD mechanosensing is essential for tumorigenesis. Together, we propose that the combined inhibition of EGFR-YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers. Citation Format: Sayan Chakraborty. An agrin mechanotransduction for EGFR-addicted cancers [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 LB069.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875935","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 LB386: Aberrant DNA polymerase beta expression is associated with dysregulated tumor immune microenvironment and its prognostic value in gastric cancer","authors":"Aashirwad Shahi","doi":"10.1158/1538-7445.am2025-lb386","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb386","url":null,"abstract":"Background: Gastric cancer (GC) is a leading cause of cancer-related deaths globally. Emerging evidence implicates aberrant DNA polymerase beta (POLB) expression in genomic instability and tumorigenesis. Previously, we demonstrated that the human gastric cancer-associated variant of POLB (Leu22Pro or L22P) lacks dRP lyase function in vitro and induces replication associated genomic instability and cellular transformation. In addition , in vivo mouse model experiment has shown that L22P mutation of POLB , leads to inefficient BER and exacerbate genomic instability and carcinogenesis . Methods: We conducted an in-silico analysis of GC datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to assess POLB expression levels and their association with the tumor immune microenvironment (TIME). Survival analyses were performed using Kaplan-Meier estimates, and the TIMER algorithm was employed to evaluate immune cell infiltration. In parallel, we utilized a dRP lyase-deficient POLB variant (Leu22Pro, L22P) in vivo model to investigate the impact of dRP lyase deficient POLB on genomic stability and inflammatory signaling. Also, Mitotic dysfunction and cytosolic DNA-mediated inflammatory responses were assessed, with and without poly(ADP-ribose) polymerase 1 (PARP1) inhibition. Results: Our analysis revealed that POLB is overexpressed in approximately 32% of GC cases, significantly correlating with the intestinal subtype of GC. POLB overexpression was associated with reduced expression of innate immune signaling genes and lower infiltration of immune cells, indicating a suppressed immune microenvironment. Conversely, tumors with high POLB expression exhibited increased mutation frequency and microsatellite instability (MSI). Notably, patients with POLB-overexpressing tumors and high immune score demonstrated improved overall survival. ROC analysis suggested that POLB overexpression holds potential as a prognostic marker for GC. In in vivo model, the L22P POLB variant increased mitotic dysfunction-associated genomic instability, leading to a cytosolic DNA-mediated inflammatory response. PARP1 inhibition exacerbated chromosomal instability and enhanced the inflammatory response in these cells. Conclusions: Aberrant POLB expression in GC is associated with a dysregulated TIME and may serve as a prognostic indicator. Defective POLB function contributes to genomic instability and activates cytosolic DNA-mediated inflammatory signaling. These findings suggest that deregulated POLB in tumor likely provide a potential opportunity to patient stratification for better immune-based therapies in GC. Citation Format: Aashirwad Shahi. Aberrant DNA polymerase beta expression is associated with dysregulated tumor immune microenvironment and its prognostic value in gastric 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; Chica","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":"143875982","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 SY27-01: Mitochondria function in normal and cancer cells","authors":"Navdeep S. Chandel","doi":"10.1158/1538-7445.am2025-sy27-01","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-sy27-01","url":null,"abstract":"Mitochondrial respiratory chain (RC) activity plays a crucial role in the proliferation of various cell types in vivo within the tumor microenvironment, especially in cancer cells, CD4+ and CD8+ T cells, and endothelial cells. This activity is vital for the production of ATP, which is essential for energy metabolism, and for the biosynthesis of key macromolecules. The mitochondrial respiratory chain is integral to the oxidative tricarboxylic acid (TCA) cycle, which generates intermediates that are used in anabolic pathways to synthesize lipids, proteins, and nucleotides—critical components for cell growth and division. However, the role of mitochondrial respiration is more complex in certain proliferating cells within tumor microenvironment, such as regulatory T cells (Tregs) and stem cells. In these cells, mitochondria are not as critical for the general process of cell proliferation but instead play a pivotal role in determining cell fate and function. Mitochondria influence these processes through various signaling mechanisms that affect how these cells differentiate and carry out their specialized functions. I will discuss how the mitochondrial respiratory chain functions as an anabolic engine that drives the proliferation of cancer cells, CD4+ and CD8+ T cells, and endothelial cells. I will also discuss how mitochondria act as central hubs that integrate metabolic signals to regulate the fate and function of Tregs and stem cells in vivo, highlighting the distinct yet interconnected roles mitochondria play in different cell types. Citation Format: Navdeep S. Chandel. Mitochondria function in normal and cancer cells [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 SY27-01.