Molecular Cancer Therapeutics最新文献

{"title":"Correction: Heat Shock Protein-90 Inhibition Alters Activation of Pancreatic Stellate Cells and Enhances the Efficacy of PD-1 Blockade in Pancreatic Cancer.","authors":"Yuchen Zhang, Michael B Ware, Mohammad Y Zaidi, Amanda N Ruggieri, Brian M Olson, Hannah Komar, Matthew R Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M Sarmiento, Rafi Ahmed, Shishir K Maithel, Bassel F El-Rayes, Gregory B Lesinski","doi":"10.1158/1535-7163.MCT-26-0614","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0614","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"25 8","pages":"1409"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670064","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":"Correction: ONC212 is a Novel Mitocan Acting Synergistically with Glycolysis Inhibition in Pancreatic Cancer.","authors":"Isacco Ferrarini, Anna Louie, Lanlan Zhou, Wafik S El-Deiry","doi":"10.1158/1535-7163.MCT-26-0613","DOIUrl":"10.1158/1535-7163.MCT-26-0613","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"25 8","pages":"1408"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670122","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":"PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4.","authors":"Calvin Lam, Arjun Dhir, Arnob Mitro, Chinmay M Jogdeo, Sipra Panda, Ekta Kapoor, Siyuan Tang, Victor J Rivero, Erin M McIntyre, Donald W Coulter, Peng Xiao, Adrian R Black, Kyle Hewitt, Svetlana Romanova, Samantha A Swenson, David Oupicky, R Katherine Hyde","doi":"10.1158/1535-7163.MCT-25-1004","DOIUrl":"10.1158/1535-7163.MCT-25-1004","url":null,"abstract":"<p><p>PAMD-Ch17 is a polymer composed of the CXCR4 inhibitor AMD3100/Plerixafor with a cholesterol modification. In previous work, we showed that PAMD-Ch17, but not AMD3100, induces cell death and differentiation in mouse acute myeloid leukemia cells. To investigate the mechanism of PAMD-Ch17's novel antileukemic effects, we tested PAMD-Ch17 against a panel of human leukemia cell lines and found that PAMD-Ch17 is effective against a variety of acute leukemias, with T-cell acute lymphoblastic leukemia (T-ALL) cell lines being highly sensitive. Surprisingly, CXCR4 knockout T-ALL cells were equally sensitive to PAMD-Ch17. Using a fluorescently tagged PAMD-Ch17, we found that the drug colocalized to mitochondria. We also found that PAMD-Ch17 induced changes in the expression of genes related to mitochondrial function, increased levels of mitochondrial superoxide, and decreased mitochondrial membrane potential. Using Seahorse assays, we found that PAMD-Ch17 decreased baseline oxygen consumption, ATP production, and proton leakage. In addition, we identified ATP synthase subunits as binding partners of PAMD-Ch17 and showed that the polymer, but not AMD3100, inhibited ATP synthase activity. In mouse primary T-ALL, but not healthy bone marrow cells, PAMD-Ch17 induced both mitochondrial superoxide and cell death. Using human bone marrow organoids, we found that PAMD-Ch17 induced mitochondrial superoxide and cell death in T-ALL cells from patients, but not in healthy stromal and hematopoietic cells. Collectively, our results indicate that PAMD-Ch17 has antileukemic effects against T-ALL cells but not healthy cells, likely mediated through a CXCR4-independent, mitochondrial-based mechanism. These findings support the further development of PAMDs as potential therapeutics for patients with T-ALL.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1369-1380"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13107973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147530703","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":"TAK-901 Targeted Inhibition of EGFR Activates Transcription Factor FOXO, Causing Cell-cycle Arrest and Apoptosis in Bladder Cancer.","authors":"Lanpeng Lu, Hui Cheng, Shanhui Liu, Yan Tao, Shengjun Fu, Jianzhong Lu, Yuwen Gong, Hui Ding, Junqiang Tian, Lanlan Li, Zhiping Wang","doi":"10.1158/1535-7163.MCT-25-0507","DOIUrl":"10.1158/1535-7163.MCT-25-0507","url":null,"abstract":"<p><p>Bladder cancer is the most prevalent malignancy of the urinary tract, characterized by an unfavorable prognosis, elevated rates of recurrence, and a lack of targeted therapeutic approaches. In this research, we evaluated the efficacy of TAK-901, a specific inhibitor targeting Aurora kinase, and elucidated the anticancer mechanisms in bladder cancer. TAK-901 exhibited a dose-dependent inhibition of proliferation, colony formation, and migration, as well as the induction of apoptosis in T24 and UMUC-3 cells. Additionally, bladder cancer cells underwent cell-cycle arrest at the G2-M-phase when exposed to TAK-901. Mechanistic studies revealed that the targeted inhibition of epidermal growth factor receptor (EGFR) by TAK-901 affected AKT and forkhead box class O3a (FOXO3a) phosphorylation, leading to the activation of FOXO-dependent transcriptional activity, which subsequently triggered apoptotic pathways by inducing BIM expression. Furthermore, our study demonstrated that TAK-901 attenuated tumor growth in the UMUC-3-luciferase xenograft model and significantly reduced Ki-67 expression in tumor tissues. Finally, we propose a novel treatment strategy involving the synergistic inhibition of bladder cancer cell growth by combining TAK-901 with afatinib. Our research strongly suggests that Aurora A and Aurora B are promising epigenetic therapeutic targets in bladder cancer. Furthermore, TAK-901 can function as a targeted kinase inhibitor and EGFR inhibitor for the treatment of bladder cancer by activating the FOXO signaling pathway, which induces apoptosis in bladder cancer cells.