Cancer research最新文献

{"title":"Abstract A034: Ketogenic diet prevents obesity-associated pancreatic cancer independent of weight loss and induces pancreatic metabolic reprogramming","authors":"Ericka Velez-Bonet, Kristyn Gumpper-Fedus, Kaylin Chasser, Zachary Hurst, Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Alexus Liette, Grace Vulic, Fouad Choueiry, Huan Zhang, Jiangjiang Zhu, Sue E. Knoblaugh, Stacey Culp, Jeff S. Volek, Zobeida Cruz-Monserrate","doi":"10.1158/1538-7445.pancreatic25-a034","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a034","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity is a risk factor for several cancers including PDAC due to metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese but not obese PDAC using genetically engineered mouse models (GEMMs). Purpose: To examine ketone treatment on PDAC metabolism and KD effects on tumor development in obesity-associated and non-obese PDAC. We examined tumor-specific metabolomic differences associated with dietary modifications after obesity-associated PDAC. Methods: PDAC cells were treated with sodium 3-hydroxybutyrate or lithium acetoacetate, followed by untargeted metabolomic analysis. PDAC GEMMs were subjected to either diet-induced obesity (DIO) using a 45% high-fat diet (HFD), as it mimics a more physiologically relevant DIO in humans, a DIO higher in fat content (60% HFD) or a low-fat (non-obese) diet for 15 weeks. Mice were then randomized to remain on their respective diets or switched to a KD or a KD control (KDC) diet for a 6-week intervention. Body composition was measured using an EchoMRI. Body weight, glucose tolerance, and ketone levels were measured at different timepoints. Tumors metabolomics were analyzed by Liquid Chromatography Mass Spectrometry (LC-MS). Results: We show that ketone treatments altered pyrimidine metabolism in PDAC cells. Moreover, in an obese PDAC GEMM, KD prevented tumor progression independent of weight loss but promoted PDAC in a non-obese PDAC GEMM. The KD-specific delay of obesity-associated PDAC was associated with pancreatic metabolic shifts in pyrimidine, cysteine and methionine, and arginine and proline pathways. Conclusions: These findings suggest potential benefits of a KD in preventing obesity-associated PDAC but highlights some risks in non-obese settings. The associated tumor-specific metabolic alterations point to nutrient pathways that may contribute to KD mediated tumor suppression in obesity and represent targets for future intervention. Citation Format: Ericka Velez-Bonet, Kristyn Gumpper-Fedus, Kaylin Chasser, Zachary Hurst, Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Alexus Liette, Grace Vulic, Fouad Choueiry, Huan Zhang, Jiangjiang Zhu, Sue E. Knoblaugh, Stacey Culp, Jeff S. Volek, Zobeida Cruz-Monserrate. Ketogenic diet prevents obesity-associated pancreatic cancer independent of weight loss and induces pancreatic metabolic reprogramming [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A034.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"18 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183105","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 B011: Functional interrogation of the pancreatic intratumoral microbial niche reveals tumor modulation and reshaping of the microenvironment","authors":"Vidhi Chandra, Le Li, Seyda Baydogan, Haoyue Liu, Javier Gomez, Steven B. Maron, Daniel Carvajal-Hausdorf, Erick M. Riquelme, Mark W. Hurd, Anirban Maitra, Luis Diaz, Ismet Sahin, Jared Burks, Michael P. Kim, Florencia McAllister","doi":"10.1158/1538-7445.pancreatic25-b011","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b011","url":null,"abstract":"Tumor resident microbes are a well-recognized component of the tumor microenvironment. Microbial subcellular location within different tumor types along with their functionality remains to be determined. Bulk microbial profiling techniques, however, lack subcellular and spatial transcriptomic resolution. To address these limitations, we developed advanced quantitative fluorescent imaging methodologies that allowed for visualization of microbial cellular compartmentalization across different tumor types. Furthermore, we performed spatial microbial transcriptomics at the regional and single cell levels to interrogate microbial regulation of signaling within pancreatic cancer cells. To confirm presence of viable microbes within tumors, we