Cancer research最新文献

{"title":"The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.","authors":"Ling Cai,Fangjiang Wu,Qinbo Zhou,Ying Gao,Bo Yao,Ralph J DeBerardinis,George K Acquaah-Mensah,Vassilis Aidinis,Jennifer E Beane,Shyam Biswal,Ting Chen,Carla P Concepcion-Crisol,Barbara M Grüner,Deshui Jia,Robert A Jones,Jonathan M Kurie,Min Gyu Lee,Per Lindahl,Yonathan Lissanu,Corina Lorz,David MacPherson,Rosanna Martinelli,Pawel K Mazur,Sarah A Mazzilli,Shinji Mii,Herwig P Moll,Roger A Moorehead,Edward E Morrisey,Sheng Rong Ng,Matthew G Oser,Arun R Pandiri,Charles A Powell,Giorgio Ramadori,Mirentxu Santos,Eric L Snyder,Rocio Sotillo,Kang-Yi Su,Tetsuro Taki,Kekoa Taparra,Phuoc T Tran,Yifeng Xia,J Edward van Veen,Monte M Winslow,Guanghua Xiao,Charles M Rudin,Trudy G Oliver,Yang Xie,John D Minna","doi":"10.1158/0008-5472.can-24-1607","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1607","url":null,"abstract":"Lung cancer, the leading cause of cancer mortality, exhibits diverse histologic subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. In this study, we established the Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMM), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCAMGDB aligned 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in the GEMMs. To accompany this resource, a web application was developed that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCAMGDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance. Significance: The Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB) provides a comprehensive and accessible resource for the research community to investigate lung cancer biology in mouse models.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"36 1","pages":"OF1-OF15"},"PeriodicalIF":11.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889332","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":"Perivascular Niche–Resident Alveolar Macrophages Promote Interstitial Pneumonitis Related to Trastuzumab Deruxtecan Treatment","authors":"Qing Wei, Teng Yang, Ziwen Zhang, Fei Wang, Yuxuan Yang, Jiayu Zhu, Xiu Zhu, Yuanzheng Li, Yun Xing, Ye Lu, Xuefei Tian, Mengyang Fan, Yuchao Zhang, Xiru Xue, Meng Li, Chuanfei Yu, Lan Wang, Takaya Shimura, Jianmin Fang, Zhiwei Cao, Jieer Ying, Peng Guo, Xiangdong Cheng","doi":"10.1158/0008-5472.can-24-2021","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2021","url":null,"abstract":"Trastuzumab deruxtecan (T-DXd) is a transformative HER2-targeting antibody–drug conjugate (ADC) for treating breast cancer. Unfortunately, T-DXd has also been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. A better understanding of the mechanistic basis of these ADC-induced adverse effects could enable development of strategies to prevent or treat T-DXd–related ILD. In this study, we determined that T-DXd–induced ILD represents an off-target adverse event rather than an on-target off-tumor adverse event. To further investigate this phenomenon, an immunocompetent murine model that recapitulates T-DXd–induced ILD events was developed, facilitating in-depth mechanistic studies. Single-cell RNA sequencing in this model implicated alveolar macrophages (AM) as the primary cell type impacted by T-DXd in the lung microenvironment. Intravital microscopy further revealed that AMs resident in perivascular niches directly engulfed blood-circulating T-DXd via Fc–FcγR engagement. This Fc–FcγR interaction with T-DXd triggered a phenotypic shift in AMs from an immunosuppressive to a pro-ILD state, characterized by inflammation and immune activation, mediated through the SPP1 pathways. Finally, mitigating nonspecific T-DXd uptake in the lung by preconditioning perivascular AMs with IgG1 or the parental antibody of T-DXd significantly reduced unintended ADC absorption. These findings elucidate a mechanism by which T-DXd ignites the lung immune microenvironment and underscore the importance of off-target endocytosis by innate immune cells in the development of ADC-related toxicities. Significance: Preconditioning the perivascular niche can prevent lung inflammation induced by antibody-drug conjugate phagocytosis by alveolar macrophages and subsequent SPP1high macrophage differentiation, providing a clinically viable strategy for mitigating interstitial lung disease.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"61 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889587","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":"Fes-Deficient Macrophages Prime CD8+ T Cells to Stimulate Anti-tumor Immunity and Improve Immunotherapy Efficacy","authors":"Brian J. Laight, Danielle Harper, Natasha Dmytryk, Connie S. Zhang, Changnian Shi, Andrew Garven, Richard W. Nauman, Jacob Kment, Faizah Alotaibi, Ivan Shapovalov, Victoria Hoskin, Yan Gao, Jeffery Mewburn, Caitlyn Vlasschaert, Ami Wang, Julian Simonetti, David LeBrun, Kathrin Tyryshkin, David M. Berman, Amber L. Simpson, Charles H. Graham, Andrew W. Craig, Sameh Basta, Madhuri Koti, Peter A. Greer","doi":"10.1158/0008-5472.can-24-3686","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3686","url":null,"abstract":"Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anti-cancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrated the role of the non-receptor tyrosine kinase Fes, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes-deficiency delayed tumor