Molecular Cancer Therapeutics最新文献

{"title":"Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.","authors":"Aleksandra Kolodziejczyk, Piotr Sicinski","doi":"10.1158/1535-7163.MCT-23-0677","DOIUrl":"10.1158/1535-7163.MCT-23-0677","url":null,"abstract":"<p><p>Cyclin-dependent kinases (CDK) are critical regulators of cell-cycle progression and transcription, and their dysregulation is a hallmark of many cancers. While cell cycle inhibitors have transformed the treatment of certain cancer types, transcriptional CDKs (tCDK) are now gaining attention as potential therapeutic targets. tCDKs regulate essential processes, including RNA polymerase activation, transcriptional elongation, and RNA processing, making them crucial for tumor growth and survival. Targeting tCDKs offers a promising strategy, particularly in tumors reliant on enhanced transcriptional activity. Inhibitors of tCDKs have demonstrated efficacy in preclinical models by selectively targeting cancer cells while sparing normal cells. This selectivity arises from how normal and cancer cells utilize transcriptional machinery, with cancer cells often exhibiting heightened dependence on transcription for survival, known as \"oncogene addiction\". Despite promising results, several challenges remain, such as the lack of specificity of tCDKs inhibitors or limited understanding of their broader impact on the tumor microenvironment and immune response. Emerging therapeutic strategies, including targeted degradation of tCDKs and their associated cyclins, offer additional means to selectively target individual cyclin-CDK complexes. Future research is essential to address those issues and bring inhibitors of tCDKs into routine cancer care.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1497-1510"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting DDR2 for Treating Pancreatic Cancer.","authors":"Chris T P Do, Prabhakar Pitta Venkata, Jack Y Prochnau, Deepika Singh, Santosh Timilsina, Panneerdoss Subbarayalu, Daisy Medina, Shahad Abdulsahib, Saif Nirzhor, Sajid Khan, Guiming Li, Srikanth R Polusani, Daohong Zhou, Pei Wang, Yidong Chen, Ratna K Vadlamudi, Matthew J Hart, Radhika Amaradhi, Stanton F McHardy, Manjeet K Rao","doi":"10.1158/1535-7163.MCT-24-1226","DOIUrl":"10.1158/1535-7163.MCT-24-1226","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited effective treatments, partly because of its complex tumor microenvironment. In this study, we report discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase, as a critical protein that promotes PDAC growth and survival. Our results reveal that DDR2 is highly expressed and its expression correlates with the worst survival outcome in patients with PDAC. Using an unbiased high-throughput screen of small-molecule inhibitor libraries, we identified CIDD-8633, a novel inhibitor targeting DDR2. Our study suggests that CIDD-8633 interacts with DDR2 and inhibits DDR2-associated signaling. Importantly, in vivo studies demonstrate that CIDD-8633 effectively blocks PDAC tumor growth in preclinical mouse models. Additionally, combining CIDD-8633 with gemcitabine enhanced its efficacy synergistically. Mechanistically, CIDD-8633 treatment induces pro-apoptotic genes in PDAC cells. These findings position DDR2 as a promising therapeutic target and CIDD-8633 as a potential DDR2 inhibitor, offering new avenues for the treatment of PDAC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1570-1583"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depleting the Action of EZH2 through PI3K-mTOR Inhibition to Overcome Metastasis and Immunotherapy Resistance in Triple-Negative Breast Cancer.","authors":"Michelle Melino, Wen Juan Tu, Helle Bielefeldt-Ohmann, Martina Proctor, Taniya Ahuja, John Vandermeide, Amanda L Bain, Gahyathiri Nallan, Sal Lee Goh, Thiru Prasanna, Jane E Dahlstrom, Mariska Miranda, Ramesh Kumar Chaudhary, Aravind Anandam, Sumit Chaudhary, Jonathan T Seal, Debottam Sinha, Shaoqian Zhang, Tam Hong Nguyen, Sriganesh Srihari, Gunter Hartel, Amy