performed multiplexed culturomics of patient tissue samples followed by Whole Genomic Sequencing (WGS) analysis. We used in vitro co-culture assays together with in vivo animal experiments for functional biological validation. Overall, our results identified several pathways under microbial regulation within cancer cells that can drive immune evasion through impaired antigen presentation. In summary, using multiple complimentary novel methodologies we characterize the microbial niche of tumors (MiNT) that uncovers microbial regulation of host cells signaling and reshaping of the surrounding tumor microenvironment. Citation Format: Vidhi Chandra, Le Li, Seyda Baydogan, Haoyue Liu, Javier Gomez, Steven B. Maron, Daniel Carvajal-Hausdorf, Erick M. Riquelme, Mark W. Hurd, Anirban Maitra, Luis Diaz, Ismet Sahin, Jared Burks, Michael P. Kim, Florencia McAllister. Functional interrogation of the pancreatic intratumoral microbial niche reveals tumor modulation and reshaping of the microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr B011.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183108","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 A125: Tumor cell plasticity, stromal rewiring, and clonal T cell expansion define response and resistance to combined PARP and PD-1 blockade (POLAR) in pancreatic cancer","authors":"Marc Hilmi, Jin Park, Wilson Mckerrow, Shigeaki Umeda, Catherine O'Connor, Yuval Elhanati, Elias-Ramzey Karnoub, Roshan Sharma, Kevin Soares, Zeynep Tarcan, Nuray Tezcan, Olca Basturk, Nicolas Lecomte, Joshua Schoenfeld, Nadeem Riaz, Vinod Balachandran, Dana Pe'er, Benjamin Greenbaum, Eileen M O’Reilly, Christine Iacobuzio-Donahue, Wungki Park","doi":"10.1158/1538-7445.pancreatic25-a125","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a125","url":null,"abstract":"Background: Combined anti-PD-1 (pembrolizumab) and PARP (olaparib) inhibition shows promising clinical activity in homologous recombination deficient (HRD) pancreatic cancer (PC), yet the drivers of resistance remain unexplored. Methods: Tumor single-cell RNA and TCR sequencing were performed on 66 longitudinal fresh tumor samples from 44 participants (pts) with metastatic PC treated with pembrolizumab and olaparib in the POLAR trial (NCT04666740) (31 baseline, 22 on-treatment at 2 months and 13 post-progression tumor biopsies). Bulk TCR sequencing was conducted in 32 pts on peripheral blood samples collected at 0, 6, 18, and 30 weeks. Data were integrated with IMPACT-HRD profiling, neoantigen prediction and histopathological analysis. Pts were enrolled across three cohorts: cohort A with canonical HRD mutations (BRCA1/2, PALB2); cohort B with non-core HRD gene alterations; and cohort C with homologous recombination proficient (HRP) tumors. This design enabled dissection of molecular mechanisms across HRD and non-HRD contexts. Results: A total of 263,780 tumor and stromal cells were successfully profiled. Primary resistant tumors were enriched with basal-like phenotype and myofibroblastic CAFs (myCAFs), regardless of HRD status. HRP tumors showed increased activation of RAS/MAPK and iron metabolism pathways. Histopathological analysis performed before treatment showed reduced CD8+ T cell infiltration in de novo resistant tumors, along with a dense stromal architecture indicative of fibroblast-mediated immune exclusion. Rapid progression (< 3.5 months) was linked to immune evasion characterized by MHC-I downregulation and adipose-like CAF enrichment. In contrast, responders (> 6 months PFS) demonstrated early activation of cytotoxic T cells, along with helper T cells showing upregulated MHC-I expression at 2 months. Secondary resistant samples from responders exhibited a phenotypic shift in tumor cells from classical to proliferative basal-like, enrichment of inflammatory CAFs (iCAFs), CD8+T cells senescence and polarization of the myeloid compartment toward foam-like M2-macrophages and toward N2 neutrophils. Peripheral blood TCRseq identified clonotypes that were expanded in the blood and infiltrated the tumor in a subset of 6 HRD patients, all long-term survivors (>18 months), including 4 with ongoing responses > 30 months. In tumor tissue, 95% of these clonotypes corresponded to CD8+ T cells exhibiting strong cytotoxic activity (PRF1hiGMZBhiGNLYhi) and increased TCR expression. Conclusions: Resistance to combined PARP and PD-1 blockade in PC arises from both tumor-intrinsic