onset in a gene dose-dependent manner and improved tumor control, survival, doxorubicin efficacy, and anti-PD-1 therapy sensitization in murine triple-negative breast cancer and melanoma models. These effects were associated with a shift to an anti-tumorigenic immune microenvironment. Fes-deficient macrophages displayed increased Toll-like receptor signaling, proinflammatory cytokine production, antigen presentation to and activation of T cells, leading to increased cancer cell killing in vitro and tumor control in vivo. This study highlights Fes as an innate immune checkpoint with potential as a therapeutic target and a predictive biomarker to guide immune checkpoint inhibitor treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"37 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889588","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":"Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control","authors":"Helen Hockings, Eszter Lakatos, Weini Huang, Maximilian Mossner, Mohammed A. Khan, Nikolina Bakali, Jacqueline McDermott, Kane Smith, Ann-Marie Baker, Trevor A. Graham, Michelle Lockley","doi":"10.1158/0008-5472.can-25-0351","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0351","url":null,"abstract":"Drug resistance results in poor outcomes for cancer patients. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. Here, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared to standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely fitter, sensitive cells re-grew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell-free DNA obtained longitudinally from ovarian cancer patients during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual ovarian cancer patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"95 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889590","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":"Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell–Mediated Antitumor Immunity by Suppressing ER Stress–Associated THBS2 Signaling","authors":"Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Fan Yang, Nabil F. Saba, Yong Teng","doi":"10.1158/0008-5472.can-24-3477","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3477","url":null,"abstract":"The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell–mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box–binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"91 1","pages":"OF1-OF13"},"PeriodicalIF":11.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884651","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":"A Cyanobacteria-derived RNA aptamer resensitizes prostate cancer to hormone therapy","authors":"Carlos D. Cruz-Hernández, Bethany Smith, Sandrine Billet, Manish Thiruvalluvan, Gabrielle Gonzales, David M. Underhill, Ekihiro Seki, Shelly C. Lu, Neil A. Bhowmick","doi":"10.1158/0008-5472.can-24-4039","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4039","url":null,"abstract":"Prostate adenocarcinoma (PCa) resistance to androgen receptor (AR) signaling inhibitor therapy is associated with elevated glutamine (L-Gln). Glutamine sensors, present in conserved riboswitches (glnA), control nitrogen metabolism in many organisms, like cyanobacteria. Iterative in silico modifications of glnA found in Synechococcus elongatus and thermodynamic analysis of a 56mer aptamer resulted in high L-Gln specificity and affinity. The optimized aptamer depleted L-Gln from PCa cells by both L-Gln sequestration and extracellular glutaminase activation, serving as an allosteric activator. Glutamine depletion reduced FOXM1 transcriptional occupancy on the promoter of fibroblast growth factor 8 (FGF8), a known mediator of PCa castration resistance. A point mutation in the binding pocket of the 56mer rendered the aptamer ineffective in L-Gln binding and FGF8 regulation. Accordingly, the L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation and promoted cell death of castration-resistant PCa alone and in combination therapy with AR antagonists, enzalutamide and apalutamide, in subcutaneous and orthotopic mouse models. Further selective tumor targeting was achieved by functionalizing gold nanoparticles with either the optimized L-Gln aptamer or the point-mutant aptamer. Castration sensitivity was restored by the L-Gln-depleting aptamer but not by the point-mutant. The functionalized nanoparticle demonstrated superior anti-tumor efficacy in an orthotopic PCa model over the untargeted aptamer. The anti-tumor activity of the aptamer helped support L-Gln as an oncometabolite in PCa that can be targeted to sensitize tumors to hormone therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"35 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884652","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":"Combining Spatial Transcriptomics, Pseudotime, and Machine Learning Enables Discovery of Biomarkers for Prostate Cancer","authors":"Martin Smelik, Daniel Diaz-Roncero Gonzalez, Xiaojing An, Rakesh Heer, Lars Henningsohn, Xinxiu Li, Hui Wang, Yelin Zhao, Mikael Benson","doi":"10.1158/0008-5472.can-25-0269","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0269","url":null,"abstract":"Early cancer diagnosis is crucial but challenging owing to the lack of reliable biomarkers that can be measured using routine clinical methods. The identification of biomarkers