Ives, Laeeq Malik, Desmond Yip, Michelle Nottage, Melissa Eastgate, Sudha Rao","doi":"10.1158/1535-7163.MCT-24-0693","DOIUrl":"10.1158/1535-7163.MCT-24-0693","url":null,"abstract":"<p><p>Almost half of patients with triple-negative breast cancer develop distant metastases, heralding unfavorable outcomes. Here, we provide novel insights into the contribution of the PI3K-mTOR pathway to the triple-negative breast cancer phenotypes that promote growth, migration, metastasis, and therapy resistance. Specifically, we demonstrate that dual targeting of PI3K and mTOR but not PI3K alone inhibits cancer cell proliferation and migration in vitro. Dual PI3K-mTOR inhibition with paxalisib not only promotes a favorable mesenchymal-to-epithelial phenotype but also inhibits signatures associated with metastasis-initiating cells, including the highly aggressive cancer stem cell phenotype, persister cancer cell phenotype (p65, FOXQ1, NRF2, and NNMT), and a cancer drug resistance signature (ABCB5, SNAIL, and ALDH1). In vivo, paxalisib overcomes immunotherapy resistance to reduce primary tumor burden, circulating tumor cells, and direct and indirect indicators of metastasis with a favorable toxicity profile. Gene expression and spatial analyses show that paxalisib profoundly affects the immune microenvironment in tumors, reducing adaptive immune phenotypes associated with immunotherapy resistance (exhausted T cells and regulatory T cells) and protumor innate immune populations such as mast cells. PI3K-mTOR blockade acts upstream of EZH2, impacting both the classic repressive catalytic p85β-EZH2-H27ME3 and active EZH2-NF-κB pathways. Our data suggest that dual targeting of the PI3K-mTOR pathway disrupts both the catalytic and noncatalytic axes of EZH2 to inhibit metastasis and enhance cancer immune visibility, potentially increasing the utility of immunotherapy in resistant individuals.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1511-1526"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intratumoral administration of engineered circRNAs encoding cytosine deaminase-uracil phosphoribosyltransferase (CDUPRT) and IL-15 elicit superior antitumor efficacy.","authors":"Dun Niu, Shaotong Zhang, Xiaozhuang Ma, Yaran Wu, Junshi Zhu, Jianglang Ran, Meihua Shan, Xufang Dai, Lu Lu, Mingzhen Yang, Jiqin Lian","doi":"10.1158/1535-7163.MCT-25-0356","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0356","url":null,"abstract":"<p><p>Gene-directed enzyme prodrug therapy (GDEPT) represents a promising antitumor strategy owing to its low systemic toxicity. However, clinical translation has been hindered by challenges in suicide gene delivery. Artificially engineered circular RNA (circRNA) demonstrates exceptional potential for gene delivery when combined with lipid nanoparticle (LNP) technology, exhibiting high stability, prolonged protein-coding capacity, and cost-effective production. We developed an in vitro synthesized circRNA encoding the cytosine deaminase-uracil phosphoribosyltransferase (circCDUPRT). Upon intratumoral administration, circCDUPRT achieved sustained intratumoral expression with minimal systemic toxicity. The combination of circCDUPRT and prodrug 5-fluorocytosine (5-FC) showed significant antitumor efficacy in both in vitro and in vivo tumor models. In advanced melanoma models, combining circCDUPRT/5-FC with IL-15-expressing circRNA (circIL) potently enhanced expansion and activation of CD8+ T and NK cells. Collectively, these findings establish the synthetic circRNA platform as a cost-effective, high-efficiency delivery system for GDEPT and immunotherapy applications.