American journal of cancer research最新文献

{"title":"Integrating shear wave elastography and multiparametric MRI for accurate prostate cancer diagnosis.","authors":"Wei Jiang, Bingjia Lai, Xiumei Li, Yuanfang Liu, Longjiahui Xu, Shaoyun He, Ming Gao","doi":"10.62347/SNMS7524","DOIUrl":"10.62347/SNMS7524","url":null,"abstract":"<p><strong>Objective: </strong>To develop a risk prediction model for prostate cancer (PCa) by integrating Shear Wave Elastography (SWE) with Multiparametric Magnetic Resonance Imaging (mpMRI), thereby improving screening accuracy and specificity while reducing unnecessary invasive procedures.</p><p><strong>Methods: </strong>A total of 479 patients who visited Sun Yat-sen Memorial Hospital between May 2019 and July 2023 were included in this retrospective study, with 162 diagnosed with PCa. The patients were randomly divided into a training set (349 cases) and a validation set (130 cases). The primary measurements consisted of the Young's modulus from SWE, the PI-RADS score from mpMRI, and laboratory indicators such as total PSA (tPSA), free PSA (fPSA), and their densities. A multifactorial prediction model integrating imaging and clinical data was constructed and validated.</p><p><strong>Results: </strong>The combined model incorporating SWE and mpMRI exhibited high accuracy and robustness in diagnosing PCa, with area under the curve (AUC) values of 0.92 for the training set and 0.91 for the validation set, significantly outperforming individual indicators (P<0.001). The model achieved a sensitivity of 94.87% and a specificity of 96.12%, indicating superior performance in distinguishing PCa from benign lesions. Receiver operating characteristic (ROC) curve analysis and DeLong's test confirmed that the combined model exhibited the highest diagnostic accuracy, reducing false positives and minimizing unnecessary biopsies.</p><p><strong>Conclusions: </strong>The multifactorial prediction model integrating both imaging and clinical data provides a more precise and reliable tool for the early diagnosis of PCa, with significant potential for clinical application.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"348-362"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of SHANK2 contributes malignant outcomes as a Hippo pathway regulator in gastric cancer.","authors":"Hiroshi Arakawa, Shuhei Komatsu, Jun Kiuchi, Taisuke Imamura, Keiji Nishibeppu, Hajime Kamiya, Yusuke Takashima, Ryo Ishida, Satoshi Hamada, Masateru Yamauchi, Takuma Ohashi, Hiroki Shimizu, Tomohiro Arita, Hirotaka Konishi, Atsushi Shiozaki, Takeshi Kubota, Hitoshi Fujiwara, Hitoshi Tsuda, Eigo Otsuji","doi":"10.62347/NZMO2658","DOIUrl":"10.62347/NZMO2658","url":null,"abstract":"<p><strong>Background: </strong>Recent studies identified that SH3 and multiple ankyrin repeat domains 2 (SHANK2) is located in a gene-amplified region 11q13 of various human cancers, and has oncogenic functions as a Hippo pathway suppressor in hepatocellular carcinoma. In this study, we tested whether SHANK2 acts as a cancer-promoting gene through its activation or overexpression in gastric cancer (GC).</p><p><strong>Materials and methods: </strong>We analyzed 5 GC cell lines and 172 primary tumor samples of GC, which were curatively resected in our hospital.</p><p><strong>Results: </strong>Overexpression of SHANK2 protein was frequently detected in GC cell lines (4/5 cell lines, 80%). Knockdown of SHANK2 inhibited cell proliferation, migration and invasion of GC cells in a <i>TP53</i> mutation-independent manner, and induced the overexpression of the Hippo pathway genes. Fluorescent immunostaining showed that overexpression of SHANK2 in cytoplasm was inversely correlated with Yes1-associated transcriptional regulator (YAP) expression, suggesting that SHANK2 may play a role in suppressing the Hippo pathway in GC. In primary GC samples, both overexpression of SHANK2 in cytoplasm and low expression of SHANK2 in nucleus, which are defined as high SHANK2 index, correlated with more aggressive venous invasion, advanced tumor and nodal stage. Patients with high SHANK2 index tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that high SHANK2 index was independently associated with poor outcomes.