features and microenvironmental barriers, including CAF-mediated immune exclusion and myeloid polarization, and is agnostic to HRD status. Durable responses are associated with both systemic expansion and effective tumor infiltration of cytotoxic T cells. These findings support combinatorial strategies targeting stroma and tumor plasticity and hig","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"18 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183199","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 B025: Star Copolymer-Mediated Delivery of Anti-miRNA Therapeutics for Pancreatic Cancer","authors":"Sofia Miron-Barroso, Eleni Chatzilakou, Shriya Varghese, Shaobai Wang, Paula Cunnea, Eirini Velliou, Alexandra E. Porter, Theoni K. Georgiou, Jonathan Krell","doi":"10.1158/1538-7445.pancreatic25-b025","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b025","url":null,"abstract":"Introduction: Pancreatic cancer has the lowest survival rate among all major cancer types, with a five-year survival rate of only 10%. Current therapies elicit only a limited response highlighting the urgent need for novel treatment strategies. RNA-based therapeutics have emerged as a promising approach for cancer treatment; however, their clinical translation is hindered by the lack of safe and effective delivery systems. Polymeric carriers are particularly attractive for RNA delivery due to their versatility, multifunctionality, and cost-effectiveness. Poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) is a cationic monomer that facilitates RNA complexation, endosomal escape, and cellular internalization. In addition, incorporating oligo(ethylene glycol) methyl ether methacrylate (OEGMA) has been shown to reduce toxicity and improve circulation time thereby enhancing in vivo performance. Materials and Methods: DMAEMA-OEGMA star copolymers with varying architectures were synthesized using group transfer polymerization. Their physicochemical properties, including hydrodynamic size, zeta potential, composition, dispersity, molar mass, pKa, and cloud point, were characterized. Polyplexes (RNA–polymer complexes) were developed by optimizing nitrogen-to-phosphate (N/P) ratios. Polyplex stability in the presence serum components was evaluated via agarose gel electrophoresis. Biocompatibility was evaluated in both 2D cell lines and 3D pancreatic cancer spheroids. Potential immunogenicity was assessed by measuring pro-inflammatory cytokine expression in macrophages using RT-qPCR. Transfection efficiency and was quantified using flow cytometry and benchmarked against gold standard transfection reagents. Endosomal escape and intracellular distribution were assessed by confocal microscopy. For translational relevance, performance was validated in 3D pancreatic cancer models engineered from fibronectin-functionalized polyurethane scaffolds, which can be tuned to mimic the biomechanical and biochemical characteristics of the tumor microenvironment. Results and Discussion: The star copolymers had molar masses around 100 kDa and hydrodynamic diameters ranging from 18–22 nm. Zeta potentials ranged from 17-20 mV and complete RNA complexation was achieved at N/P ratios of 5 or below. In 3D pancreatic cancer spheroids, the star polymers demonstrated excellent biocompatibility, with lower toxicity than polyethyleneimine (PEI), a polymer delivery standard. Several star copolymers exhibited superior transfection efficiency reaching up to 85%, compared to PEI (50%), Confocal imaging confirmed efficient cellular uptake and endosomal escape. The polymers also performed well in the scaffold-based 3D models, highlighting their translational potential. Conclusion: DMAEMA-OEGMA star copolymers exhibit a favorable balance of safety and transfection efficiency, outperforming conventional standards in both 2D and 3D models. These findings support their potential as a robust p","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"7 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183203","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 A048: Robust Pancreatic Cancer Liver Metastatic Model System Reveals Cancer Cell Dependent Organotropism and Site-specific Tumor Microenvironment Regulation","authors":"Christina R. Larson, Jace Baines, Ayushi Mandloi, Meet Patel, Tuan Tran, Nailah Jones, Ateeq M. Khaliq, Christopher A. Risley, Robert S. Welner, Satwik Acharyya, Julienne