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antineoplastic Activity of a Novel Trispecific Single-Chain Antibody Targeting the hERG1/β1 Integrin Complex and TRAIL Receptors.","authors":"Claudia Duranti, Jessica Iorio, Chiara Capitani, Tiziano Lottini, Michele Martinelli, Julia Roosz, Nicole Anderle, Tengku Ibrahim Maulana, Peter M Loskill, Rossella Colasurdo, Cesare Sala, Lara Magni, Annarosa Arcangeli","doi":"10.1158/1535-7163.MCT-24-0646","DOIUrl":"10.1158/1535-7163.MCT-24-0646","url":null,"abstract":"<p><p>Targeted therapies and immunotherapies have largely improved cancer treatment in the last years. One of the most promising approaches is the induction of tumor apoptosis by TRAIL through its binding to apoptosis-inducing receptors DR4 and DR5 on the plasma membrane of target cells. However, some constraints (e.g., the short in vivo half-life and the poor activity on DR5 receptors) hinder the use of naked, soluble forms of TRAIL. Previous studies have shown that fusing TRAIL sequences with antibody-based moieties may represent a novel and efficacious strategy to overcome such hindrances. On these bases, novel TRAIL-related anticancer therapeutic strategies are being developed. In the present article, we describe a novel antibody represented by a single-chain diabody directed against a cancer-specific target, i.e., the hERG1/β1 integrin complex-scDb-hERG1-β1-fused with three TRAIL sequences. The scDb-hERG1-β1-TRAIL antibody combines the specific targeting and downregulation of cancer-specific signaling pathways by scDb-hERG1-β1 with the proapoptotic activity triggered by TRAIL. We provide substantial evidence of the efficacy of the scDb-hERG1-β1-TRAIL antibody to decrease tumor growth triggering apoptotic cell death in vitro in breast cancer cells as well as in vivo in a mouse model of triple-negative breast cancer. Being characterized by a favorable pharmacokinetic and toxicity profile, the scDb-hERG1-β1-TRAIL antibody can be proposed for the treatment of difficult-to-treat cancers, such as triple-negative breast cancer, which express the hERG1/β1 complex and TRAIL receptors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1584-1599"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination Therapy of Avutometinib and MRTX1133 Synergistically Suppresses Cell Growth by Inducing Apoptosis in KRASG12D-Mutated Pancreatic Cancer.","authors":"Ema Toyokuni, Mano Horinaka, Emi Nishimoto, Akihiro Yoshimura, Michiaki Fukui, Toshiyuki Sakai","doi":"10.1158/1535-7163.MCT-24-0831","DOIUrl":"10.1158/1535-7163.MCT-24-0831","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma is a lethal malignancy with a poor prognosis, and more than 90% of pancreatic ductal adenocarcinoma cases involve activating mutations in the oncogene KRAS. Therapeutic strategies that inhibit the mitogen-activated protein kinase pathway, a critical effector pathway in KRAS-mutated cancers, have garnered significant attention. Among several molecular-targeted drugs, avutometinib [CKI27(2)/CH5126766/RO5126766/VS-6766], a novel dual RAF/MEK clamp, shows promise for patients with KRAS-mutated cancers. However, its efficacy as a single agent remains insufficient, highlighting the need for more effective treatment strategies. In this study, we found that avutometinib alone was insufficiently effective against pancreatic cancer cells with the KRASG12D mutation. In these cells, combining avutometinib with the KRASG12D inhibitor MRTX1133 demonstrated synergistic inhibitory effects on cell growth. We further investigated the efficacy of this combination therapy in in vitro and in vivo experiments. In these experiments, the combination therapy upregulated BIM, downregulated survivin, and induced apoptosis in pancreatic cancer cells with the KRASG12D mutation. In in vivo experiments, the combination therapy markedly delayed tumor growth compared with either therapy alone. Therefore, the combination of avutometinib and MRTX1133 may represent a promising therapeutic approach for KRASG12D-mutated pancreatic cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1537-1545"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the Promoter: Total MGMT Gene Methylation Modulates Response to DNA-Alkylating Agents in Glioma.","authors":"Nicole J Briceno, Jinkyu Jung, Aiguo Li, Chunzhang Yang, Mioara Larion, Lorinc S Pongor, Fathi Elloumi, Sudhir Varma, William C Reinhold, Yves Pommier, Mark