</p><p><strong>Conclusions: </strong>These findings suggest that SHANK2 plays a crucial role in tumor malignant potential through the Hippo pathway suppression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"363-374"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel reduced toxicity conditioning regimen for older myelodysplastic neoplasms patients undergoing haploidentical stem cell transplantation: a prospective cohort study.","authors":"Wen-Jing Yu, Yu-Qian Sun, Xiao-Hui Zhang, Lan-Ping Xu, Xiao-Dong Mo, Meng Lv, Xiao-Jun Huang, Yu Wang","doi":"10.62347/OFXJ3130","DOIUrl":"10.62347/OFXJ3130","url":null,"abstract":"<p><p>A novel reduced-toxicity conditioning (RTC) regimen of busulfan, fludarabine, cyclophosphamide, and antithymocyte globulin (Bu/Flu/Cy/ATG) followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients with hematologic malignancies has been reported and the results was encouraging. However, the safety and efficacy of this regimen was unknown in older myelodysplastic neoplasms (MDS) patients. From January 2018 to December 2021, 68 consecutive older patients (aged over 50) using the RTC regimen for T-cell replete haplo-HSCT (RTC group) at our center were eligible, 68 patients aged under 50 using modified busulfan, cyclophosphamide plus antithymocyte globulin regimen (Bu/Cy/ATG) (Bu/Cy/ATG group) were randomly selected from 223 MDS patients during the same period in a 1:1 ratio matched-pair analysis for patient sex, World Health Organization (WHO) category, international prognostic scoring system (IPSS) risk group, time from diagnosis to HSCT, chemotherapy in advanced, response after chemotherapy, donor sex, infused mononuclear cells and the CD34-positive cell count. The transplant outcomes were also compared between the RTC group and the matched sibling donor (MSD) haploidentical stem cell transplantation (HSCT) with the busulfan and cyclophosphamide (Bu/Cy) conditioning regimen. The cumulative incidences of grade II-IV acute graft versus host disease (aGVHD) in the RTC group were significantly lower than that in the Bu/Cy/ATG group. The 3-year cumulative incidences of treatment related mortality (TRM) in the two groups were 12.3% versus 14.7% (P=0.613). The cumulative incidences of relapse, disease-free survival (DFS) and overall survival (OS) were comparable between the two groups. The outcomes were better in RTC group than those patients received MSD transplant, with lower incidence of TRM, and higher OS and DFS. The advantages were still significant when comparing patients receiving children donors HSCT in RTC group with MSD transplant in survival and TRM. Children donor with the RTC regimen could be a better choice than the MSD HSCT with Bu/Cy regimen for the elderly MDS patients. The encouraging results suggest that the RTC regimen followed by haplo-HSCT is a potentially promising method for older MDS patients. The trail number of the prospective study is \"NCT03412409\" and the trial URL is \"https://clinicaltrials.gov/study/NCT03412409?term=NCT03412409&rank=1\".</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"182-194"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathologic features and exploration of new molecular mechanisms of radiation-induced bone injury: report of two cases and review of the literature.","authors":"Lide Tao, Chaowen Bai, Xiang Gao, Mingchao Zhang, Xueli Qiu, Yuqian Yao, Shuai Wei, Xushen Zhao, Lijun Wu, Xiaozhong Zhou, Bingchen Shan, Jinyu Bai, Huajian Shan","doi":"10.62347/OABR4439","DOIUrl":"10.62347/OABR4439","url":null,"abstract":"<p><p>Radiation-induced bone injury (RBI) has a multifaceted mechanism of occurrence, is influenced by various factors, and is difficult to prevent. Clinicopathologic features and manifestations of disease progression were observed in two patients with distinct fractures: one with a left-sided fourth rib fracture after postoperative radiotherapy for lung cancer, and the other with a right-sided intertrochanteric femur fracture following accidental exposure to a ¹⁹²Ir radiation source 5 years prior. These two clinical case reports discussed the clinicopathologic features of RBI and disease progression and utilized transcriptome sequencing to explore potential new targets for treating this type of RBI. Both patients exhibited similar incurable osteolytic bone destruction and fatty infiltration in their pathology. It is proposed that XIST, the most significantly upregulated gene identified by transcriptome sequencing analysis, maybe a potential target for understanding these molecular mechanisms.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"209-216"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment and clinical value of a circulating tumor cell system based on a multi-site immune lipid magnetic sphere technique in laryngopharyngeal head and neck tumors.","authors":"Wei Chen, Qin Lin, Desheng Wang, Wenting Xie, Chunyan Huang, Wenjing Fan, Shipu Wu, Xiaomei Fan, Chen Li","doi":"10.62347/MVRG3697","DOIUrl":"10.62347/MVRG3697","url":null,"abstract":"<p><p>This study aimed to construct multi-site magnetic nanospheres to capture circulating tumor cells (CTCs) from peripheral blood specimens of laryngopharyngeal head and neck tumors. Separated CTCs were used to measure downstream molecular markers and to detect and analyze the disease status. A stable CTC multisite nano-enrichment system was used to determine changes in CTCs levels in Programmed Death-Ligand-1 (PD-L1)-positive patients and to assess the extent of real-time changes in CTCs over the course of the disease in correlation with clinicopathological indicators. The results demonstrated that the constructed immunomagnetic spheres could effectively capture CTCs and that the constructed lipid nanoparticles exhibited high capture efficiency and low cytotoxicity. The results of the concordance or complementarity analyses of PD-L1 expression at the CTC and tissue levels indicated good concordance between the two at up to 70%. The analysis of PD-L1 expression and the changes in CTCs in PD-L1-positive cells plays an auxiliary role in clinical diagnosis and can be used as a dynamic detection index for the course of head, neck, and throat tumor treatment and as a predictor of recurrence risk.