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876039","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 LB031: A modular framework for cell and gene therapy assessment in preclinical mouse models","authors":"Emilie Bayon, Pierre Wallet, Joséphine Zangari, Iris Nkamba, Sébastien Tabruyn, Dan Georgess","doi":"10.1158/1538-7445.am2025-lb031","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb031","url":null,"abstract":"The development of cell and gene therapies (CGTs) and biologics relies on designing custom preclinical strategies that provide high-confidence data using predictive animal models. To help investigators navigate navigating the increasingly complex and customizable preclinical landscape, we present a modular design framework for the preclinical evaluation of oncology therapies using traditional and next-generation mouse models. This guide illustrates how investigational requirements specific to each therapeutic candidate influence the selection of model features, including tumor characteristics (such as indication, markers, and engraftment site), immune system status (immunodeficient, immunocompetent, humanized), and compatible readouts. Through a series of proof-of-concept studies, we demonstrate optimal strategies for evaluating persistence, biodistribution, efficacy, safety, and in vivo mechanisms of action of various CGTs such as extracellular vesicles, CAR-NKs, TCR-Ts, and CAR-Ts in autologous and allogeneic settings. The dissemination of such expertise-based frameworks coupled with the increased availability and affordability of custom and/or humanized immune system mice, is poised to mitigate drug candidate attrition in oncology clinical trials. Modularity of the disease feature in this framework, e.g. swapping the tumor for infectious or inflammatory agent, further expands it impact to immuno-inflammatory and infectious disease areas. Citation Format: Emilie Bayon, Pierre Wallet, Joséphine Zangari, Iris Nkamba, Sébastien Tabruyn, Dan Georgess. A modular framework for cell and gene therapy assessment in preclinical mouse models [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 LB031.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876040","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 LB329: Pathway-based analysis of genomic alterations in infant ALL","authors":"Byunggil Yoo, Erin Guest, Midhat S. Farooqi","doi":"10.1158/1538-7445.am2025-lb329","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb329","url":null,"abstract":"Introduction: Infant acute lymphoblastic leukemia (ALL) is an aggressive subtype, characterized by early onset and poor clinical outcomes, with about 70% of cases involving KMT2A gene rearrangements (KMT2A-r). This study investigates whether pathway-specific genomic alterations influence prognosis by analyzing sequence variants in infant ALL patients from the Children’s Oncology Group trial AALL0631. Methods: We conducted WGS and WES on DNA extracted from peripheral blood or bone marrow from 48 infant ALL patients across three cohorts at diagnosis and at remission. The three infant ALL cohorts included: Cohort A (infants with KMT2A-r ALL who experienced relapse, n=21), Cohort B (infants with KMT2A-r ALL who remain in remission to date, n=12), and Cohort C (infants with KMT2A germline ALL who remain in remission to date, n=15). Sequencing was conducted using an Illumina HiSeq 4000 or 2500 platform, achieving a minimum coverage depth of 90 Gb for WGS and 15 Gb for WES. Alignment and germline variant calling were performed using BWA and GATK for WGS, and the Illumina Dragen for WES. Somatic variant calling utilized GATK4-Mutect. Genomic variants were classified based on the 2015 ACMG/AMP guidelines. Variants categorized as benign, likely benign, or non-exonic variants of unknown significance were excluded. Further filtering removed germline variants with a population allele frequency exceeding 1% and somatic variants with a frequency above 0.1%. The analysis focused on variants within 22 KEGG pathways, selected for their relevance to cancer mechanisms and DNA repair processes. Variant counts in these pathways were subsequently analyzed to identify potential contributions to disease pathogenesis. Results: Analysis of somatic variants revealed significant differences between Cohort A and Cohort B. Somatic mutations in the non-homologous end-joining (NHEJ) pathway were more frequent in Cohort A (Kruskal-Wallis p = 0.043), while somatic mutations in the Wnt signaling pathway were more common in Cohort B (p = 0.048). For germline variants, mutations in the Notch signaling pathway were more frequently observed in KMT2A-r infant ALL patients. Conclusion: Pathway-specific genomic alterations may impact outcomes in infant ALL. Relapsed KMT2A-r ALL patients showed an enrichment of somatic mutations in the NHEJ pathway, while somatic mutations in the Wnt pathway were more common in patients who remained in remission. Additionally, germline variants in the Notch pathway were prevalent in KMT2A-r cases, suggesting a potential predisposition. These findings offer insights into the molecular mechanisms of infant ALL and highlight potential therapeutic targets. Citation Format: Byunggil Yoo, Erin Guest, Midhat S. Farooqi. Pathway-based analysis of genomic alterations in infant ALL [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. Philad","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876110","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 LB213: Heterogeneous expression of IL13Ra2 in melanoma patient-derived xenograft models and targeting with bispecific T cell engager for melanoma therapy","authors":"Shushu Zhao, Yeqing Chen, Pratik S. Bhojnagarwala, Cory Livingston, Joshua Jose, Yangcheng Gao, Daniel Park, Meenhard Herlyn, David B. Weiner","doi":"10.1158/1538-7445.am2025-lb213","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb213","url":null,"abstract":"Melanoma is a highly aggressive skin cancer, especially diagnosed in