R Gilbert, Orieta Celiku","doi":"10.1158/1535-7163.MCT-24-0977","DOIUrl":"10.1158/1535-7163.MCT-24-0977","url":null,"abstract":"<p><p>Patients with malignant gliomas with methylated MGMT promoters are generally more sensitive to alkylating chemotherapy as this modification impedes DNA repair. However, inconsistencies in the predictive accuracy of MGMT promoter methylation have been observed. We hypothesize that these variations may be partially explained by a counteracting influence of MGMT gene body methylation. Data from The Cancer Genome Atlas were analyzed to assess correlations between MGMT promoter and body methylation with transcript production across cancer types and within glioma subcohorts. Thirty-six human glioma cell lines underwent molecular profiling via Illumina 850k Methylation Arrays and RNA sequencing. A subset was further tested for MGMT protein levels and carmustine response. Correlations and linear regression analyses were conducted to investigate association of carmustine sensitivity with different levels of MGMT expression. MGMT mRNA expression was positively correlated with body methylation and negatively correlated with promoter methylation across cancers from The Cancer Genome Atlas. Body and promoter methylation were anticorrelated in the non-glioma cohort and IDH1/2 wild-type glioma subcohort but not correlated in the IDH1/2-mutated subcohort. Most glioma cell lines did not express MGMT mRNA. In the cell lines tested for carmustine response, sensitivity was negatively correlated with body methylation and mRNA expression and positively correlated with promoter methylation. Our findings further expound the relationship between MGMT methylation patterns and alkylating agent response, with body methylation playing a significant role. The identified role of gene body methylation underscores the need to integrate the interplay between promoter and body methylation in clinical testing and predicting treatment outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1653-1663"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANXA1 Binds and Stabilizes EGFR to Promote Nasopharyngeal Carcinoma Radioresistance.","authors":"Ting Zeng, Ding Xiao, Wei Zhu, Di Wu, Hong Yi, Wei Huang, Shan-Shan Lu, Zheng-Zheng Yu, Qi Wen, Yun-Xi Peng, Li Yuan, Zhi-Qiang Xiao, Jinwu Peng","doi":"10.1158/1535-7163.MCT-24-0944","DOIUrl":"10.1158/1535-7163.MCT-24-0944","url":null,"abstract":"<p><p>Radioresistance is a serious obstacle to successful nasopharyngeal carcinoma (NPC) treatment. Annexin A1 (ANXA1) is associated with EGFR and is involved in EGFR-promoting tumors, but the mechanisms of ANXA1-stabilizing EGFR and its effect on NPC radioresistance are unclear. In this study, we report that ANXA1 competes with the E3 ubiquitin ligase Cbl for binding to EGFR and increases its stability by inhibiting Cbl-mediated EGFR ubiquitination degradation in NPC cells. ANXA1 increases in vitro and in vivo NPC cell radioresistance by stabilizing EGFR. Expression levels of ANXA1 and EGFR are positively correlated in NPC tissues and are significantly higher in the radioresistant NPC tissues than in the radiosensitive NPC tissues. Patients with NPC with high expression of both proteins have poorer overall survival and disease-free survival relative to patients with high expression of one protein alone, and a combination of ANXA1 and EGFR predicts NPC radiosensitivity superior to that of the individual proteins. Based on the amino acid residues of ANXA1 responsible for binding to EGFR, we developed a nine amino acid-long ANXA1-derived peptide (HDMNKVLDL), which disrupts the connection of ANXA1 with EGFR, successfully downregulates EGFR expression, and dramatically increases NPC cell radiosensitivity in vitro and in mice. Our findings suggest that ANXA1 promotes NPC radioresistance by binding to and stabilizing EGFR, and we present a strategy for targeting EGFR degradation and NPC radiosensitization with a peptide.