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"19-31"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALKBH1-mediated N6-methyladenosine methylation of TRAF1 promotes osteosarcoma proliferation and metastasis.","authors":"Zhichao Wang, Yuli Fang, Yang Yu, Haile Pan","doi":"10.62347/ALXR1853","DOIUrl":"10.62347/ALXR1853","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a highly malignant bone tumor with poor prognosis and limited therapeutic options. Recent studies have highlighted the critical role of RNA modifications, particularly N6-methyladenosine (m6A) methylation, in cancer progression. This study aimed to investigate the role of ALKBH1, a m6A demethylase, in the proliferation and metastasis of OS through the regulation of TRAF1. Our findings showed that lower ALKBH1 expression correlates with poorer overall survival in OS patients. Knockdown of ALKBH1 significantly enhanced the proliferation, migration, and clonogenicity of OS cell lines (MG63 and HOS cells), while overexpression had the opposite effects. Transcriptomic analysis revealed that ALKBH1 regulates the expression of key oncogenes, including TRAF1, through m6A methylation. m6A-RIP and qPCR assays further confirmed that overexpression of ALKBH1 significantly decreased the m6A methylation and expression of TRAF1 in both MG63 and HOS cells, and ALKBH1 knockdown had the opposite roles. Combined knockdown of ALKBH1 and TRAF1 further reduced the oncogenic properties of osteosarcoma cells compared to individual knockdown for ALKBH1. In conclusion, ALKBH1 silence promotes osteosarcoma proliferation and metastasis by regulating TRAF1 expression through m6A methylation. Targeting the ALKBH1-TRAF1 axis may provide a novel therapeutic strategy for osteosarcoma.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"375-389"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid receptor-β deletion in a model of early pancreatic ductal adenocarcinoma (PDAC) tumorigenesis.","authors":"Eduardo Mere Del Aguila, Xiao-Han Tang, Lorraine J Gudas","doi":"10.62347/XFOT8509","DOIUrl":"10.62347/XFOT8509","url":null,"abstract":"<p><p>Vitamin A (VA, retinol) and its metabolites, including retinoic acid (RA), play a major role in the maintenance of cell populations in the adult pancreas. Pancreatic ductal adenocarcinomas (PDACs) contain lower amounts of VA and express lower levels of retinoic acid receptors (RARs) compared to normal human pancreatic tissues. Our goal was to determine if VA signaling directly impacts molecular events underlying pancreatic carcinogenesis using cell-type specific genetic approaches in mice. We knocked out retinoic acid receptor beta (RAR-β) selectively in pancreatic cells by tamoxifen treatment after crossing these adult RAR-β^fl/fl mice with Pdx1/CreER (PC^er) and lox-stop-lox KRas^G12D transgenic mice. Our data show that the rounds of tamoxifen we used were able to induce the knockout of the RAR-β gene in pancreatic cells in this PC^er;KRas;RAR-β^fl/fl transgenic model. We detected increases in proteins involved in RA metabolism (CYP26A1, RBP1, and ALDH1A2) in the PC^er;RAR-β^D/wt pancreata, but the levels of RBP1 and ALDH1A2 were decreased in PC^er;RAR-β^D (both RAR-β alleles deleted) compared to PC^er;KRas;RAR-β^D and wild-type pancreata. Ki67 and vimentin proteins exhibited lower levels in the PC^er;KRas;RAR-β^D and PC^er;RAR-β^D pancreata compared to wild-type, indicating that deletion of RAR-β reduced cell proliferation in acinar cells. Expression of SOX9, a key protein required for formation and maintenance of PDAC, was higher in PC^er;RAR-β^D/wt and PC^er;RAR-β^D pancreata compared to wild-type, indicating that deletion of RAR-β increases SOX9 levels even without the KRas activating mutation. In summary, lack of RAR-β in pancreatic acinar cells reduced cell proliferation and increased SOX9 protein levels in this transgenic model.