for early detection is complicated by each tumor involving changes in the interactions between thousands of genes. In addition to this staggering complexity, these interactions can vary among patients with the same diagnosis as well as within the same tumor. We hypothesized that reliable biomarkers that can be measured with routine methods could be identified by exploiting three facts: (1) the same tumor can have multiple grades of malignant transformation; (2) these grades and their molecular changes can be characterized using spatial transcriptomics; and (3) these changes can be integrated into models of malignant transformation using pseudotime. Pseudotime models were constructed based on spatial transcriptomic data from three independent prostate cancer studies to prioritize the genes that were most correlated with malignant transformation. The identified genes were associated with cancer grade, copy number aberrations, hallmark pathways, and drug targets, and they encoded candidate biomarkers for prostate cancer in mRNA, immunohistochemistry, and proteomics data from the sera, prostate tissue, and urine of more than 2,000 patients with prostate cancer and controls. Machine learning-based prediction models revealed that the biomarkers in urine had an AUC of 0.92 for prostate cancer and were associated with cancer grade. Overall, this study demonstrates the diagnostic potential of combining spatial transcriptomics, pseudotime, and machine learning for prostate cancer, which should be further tested in prospective studies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"44 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884653","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":"Blocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors","authors":"Jyoti Srivastava, Vipin K. Yadav, Rachel V. Jimenez, Pravin R. Phadatare, Ninad A. Inamdar, Montana M. Young, Antonella Bacchiocchi, Ruth Halaban, Bin Fang, Alvaro de Mingo. Pulido, Kenneth Y. Tsai, Keiran S.M. Smalley, John M. Koomen, Paulo C. Rodriguez, Sanjay Premi","doi":"10.1158/0008-5472.can-24-0693","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0693","url":null,"abstract":"Activating NRAS mutations occur in 15-25% of all melanomas. However, this subtype remains refractory to existing therapeutics, including immunotherapy and RAS inhibitors; therefore, identifying innovative treatment strategies is of utmost importance. We investigated the role of nitrosylation, a nitric oxide-induced post-translational modification, in melanoma progression and therapeutic resistance. Inhibiting nitrosylation sensitized NRAS-mutant melanomas to targeted MEK inhibitors (MEKi), leading to sustained downregulation of the ERK-MAPK pathway, along with concomitant de-nitrosylation of NRAS, MEK, ERK, RSK1, and DUSPs. Global nitrosylome profiling using mass-spectrometry revealed nitrosylation of multiple ERK regulators. Gain- and loss-of-function studies confirmed a positive association between nitrosylation and ERK activation. ERK and MEK proteins harbored potential nitrosylation sites, mutation of which abrogated their phosphorylation and inhibited cell growth. The nitrosylome also contained death-associated molecular patterns (DAMPs), factors known to induce immunogenic cell death (ICD). Notably, nitrosylation inhibition combined with MEKi markedly inhibited Nras-mutant melanoma growth in an immunocompetent mouse model. This was accompanied by downregulated MEK-ERK signaling and extracellular release of DAMPs like calreticulin, phospho-eIF2α, and HMGB1, confirming ICD induction. Furthermore, the combination significantly increased the repertoire of CD8+ T cells, dendritic cells (DCs), and macrophages in the tumor microenvironment, which was validated in co-cultures of DCs and T-lymphocytes. In conclusion, the current study demonstrates that nitrosylation inhibition sensitizes NRAS-mutant melanomas to targeted MEKi-induced cell death and causes the release of non-nitrosylated (active) DAMPs that induce a potent anti-melanoma immune response via ICD. These findings highlight potential therapeutic vulnerabilities in the currently untreatable NRAS-mutant melanoma subtype.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880703","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 CT092: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: Vaginal cancers","authors":"Young K. Chae, Josie Czeskleba, Sandip P. Patel, Alex Menter, William Robinson, Nathaniel L. Jones, Murtuza Rampurwala, Aung Naing, Joseph M. Beck, Carolyn Moloney, Liam IL-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Sara Threlkel, Megan Othus, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock","doi":"10.1158/1538-7445.am2025-ct092","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct092","url":null,"abstract":"Background: SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) administered ipilimumab and nivolumab to patients with primary vaginal cancers. Methods: DART is a prospective, open-label, multicenter, multi-cohort phase II clinical trial of ipilimumab (1 mg/kg intravenously) every six weeks plus nivolumab (240 mg intravenously) every two weeks. The trial was carried out by the Early Therapeutics and Rare Cancers Committee (NCI/SWOG) and opened at >1000 sites. Cohort 33 included patients with vagina cancers