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1611-1625"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of a Novel 2 + 2 BCMA × CD3 Bispecific Antibody for Minimized Cytokine Release and Potent Efficacy.","authors":"Danqing Wu, Lini Huang, Gaowa Naren, Rui Zhang, Shiyong Gong, Xuan Wu, Chengbin Wu","doi":"10.1158/1535-7163.MCT-24-0846","DOIUrl":"10.1158/1535-7163.MCT-24-0846","url":null,"abstract":"<p><p>Cytokine release syndrome remains a critical challenge for clinical use of bispecific T-cell engagers. We present the preclinical development of a novel B-cell maturation antigen × CD3 bispecific antibody with the aim of reducing cytokine release while maintaining potent efficacy in the treatment of multiple myeloma. Based on the Fabs-in-tandem (FIT) geometry, bispecific molecules with two target arms in cis-configuration were constructed. A panel of anti-CD3 mAbs with varying affinities was generated, and the impact of binding arm geometry, valency, and anti-CD3 affinity on the T-cell engager's safety and efficacy profile was evaluated both in vitro and in vivo. By comparing with different formats, including a reference tandem scFv, we show that both binding arm valency and CD3 affinity determine redirected T-cell cytotoxicity in vitro. The FIT-Ig with 2 + 2 binding valencies and medium CD3 affinity (CD3med FIT-Ig) can achieve the same potent antitumor activity as the reference tandem scFv, but it induced much less cytokine release. Importantly, bivalent CD3 binding does not introduce target-irrelevant T-cell activation in the FIT-Ig format. The low cytokine release profile of the CD3med FIT-Ig was further validated in human peripheral blood mononuclear cells engrafted mice and cynomolgus monkeys. The CD3med FIT-Ig (also known as EMB-06) could offer a differentiated safety profile with effective antitumor activity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1600-1610"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the SALL4 Promoter Inhibits the Growth of Rhabdoid Tumors.","authors":"Satoru Oya, Hideki Yoshida, Akimasa Tomida, Mitsuru Miyachi, Shigeki Yagyu, Yoshiki Katsumi, Ken Kikuchi, Kunihiko Tsuchiya, Eiichi Konishi, Subbaya Subramanian, Masato Yamamoto, Tomoko Iehara","doi":"10.1158/1535-7163.MCT-24-0710","DOIUrl":"10.1158/1535-7163.MCT-24-0710","url":null,"abstract":"<p><p>Rhabdoid tumors (RT) are highly aggressive pediatric malignancies with limited treatment options. SALL4, a gene essential for embryonic stem cell pluripotency and self-renewal, is frequently overexpressed in RTs. To exploit this, we developed a conditionally replicating oncolytic adenovirus (pSALL4-OAd) by placing the E1 region under the control of the SALL4 promoter, restricting viral replication to SALL4-positive cells. SALL4 protein expression was analyzed in 10 clinical RT specimens via IHC, whereas SALL4 mRNA levels and promoter activity were assessed in eight RT cell lines using qPCR and dual-luciferase assays. The replication selectivity and cytopathic effects of pSALL4-OAd were tested in vitro at doses of 0 to 1,000 viral particles/cell. In vivo, 1.0 × 107 G401 cells were implanted subcutaneously into immunodeficient mice, followed by intratumoral administration of pSALL4-OAd (3 × 1010 viral particles) or PBS. Tumor growth was monitored over the treatment period. SALL4 protein was detected in 40% of clinical RT specimens, and RT cell lines exhibited four- to 400-fold higher SALL4 mRNA levels compared with normal tissues. Elevated SALL4 promoter activity was confirmed in three of five RT cell lines. pSALL4-OAd selectively replicated in SALL4-positive cells and induced significant cytopathic effects proportional to promoter activity in vitro. In vivo, pSALL4-OAd administration caused tumor necrosis, reduced SALL4-positive cells, and suppressed tumor proliferation. These results demonstrate the potential of pSALL4-OAd as a targeted and effective therapeutic strategy for SALL4-expressing RTs.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1527-1536"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}