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"127-140"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.","authors":"Minjing Zhu, Yanyan Hu, Yangjia Gu, Xuedan Lin, Xiang Jiang, Chaoju Gong, Zejun Fang","doi":"10.62347/ZSOO2247","DOIUrl":"10.62347/ZSOO2247","url":null,"abstract":"<p><p>This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"233-247"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnancy is associated with the prognosis of ovarian cancer patients with abdominal metastasis.","authors":"Hai-Tao Cui, Qian-Yong Zhu, Hong-Wei Zhao, Hui-Li Liu, Na Wang","doi":"10.62347/JUJQ9225","DOIUrl":"10.62347/JUJQ9225","url":null,"abstract":"<p><p>This study aims to explore a new approach to reduce the recurrence risk and improve the prognosis of ovarian cancer (OC) patients with abdominal metastasis by analyzing the clinical characteristics and prognostic factors. A total of 292 OC patients with abdominal metastasis, treated at Henan Provincial People's Hospital between 2021 and 2023 were included in this retrospective study. Follow-up was conducted for one year to observe the recurrence, with 285 patients completing the observation. The patients were then categorized into relapsing and non-relapsing groups based on whether they experienced a relapse within one-year follow-up. Independent sample t-tests and <i>χ</i> ² tests were used for inter-group comparison. Both univariate and multivariate logistic regression analyses were utilized to screen factors affecting recurrence. The variance inflation factor (VIF) was used to analyze whether the variables in the model had multicollinearity. Receiver Operating Characteristic (ROC) curves and nomographs were used to construct models for predicting one-year recurrence in OC patients with abdominal metastasis. Area under curve (AUC) of ROC and Hosmer-Lemeshow goodness of fit test were used to evaluate the accuracy of the model. The prediction model was verified by internal verification and external verification. The number of pregnancies, the number of births, diabetes mellitus, tumor diameter, tumor reduction combined with intraperitoneal chemotherapy, CA-125, HE-4, NLR, PLR, MLR showed association with patient recurrence. Logistic regression analysis revealed that lower pregnancy frequency and elevated levels of CA-125, HE-4, PLR and MLR were independent risk factors for increased risk of recurrence. In addition, the nomogram-based model demonstrated strong predictive accuracy for one-year recurrence. OC patients with abdominal metastasis present diverse clinical manifestations, among which fewer pregnancies and elevated levels of CA-125, HE-4, PLR, and MLR may be independent risk factors for increased risk of recurrence. Individualized interventions based on these prognostic factors are essential to reduce risk and enhance patient quality of life.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"168-181"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAIL receptor agonist TLY012 in combination with PD-1 inhibition promotes tumor regression in an immune-competent mouse model of pancreatic ductal adenocarcinoma.","authors":"Anna D Louie, Kelsey E Huntington, Young Lee, Jared Mompoint, Laura Jinxuan Wu, Seulki Lee, Thomas J Miner, Wafik S El-Deiry","doi":"10.62347/ROAT5658","DOIUrl":"10.62347/ROAT5658","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) has an immunosuppressed, apoptosis-resistant phenotype. TLY012 is pegylated recombinant Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), an orphan drug for chronic pancreatitis and systemic sclerosis. Innate immune TRAIL signaling suppresses cancer. We hypothesized that the combination of immune checkpoint-blocking anti-PD-1 antibody and TLY012 would have synergistic anti-tumor efficacy in immune-competent PDAC-bearing mice. PDAC tumor-bearing C57Bl/6 mice treated with 10 mg/kg anti-mouse PD-1 antibody twice weekly and 10 mg/kg TLY012 three times weekly had reduced tumor growth and tumor volume at 70 days compared to either drug alone (all P < 0.005). B-cell activating factor (BAFF), which promotes PDAC tumors, decreased to 44% of control mice with dual treatment at 7 days and remained decreased at 3 months. Long-term dual treatment showed the highest plasma levels of proinflammatory cytokines interferon-gamma (average 5.6 times control level, P=0.046), CCL5 (average 14.1 times control level, P=0.048), and interleukin-3 (IL-3, average 71.1 times control level, P=0.0053). Flow cytometry showed trends toward decreased circulating regulatory T cells, increased NK cells, and a higher proportion of CD8+ T cells within tumors in the dual treatment group. In summary, the combination of anti-PD-1 and TLY012 prevented the growth of PDAC in an immunocompetent mouse model while increasing tumor-infiltrating CD8+ T cells, decreasing circulating T-regulatory cells and altering plasma cytokine expression of CCL5, interferon-gamma, and IL-3 to promote proinflammatory, antitumor effects. Combining TLY012 and anti-mouse PD-1 modifies immune cell and cytokine levels to induce a more proinflammatory immune environment that contributes to decreased PDAC tumor growth.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"286-298"},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}