L. Carstens","doi":"10.1158/1538-7445.pancreatic25-a048","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a048","url":null,"abstract":"Metastatic pancreatic adenocarcinoma is the dominant clinical presentation with a grim 3% 5-year survival rate. Over 80% of metastatic disease occurs in the liver and has the poorest outcomes. Overall, there is little mechanistic understanding of what promotes liver metastatic outgrowth and organotropism. Our recent work using spatial transcriptomics on unique matched primary tumors and metastases revealed distinct cellular ecosystems, noting reduced desmoplasia, high proliferation, spatially constrained metabolism, and heightened pro-tumorigenic myeloid infiltration and T-cell dysfunction at the invasive border of liver metastases. However, moving beyond these observations requires establishing causal links between molecular drivers and metastatic competence. Causal studies are limited by current model systems, the spontaneous genetically engineered mouse models (GEMM) that form the basis of pre-clinical studies do not sufficiently model the clinical metastatic reality with robust matched pancreas and liver tumors, and are further hampered with inconsistent metastatic rates and unpredictable progression for timed analysis. Syngeneic transplants of GEMM-derived cancer lines into wild-type mice provide a rapid pre-clinical model system of liver disease. However, the liver-metastatic rates varies between cell lines, even with identical driving mutations. We suspected that the unexplored mechanisms driving these differences in metastatic outgrowth present an opportunity to understand critical biology. Here we report the development a consistent model system of matched pancreatic and liver tumors using syngeneic cell lines with high and low tropism for liver metastatic outgrowth in C57Bl/6 mice. These lines are transplanted at low cell numbers to better allow the evolution of the site-specific tumor microenvironment and provide a reliable model system to examine both cancer-cell intrinsic and site-specific microenvironmental factors dictating liver outgrowth. Our observations of comparable pancreatic growth, successful metastatic growth in other organs (peritoneum or lung), and micro-metastatic lesions in the liver at early time points, suggests the liver-tropic differences fall within the ability of these cells to successfully outgrow in the liver microenvironment, rather than in vivo proliferative or extravasation differences. Comparison of gene expression between high and low liver-tropic cell lines identified several immune regulatory genes and a general increase in lipid metabolism, consistent with our published patient data. Finally, spatial quantifications of these lesions using a novel 46-plex murine immunotyping panel on FFPE tissues show similar suppressive immune cells at the interface of the tumor and normal liver as observed in our patient data, but evolves across differing lesion size, suggestive of a spatiotemporal progression. Altogether, this model system provides a robust, efficient pre-clinical platform to dissect spatiotemporal dr","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"38 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183257","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 A032: Interstitial insulin enrichment drives pancreatic cancer growth by enhancing cancer cell metabolic plasticity","authors":"Jeffrey SH. Lin, James D. Johnson, Christoph H. Borchers, David F. Schaeffer, Janel L. Kopp","doi":"10.1158/1538-7445.pancreatic25-a032","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a032","url":null,"abstract":"Metabolic diseases, such as type 2 diabetes, insulin resistance, and obesity, often coexist with pancreatic ductal adenocarcinoma (PDAC) and predict poor survival. Using a mouse model of diet-induced obesity, we showed that a high-fat diet (HFD) consumption that induces hyperinsulinemia, but not hyperglycemia, in mice accelerated the growth of xenografted patient-derived PDAC organoids (PDOs). Strikingly, even in the fasting state, insulin was highly enriched in the tumor interstitial fluid of pancreatic tumors under HFD. Modelling this elevated interstitial insulin concentration in vitro significantly increased PDO growth regardless of glucose levels. Mechanistically, chronic high-insulin exposure robustly enhances metabolic plasticity and nutrient utilization in PDOs by selectively