only. The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] (RECISTv1.1), progression-free survival (PFS), and overall survival (OS); clinical benefit rate [CBR: ORR plus stable disease (SD)>6 months] and toxicity were secondary endpoints. Results: Seven evaluable patients (median age, 60 years; performance status 0-1; no prior exposure to immunotherapy) were analyzed (adenocarcinoma, N=3; squamous cell carcinoma (SCC) (N=2); small cell carcinoma and undifferentiated histology (N=1 each). The ORR was 29%: one, CR (undifferentiated) (lasting 14.8 months); one, PR (SCC) (lasting 45.2 months). The CBR was 43% (3/7 patients) (included one adenocarcinoma with 8 months SD). The 6-month PFS rate was 43%; median OS, 11.7 months. Five patients (71.4%) experienced an adverse event (AE); four, a grade 3-4 AE including one patient (14.3%) with elevated liver function tests leading to drug discontinuation. The most common AEs (any grade, at least possibly related to treatment) were cough (42.9%), fever (42.9%) and diarrhea (42.9%). Conclusion: Ipilimumab plus nivolumab in vaginal cancers resulted in an ORR of 29% and CBR of 43% including one CR, one PR and one patient with 8 months of stable disease; the longest response lasted 45.2 months. Further prospective studies exploring the role of both monotherapy and dual immunotherapy in vaginal cancers are warranted. Citation Format: Young K. Chae, Josie Czeskleba, Sandip P. Patel, Alex Menter, William Robinson, Nathaniel L. Jones, Murtuza Rampurwala, Aung Naing, Joseph M. Beck, Carolyn Moloney, Liam IL-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Sara Threlkel, Megan Othus, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: Vaginal 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 CT092.","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":"143876107","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 LB055: A ketogenic diet sensitizes pancreatic cancer to inhibition of glutamine metabolism","authors":"Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina Boutros, Jonathan Hue, Parnian Naji, Jacob A. Boyer, Soubhi Tahhan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Priyashree Sunita, Goutam Dey, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder Lund, Luke Rothermel, Joshua D. Rabinowitz, Jordan M. Winter","doi":"10.1158/1538-7445.am2025-lb055","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb055","url":null,"abstract":"Background: A ketogenic diet, with high fat (90% kCal) and low carbohydrate (5% kCal) intake, induces ketosis [2], altering cancer cell carbon utilization toward the tricarboxylic acid cycle (TCA) [3]. While the overall impact on cancer growth is unclear, most literature suggests an anti-cancer effect. Our hypothesis aims to uncover pancreatic cancer cell adaptations to the ketogenic diet, revealing metabolic vulnerabilities for informed therapeutic strategies. Methods: Mice on a ketogenic or normal diet (control) underwent pancreatic cancer xenograft observation. Tumor metabolites were analyzed with LC/GC-MS, oxidative stress with NAD(P)+/NAD(P)H, and Lipid Peroxidation assays. Western blot assessed enzyme expression. In vitro studies used Seahorse FX Analyzer for mitochondrial function and PicoGreen for cell growth quantification. Ivosidenib and CB839 were used for combination therapies. Result: A ketogenic diet induces a metabolic shift in pancreatic cancer, altering nutrient and metabolite levels in diverse in vivo models. Besides the expected increase in TCA metabolites, heightened amino acid anaplerosis, particularly with glutamine and glutamate, was observed. Examination of the diet's impact on oxidative phosphorylation enzymes revealed increased BDH1 expression, aiding ketone body utilization, and upregulation of cytosolic IDH1 for antioxidant defense. Enzymes involved in glutamine uptake and conversion, like ASCT2 and GLS, showed altered expression. Simultaneously, we explored tumor microenvironment vulnerabilities, detecting a significant increase in reactive oxygen species (ROS) levels, specifically lipid peroxidation, in mice on the ketogenic diet. Given these pancreatic cancer adaptations, we hypothesized that combining therapeutics to elevate ROS levels and target the glutamine pathway would substantially impede tumor growth. To test this, we combined a ketogenic diet with an IDH1 inhibitor for antioxidant defense hindrance and a glutaminase inhibitor to impair mitochondrial function, resulting in a marked reduction in tumor proliferation compared to individual treatments. Conclusion: A ketogenic diet demonstrates a robust anti-tumor effect in various pancreatic cancer mouse models, likely arising from the diminished glucose and increased fatty acid load inherent in the diet. Metabolic adaptation towards an oxidative phosphorylation (OXPHOS) phenotype makes pancreatic cancer especially susceptible to antioxidant and mitochondrial inhibitors, as well as inhibitors of glutamine-metabolizing enzymes. Citation Format: Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina Boutros, Jonathan Hue, Parnian Naji, Jacob A. Boyer, Soubhi Tahhan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Priyashree Sunita, Goutam Dey, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengrab","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":"143875713","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}