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1317-1329"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998660","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":"MCT1 Inhibition Remodels the Tumor Immune Microenvironment for Enhanced Cancer Immunotherapy.","authors":"Yipeng Zhang, Chun Liu, Fuxin Han, Chuan Tong, Yelei Guo, Yuting Lu, Weidong Han, Yao Wang","doi":"10.1158/1535-7163.MCT-25-1026","DOIUrl":"10.1158/1535-7163.MCT-25-1026","url":null,"abstract":"<p><p>Despite advances in cancer immunotherapies such as immune checkpoint blockade (ICB), durable patient responses remain constrained, which is largely due to the highly suppressive tumor immune microenvironment (TIME). In this study, by analyzing cohorts of patients with pan-cancer and experimental validation, we found that monocarboxylate transporter 1 (MCT1) expression is broadly upregulated in malignant and myeloid compartments within the TIME. MCT1 expression is also associated with worse survival, a suppressive TIME state, and poor treatment response to ICB therapy. Functionally, MCT1-mediated lactate uptake by tumor cells and tumor-associated macrophages (TAM) suppresses CD8+ T-cell activation and cytotoxicity in the ex vivo coculture models. Mechanistically, lactate exposure and uptake via MCT1 in tumor cells and TAMs induce IL10 production, which contributes to the inhibition of the antitumor response of CD8+ T cells. Moreover, in MC38 and LLC mouse cancer models, pharmacologic MCT1 inhibition reprograms the immunosuppressive myeloid populations, improves CD8+ T-cell infiltration and function, and triggers tumor regression. Therefore, these results indicate that MCT1 has the potential to be a biomarker for patients across cancer types and to be a promising therapeutic target for enhanced cancer immunotherapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1330-1341"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998638","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":"Retraction: A Novel Therapeutic Induces DEPTOR Degradation in Multiple Myeloma Cells with Resulting Tumor Cytotoxicity.","authors":"Mario I Vega, Yijiang Shi, Patrick Frost, Sara Huerta-Yepez, Gabriela Antonio-Andres, Rogelio Hernandez-Pando, Jihye Lee, Michael E Jung, Joseph F Gera, Alan Lichtenstein","doi":"10.1158/1535-7163.MCT-26-0617","DOIUrl":"10.1158/1535-7163.MCT-26-0617","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"25 8","pages":"1413"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670069","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":"Retraction: Inhibition of SAPK2/p38 Enhances Sensitivity to mTORC1 Inhibition by Blocking IRES-Mediated Translation Initiation in Glioblastoma.","authors":"Cheri Cloninger, Andrew Bernath, Tariq Bashir, Brent Holmes, Nicholas Artinian, Teresa Ruegg, Lauren Anderson, Janine Masri, Alan Lichtenstein, Joseph Gera","doi":"10.1158/1535-7163.MCT-26-0616","DOIUrl":"10.1158/1535-7163.MCT-26-0616","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"25 8","pages":"1412"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670095","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":"VHH-Based CAR-T Cells Targeting DLL3 Show High Efficacy in Small Cell Lung Cancer Models.","authors":"Han Guo, Chunjiang Yue, Di Ma, Jingyi Zhou, Min Tang, Rongze Sun, Binle Tian, Zhaoying Wang, Yishu Xing, Chenjun Lv, Chuan Liu, Lin Yuan, Xuekai Zhu, Yunfeng Feng, Qi Li","doi":"10.1158/1535-7163.MCT-25-0965","DOIUrl":"10.1158/1535-7163.MCT-25-0965","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high relapse rate, limited treatment options, and a poor prognosis. Delta-like ligand 3 (DLL3) has emerged as a promising target for SCLC. Notably, chimeric antigen receptor T (CAR-T) cells that use the variable domain of heavy-chain-only antibodies (VHH) demonstrate superior efficacy compared with their ScFv counterparts. However, the therapeutic effectiveness of anti-DLL3 VHH CAR-T cells is yet to be fully explored. To leverage the therapeutic potential of VHHs, we first immunized alpacas and screened for anti-DLL3 VHHs using yeast display. Then, 1-B12 and 5 identified the positive clones and compared them based on their affinity, specificity, and cytotoxicity in CAR-T cell models. Moreover, 1-B12 was selected as the humanized sequence due to its higher affinity, greater specificity, and stronger cytotoxicity. Finally, the functionality of the four humanized VHH-CAR-T cells from the 1-B12 sequence was evaluated through in vitro assays that measured cytokine production and cytotoxicity, followed by in vivo studies to assess their antitumor efficacy. The anti-DLL3 VHHs exhibited strong affinity, specificity, and cytotoxicity in CAR-T cell models. Notably, the HM-CAR-T cells exhibited robust cytokine secretion and cytotoxic activity against tumor cells. Moreover, these HM-CAR-T cells demonstrated significant antitumor efficacy in vivo. This study highlights effective strategies for developing DLL3-specific VHHs and their application in CAR-T therapy, which supports their clinical potential as a promising immunotherapeutic approach for cancers that express DLL3.