upregulating distinct metabolic pathways in response to differences in extracellular glucose levels. Thus, the presence of robust insulin levels continuously supports tumor growth as glucose availability changes. Specifically, under low-glucose conditions, elevated insulin activates nutrient uptake machinery and amino acid metabolism, whereas it promotes aerobic glycolysis in high-glucose conditions. Pharmacological inhibition of these metabolic pathways attenuated insulin-mediated growth. Our study identifies insulin enrichment in the tumor-interstitial fluid as an important driver of metabolic adaptation in PDAC cells. Citation Format: Jeffrey SH. Lin, James D. Johnson, Christoph H. Borchers, David F. Schaeffer, Janel L. Kopp. Interstitial insulin enrichment drives pancreatic cancer growth by enhancing cancer cell metabolic plasticity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A032.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"97 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183302","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":"TRIM49 Deficiency Stabilizes a Galectin-3/EGR1 Transcriptional Complex that Drives Invasiveness of Gastric Adenocarcinoma.","authors":"Zhong-Yi Qin,Lin-Rong Che,Shuoran Tian,Xianfeng Li,Xiang-Yu Du,Jinyang Li,Qin Liu,Ke-Wei Liu,Zhaole Chu,Mengyi Han,Xu Chen,Linyu Wu,Sen Yang,Chenhui Wang,Yuanyu Deng,Xiaohan Wang,Deshun Zeng,Xiao-Ning Zhang,Min Mao,Qingning Zhao,Jingyuan Li,Hong Zhou,Li-Ting Shen,Shiyin Peng,Ning Li,Dongfeng Chen,Liangzhi Wen,Qiaoqiao Zhang,Ke Li,Tao Wang,Junyv Xiang,Xiu-Wu Bian,Bin Wang","doi":"10.1158/0008-5472.can-25-0252","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0252","url":null,"abstract":"Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, TRIM49, was identified as a potent suppressor of cancer invasiveness. In two-thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, where TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multi-organ metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely due to the failure to undergo TRIM49-mediated poly-ubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a pro-invasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying pro-invasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a pro-invasive galectin-3/EGR1 transcriptional complex was exploited by TRIM49-deficient GAC to fuel tissue invasion, representing an Achilles'heel that is potentially targetable to prevent metastasis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"41 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140222","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 A030: Accelerating Therapeutic Discovery for Pediatric Cancer: Optimization of 80S Ribosome Inhibitors for T-Cell Acute Lymphoblastic Leukemia","authors":"Iris Valtingojer, Jean-François Peyron, Véronique Imbert, Marielle Nebout, Celia Durano, Muhamad Mustafa, Jean-Yves Winum, Bruno Klaholz, Marie-Pierre Harnist, Loreley Calvet, David Machnik, Sasha Lievre, Joe Kiwan, Valeria Fantin","doi":"10.1158/1538-7445.pediatric25-a030","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a030","url":null,"abstract":"Cancer remains the leading cause of disease-related death in children across many regions of the world. Yet, despite this urgent medical need, the discovery and development of novel therapies for pediatric cancers continues to progress slowly. Current treatment protocols often still rely on decades-old chemotherapy regimens. Moreover, the initiation of clinical trials for pediatric patients typically lags 6–7 years behind comparable trials in adults. Key barriers to innovation include the rarity of childhood cancers and the ultra-rare nature of many subtypes, which contribute to small trial populations, perceived low return on investment, and recruitment challenges. Historically, children have also been viewed as a uniquely vulnerable group, complicating drug development efforts. However, current evidence shows that, aside from their disease, children are generally healthier than adults with cancer and often tolerate higher relative doses of chemotherapy, challenging these outdated assumptions. To address these challenges, at Sanofi, we are committed to transforming outcomes for children with cancer through our dedicated Sanofi Childhood Cancer Program, part of the company’s broader societal impact strategy. A central element of this program is the formation of