advanced stages. While current treatments such as targeted therapies and immunotherapies have made promising progress, challenges like drug resistance and limited effectiveness in some patients persist. Therefore, ongoing development of novel therapies, particularly for late-stage melanoma, is crucial. In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13Rα2) in melanoma patient-derived xenograft (PDX) models. Our findings revealed heterogeneous expression of IL13Rα2, particularly in samples from advanced stages of melanoma. Then we investigated IL13Rα2 as a potential target for melanoma treatment by employing an IL13Rα2-CD3 bispecific T cell engager (BTE). We tested the effect of IL13Rα2-CD3 BTE to T cells activity by flow cytometry. The IL13Rα2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T-cells. We studied the potency of IL13Rα2-CD3 BTE in tumor killing assay in vitro. We also observed the ability of IL13Rα2-CD3 BTE to direct T cells to kill multiple melanoma patient-derived cell lines through xCELLigence assay in vitro, including those with various mutations associated with late-stage metastatic melanoma. For in vivo studies, we administered DNA expression constructs encoding IL13Rα2-CD3 BTE (IL13Rα2-CD3 dBTE) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL13Rα2-CD3 dBTE versus control and reconstituted with human PBMCs or T cells. Tumor development was monitored, and T cells infiltration in tumor was analyzed through flow cytometry. IL13Rα2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor microenvironment. These promising findings underscore the potential of targeting IL13Rα2 as a relevant target for the development of biologics including dBTE aimed at treating specific subsets of melanoma. Citation Format: Shushu Zhao, Yeqing Chen, Pratik S. Bhojnagarwala, Cory Livingston, Joshua Jose, Yangcheng Gao, Daniel Park, Meenhard Herlyn, David B. Weiner. Heterogeneous expression of IL13Ra2 in melanoma patient-derived xenograft models and targeting with bispecific T cell engager for melanoma therapy [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 LB213.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872943","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 LB308: Rewiring of methylation during embryogenesis can seed cancer decades later","authors":"Lori D. Kregar, Nicholas Williams, Joe Lee, Michael Spencer-Chapman, Oleksii Nikolaienko, Emily Mitchell, Liv B. Gansmo, Per E. Lønning, Elisa Laurenti, Lucy Yates, Stian Knappskog, Jyoti Nangalia, Peter Campbell","doi":"10.1158/1538-7445.am2025-lb308","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb308","url":null,"abstract":"As we age, cells accumulate somatic mutations, undergo epigenetic alterations, and experience telomere shortening. In older individuals, normal tissues are often overtaken by expanding clones of cells that have acquired mutations promoting proliferation. Whether epigenetic changes can also provide selective advantage and induce clonal expansion in ageing is less clear. Here, we sequenced 719 whole genomes and methylomes of single-cell colonies derived from HSCs of three healthy individuals and three breast cancer patients. Using somatic mutations, we built lineage trees of the HSCs for each individual. To establish whether loss or gain of methylation was heritable, we developed a method that accurately infers, for each CpG site, its zygotic methylation state as well as the number and timing of ancestral methylation changes that explain the observed methylation state of each somatic cell. We analysed ∼24 million CpG sites per individual and find that methylation states are, in general, stably heritable over decades of life. We find that during embryogenesis, when the embryo comprises a few thousand cells, developmental cells lay down unique methylation haplotypes, spanning hundreds of base pairs in size, that are stably inherited by descendants. This phase of rewiring the methylome has striking properties: (1) thousands of regions genome-wide show heterogeneity of methylation profiles laid down during this phase; (2) these regions are often conserved across different individuals; (3) it precedes gastrulation, so that the same changes are seen in all germ layers; (4) the process happens quickly, completing within a few generations of cell division; (5) it coincides with establishment of inactive X chromosome methylation in females; and (6) the methylation affects many key regulatory regions of the genome. To assess whether embryonic methylation rewiring can contribute to cancer development, we studied women with breast cancer who had BRCA1 promoter methylation. The tumour samples did not have germline or somatic mutation of BRCA1 (or other DNA repair genes), but had BRCA1 methylation along with the typical mutational signatures of homologous recombination deficiency. Intriguingly, we found that the same methylation change was present heterozygously in a subset of HSCs; that these HSCs all derived from one embryonic cell that pre-dated gastrulation; and that the somatic mutations defining this lineage of HSCs were also present clonally in the breast cancer. Thus, aberrant methylation of the BRCA1 promoter in embryogenesis was transmitted across germ layers, in blood and breast epithelium, and (with loss-of-heterozygosity) drove homologous recombination deficiency in a breast clone that transformed to cancer 4-6 decades later. By comparing normal healthy individuals of different ages with cancer patients, we have been able to unravel the process of normal ageing from cancer development at an unprecedented resolution. Citation Format: Lori D. Kregar, ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"25 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875933","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}