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1305-1316"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165971","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 Menin in T-lineage Acute Lymphoblastic Leukemia.","authors":"Kathryn Shimamoto, Diren Arda Karaoglu, Olivia Arnold, Arjun Dhar, Zachary Chan, Giorgia Giordano, Jason X Cheng, Hamed R Youshanlouei, Anand A Patel, Adam S DuVall, Michael W Drazer, Linda Kessler, Francis Burrows, Olatoyosi Odenike, Michael J Thirman, Wendy Stock, Caner Saygin","doi":"10.1158/1535-7163.MCT-25-0969","DOIUrl":"10.1158/1535-7163.MCT-25-0969","url":null,"abstract":"<p><p>T-lineage acute lymphoblastic leukemia (T-ALL) lacks effective targeted therapies, with poor outcomes in relapsed/refractory (R/R) disease. HOXAhigh T-ALL is biologically aggressive and often resistant to standard therapy. Menin inhibitors, recently approved for KMT2A-rearranged leukemias, may be effective in T-ALL, but biomarkers of response remain undefined. This study aims to evaluate the efficacy of menin inhibition in T-ALL and identify molecular predictors of sensitivity. We tested menin inhibitors (ziftomenib, revumenib, and VTP50469) in 14 primary T-ALL samples and 8 cell lines, representing HOXAhigh and HOXAlow genotypes. In vitro sensitivity assays, xenograft mouse models, transcriptomics, proteomics, and phosphoproteomics were used to characterize drug response. MEF2C modulation experiments and combination studies with cyclin-dependent kinase (CDK) 1/2 and ERK1/2 inhibitors were performed in vitro and in vivo. Menin inhibitors suppressed leukemic growth in a subset of HOXAhigh and HOXAlow primary human T-ALL samples. Similarly, ziftomenib was effective in reducing tumor burden in xenografts without major toxicity. Upon treatment, we observed downregulation of canonical menin targets (HOXA, MEIS1, and MEF2C) and upregulation of T-cell differentiation programs. Phosphoproteomic studies identified MEF2C S222 phosphorylation-mediated by CDK1/2 and ERK1/2-as a predictor of ziftomenib sensitivity in T-ALL. MEF2C overexpression promoted proliferation and ziftomenib resistance, whereas its knockdown impaired growth. Ziftomenib synergized with CDK1/2 and ERK1/2 inhibitors in vitro and improved survival in xenografted mice. In conclusion, a subset of T-ALL, defined by high p-MEF2C S222, is sensitive to menin inhibition. Combining ziftomenib with CDK or ERK inhibition offers synergistic efficacy, supporting biomarker-driven clinical trials of this strategy in R/R T-ALL.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1294-1304"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355812","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":"Unfolded Protein Response as a Therapeutic Target: 4-(Heptyloxy)phenol Induces Programmed Cell Death in Ewing Sarcoma.","authors":"Nenggang Zhang, Mary Perez, Gaye N Jenkins, Terzah M Horton, Scott R Gilbertson, Debananda Pati","doi":"10.1158/1535-7163.MCT-25-0798","DOIUrl":"10.1158/1535-7163.MCT-25-0798","url":null,"abstract":"<p><p>Ewing sarcoma is a rare and aggressive pediatric malignancy with limited therapeutic options, particularly for relapsed or refractory cases, highlighting the urgent need for innovative treatment strategies. In this study, we identify endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as critical therapeutic vulnerabilities in Ewing sarcoma and introduce 4-(heptyloxy)phenol (AC-45594) as a novel small-molecule agent that exploits these stress pathways. AC-45594 selectively inhibited the growth of Ewing sarcoma cells among 13 cancer and 6 noncancerous cell lines, demonstrating marked tumor specificity. Structure-activity relationship studies revealed that both the phenolic hydroxyl group and an optimal alkoxy chain length (7-9 carbon atoms) are essential for its activity. Mechanistically, AC-45594 induces ERS, activates UPR, and drives a shift from adaptive to terminal stress signaling, culminating in apoptosis of Ewing sarcoma cells. Proteomic and gene expression analyses further supported the selective activation of proapoptotic UPR signaling. These findings establish ERS and UPR as actionable targets in Ewing sarcoma and position AC-45594 as a first-in-class compound capable of selectively inducing stress-driven cell death. This work lays the foundation for a new class of therapeutics targeting maladaptive stress responses in pediatric sarcomas and potentially other hard-to-treat cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1342-1356"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157675","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}