strong academic-industry partnerships to jointly advance the development of novel pediatric therapies. One such collaboration is with Jean-François Peyron and his team at the C3M–U1065 INSERM Institute in southern France. This partnership focuses on T-cell acute lymphoblastic leukemia (T-ALL), a highly proliferative disease that, unlike B-ALL, lacks effective targeted therapies, immunotherapies, and robust biomarkers for risk and relapse. Given the high rate of protein synthesis required for T-ALL cell proliferation, inhibiting translation emerges as a promising therapeutic strategy. Within the framework of this research project, the team has used cryo-EM-guided design to optimize 80S ribosome inhibitors. These compounds were further refined for potency and drug-like properties, resulting in a series of lead molecules with low-nanomolar in vitro efficacy in T-ALL cell lines and demonstrable in vivo activity in T-ALL patient-derived xenograft (PDX) mouse models. Additionally, the project has included efforts to identify and characterize pharmacodynamic biomarkers for these compounds. This research is funded by the Sanofi i-awards program and serves as a compelling example of how public–private collaboration can successfully accelerate the early discovery of targeted therapies for pediatric cancers, particularly for high-risk and underserved patient populations. Citation Format: Iris Valtingojer, Jean-François Peyron, Véronique Imbert, Marielle Nebout, Celia Durano, Muhamad Mustafa, Jean-Yves Winum, Bruno Klaholz, Marie-Pierre Harnist, Loreley Calvet, David Machnik, Sasha Lievre, Joe Kiwan, Valeria Fantin. Accelerating Therapeutic Discovery for Pediatric Cancer: Optimization of 80S Ribosome ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"89 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140540","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 A041: Therapeutic induction of tertiary lymphoid structures by STING and lymphotoxin-β receptor agonists sensitizes poorly immunogenic rhabdomyosarcoma to PD-1 blockade","authors":"Yasuhiro Kikuchi, Maxwell Duah, Tomoko Stansel, Fumiaki Kanamori, Masanobu Komatsu","doi":"10.1158/1538-7445.pediatric25-a041","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a041","url":null,"abstract":"Metastatic rhabdomyosarcoma (RMS) remains a clinically challenging pediatric malignancy with limited response to immunotherapy and poor prognosis. The 76-9 murine RMS exhibits low MHC class I expression and poor immunogenicity, making it a model to evaluate immune-activating treatment strategies. Tertiary lymphoid structures (TLS), ectopic lymphoid aggregates resembling secondary lymphoid organs, are increasingly recognized as critical sites for local lymphocyte priming and have been associated with improved survival and responsiveness to immune checkpoint inhibitors in several adult cancers. However, their role and therapeutic potential in RMS remain largely unexplored. We investigated whether TLS could be therapeutically induced in RMS to potentiate anti-tumor immunity and sensitize tumors to immune checkpoint blockade. Here we show that a combination therapy with stimulator of interferon genes (STING) and lymphotoxin-β receptor (LTβR) agonists induces the formation of intratumoral TLS exhibiting germinal center B cell responses in 76-9 RMS tumors, leading to the inhibition of tumor growth and metastasis and prolonged survival. Increased levels of tumor-specific IgG were detected in blood serum following this treatment. Histological examination showed no significant differences in the number or size of germinal centers in draining lymph nodes between the treated and untreated groups, suggesting that intratumoral TLS were the main source of the anti-tumor IgG. Functional assays showed that the tumor-specific IgG bound to RMS cells and triggered NK cell–mediated antibody-dependent cellular cytotoxicity (ADCC), resulting in tumor cell killing in vitro. Flow cytometry demonstrated increased accumulation of TCF1+CD8+ progenitor exhausted/stem-like T cells in the treated tumors, and immunofluorescence revealed that the stem-like T cells were localized in the close proximity to TLS that created unique niches for these T cells. Finally, the administration of anti–PD-1 antibody following agonist-induced TLS formation significantly prolonged survival while PD-1 blockade alone did not improve survival, indicating that TLS reprogrammed the tumor microenvironment to heighten the responsiveness to immune checkpoint blockade therapy. In conclusion, our study demonstrates that STING/LTβR agonist therapy induces functional TLS in “immune cold” RMS tumors, overcoming the inherent resistance to immunotherapy through the development of humoral and cellular immunity against RMS. TLS induction by the agonist combination represents a promising strategy for potentiating immunotherapy in sarcomas with low immunogenicity. Citation Format: Yasuhiro Kikuchi, Maxwell Duah, Tomoko Stansel, Fumiaki Kanamori, Masanobu Komatsu. Therapeutic induction of tertiary lymphoid structures by STING and lymphotoxin-β receptor agonists sensitizes poorly immunogenic rhabdomyosarcoma to PD-1 blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery a","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140873","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 A042: Immune heterogeneity across pediatric ependymoma subtypes revealed by B cell repertoire profiling","authors":"Amelia Stepniak, Stephen C. Frederico, Sydney Jackson, Itay Raphael, Dhivyaa Rajasundaram, Gary Kohanbash","doi":"10.1158/1538-7445.pediatric25-a042","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a042","url":null,"abstract":"Background Ependymomas (EPNs) account for approximately 9% of all primary central nervous system tumors in children, with peak incidence in those under five years old. These tumors are highly heterogeneous and classified into distinct subtypes, such as myxopapillary (MPE), posterior fossa A (PFA), classic spinal, supratentorial YAP1-fused and ZFTA-fused EPN. The clinical behavior varies widely, with PFA EPNs representing the most prevalent and aggressive subtype in young children. While ongoing efforts continue to explore the tumor immune microenvironment, the diversity and functional architecture of B cells in pediatric EPN remain unknown. Defining B cell phenotypes across EPN subtypes may uncover new insights into oncogenic pathways and novel opportunities for targeted immunotherapies. Methods We analyzed non-targeted bulk RNA-sequencing data from over 2,000 pediatric brain tumors using bcRflow, a Nextflow pipeline for reconstructing B cell receptor (BCR) repertoires. This cohort included 179 EPN samples spanning all major subtypes. For each tumor, we examined B cell isotype distribution, clonal expansion, class switch recombination (CSR), somatic hypermutation (SHM) rates, and overall repertoire diversity using diversity metrics such as Chao1, ACE, and the inverse Simpson index. Results Across all samples, EPN demonstrated relatively lower BCR repertoire diversity quantified by diversity indices including Chao1, ACE, and inverse Simpson index. EPNs were further characterized by a dominance of hyperexpanded B cell clonotypes. The majority of the BCR repertoire space was occupied by clones within the [1–10] and [11–100] frequency bins, indicating the expansion of select clonal populations rather than a broadly polyclonal response. Within EPN subtypes, there was notable heterogeneity in isotype usage, IGHV gene usage, and CSR dynamics. The frequency of IgM-expressing B cells is comparatively low across all subtypes. None of the subtypes display IgM as the most abundant isotype, indicating that most B cells within these tumors have undergone CSR away from the naïve IgM phenotype. Conclusions Pediatric EPNs exhibit markedly restricted BCR diversity compared to other pediatric brain tumors, suggesting a limited and potentially oligoclonal B cell repertoire. This indicates a focused, potentially tumor antigen-driven response. Most infiltrating B cells within the samples had already undergone class-switching, with IGHA1 and IGHG1 isotypes predominating over IgM. This shift away from naïve B cells points to immune engagement shaped by unique tumor antigens. Importantly, the immune architecture varied substantially across subtypes like PFA, MPE, spinal, YAP1-fused and ZFTA-fused EPNs. This highlights that EPNs are not immunologically uniform and may reflect distinct immunological pressures and potential therapeutic vulnerabilities. Taken together, these findings reveal a previously underappreciated layer of immune complexity in EPNs and opens new avenue","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"28 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140936","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}