Molecular Cancer Therapeutics最新文献

{"title":"Combined ATR and mitotic inhibition is effective against MYCN-amplified neuroblastoma.","authors":"Katarzyna Radke, Karin Hansson, Subhayan Chattopadhyay, Dora Adamic, Aleksandra Adamska, Javanshir Esfandyari, Martina Pasetto, Raka Mitra, Jani Saarela, Aleksandr Ianevski, Philipp Ianevski, Aurélie Baudet, Mattias Magnusson, David Gisselsson, Kristina Aaltonen, Ruth H Palmer, Daniel Bexell","doi":"10.1158/1535-7163.MCT-26-0270","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0270","url":null,"abstract":"<p><p>High-risk neuroblastoma (NB) is an aggressive pediatric malignancy characterized by a high proliferative capacity, intrinsic replication stress, and poor clinical outcomes. Although mitotic inhibitors show preclinical efficacy, their clinical use is limited by dose-dependent toxicity. Here, we performed high-throughput combinatorial drug screening using MYCN-amplified human NB tumoroids to identify drugs with orthogonal mechanisms that synergize with low-dose mitotic inhibition. Promising drug combinations were prioritized using a multifactorial approach including dose-response matrices across multiple NB tumoroids and CD34⁺ cord blood cells, synergy area scores, and machine learning-based response predictions. Several therapeutic classes were selected, including kinase inhibitors, differentiation agents, and hormone therapies. Notably, combined ATR inhibition by elimusertib and mitotic KSP inhibition showed additive to mild synergy and induced NB cell death. This combination reduced tumor growth and prolonged survival in NB MYCN-amplified, chemoresistant patient-derived xenografts. Furthermore, alternating dosing schedules were well tolerated and maintained stable disease control in vivo. Collectively, these findings establish combined ATR and low-dose mitotic inhibition as a promising therapeutic strategy for MYCN-amplified NB.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224495","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 YAP/TEAD signaling disturbs RNA Pol II activity and enhances immunotherapy response via activated cytosolic DNA sensing pathway in gastroesophageal cancer.","authors":"Yan-Ting Yann Zhang, Ayna Mammedova, Dipti Athavale, Curt Balch, Mikel Ghelfi, Xiaodan Yao, Gennaro Calendo, Songjie Liu, David Pulipati, Yahui Li, Philip Evans, Xiaoxin Chen, Francis Spitz, Generosa Grana, Vladimir Khazak, Shumei Song","doi":"10.1158/1535-7163.MCT-25-1491","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1491","url":null,"abstract":"<p><p>Gastroesophageal adenocarcinoma (GEAC) is a significant global cancer burden. Our previous studies demonstrated that YAP/TEAD are highly expressed in GEAC, and play a critical role in tumor progression, therapy resistance, and metastasis. Thus, targeting YAP/TEAD signaling presents a promising therapeutic strategy. Here, we demonstrate that VT00278, a novel compound derived from YAP/TEAD inhibitor CA3, strongly downregulated YAP/TEAD transcriptional activity and potently suppressed tumor-promoting phenotypes including proliferation, invasion and tumor sphere formation. VT00278 induced apoptosis and inhibited tumor growth in vivo especially in radiation-resistant FLO-1 XTR esophageal cancer cells. Mechanistically, in addition to impairing YAP/TEAD signal, VT00278 or YAP depletion repressed RNA polymerase II (RNAPII) transcriptional regulators, reduced RNAPII S2 phosphorylation and decreased anti-apoptotic MCL-1 expression. More interestingly, VT00278 strongly inhibited DNA damage repair, activated cytosolic DNA sensing pathway, and upregulated innate immune genes (e.g., IFNβ). Meanwhile, the upregulation of PD-L1 in VT00278-treated tumor cells possibly contributes to a suppressive immune microenvironment. In a KP-luc2 syngeneic gastric cancer mouse model, combining VT00278 with anti-PD-1 therapy strongly inhibited tumor growth, increased CD3+ and CD8+ T cell infiltration, and induced the production of IFNγ from CD3 and CD8 cells. These findings support that targeting YAP/TEAD with VT00278 as a promising novel therapeutic strategy for GEAC treatment, either alone or in combination with immunotherapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137913","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":"PLK1 inhibition by onvansertib enhances paclitaxel efficacy and overcomes resistance in HR+/HER2- breast cancer refractory to endocrine therapy and CDK4/6 inhibitors.","authors":"Sreeja Sreekumar, Migdalia E Gonzalez, Davis Klein, Zeena Eblimit, Elodie Montaudon, Peter J P Croucher, Héloïse Derrien, Laura Sourd, Chu-Chiao Wu, Tod Smeal, Elisabetta Marangoni, Maya Ridinger","doi":"10.1158/1535-7163.MCT-26-0239","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0239","url":null,"abstract":"<p><p>Hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer that progresses on CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) faces a major therapeutic challenge, and chemotherapy is frequently used despite its modest clinical benefit. Paclitaxel is commonly used in this setting; however, intrinsic and acquired resistance substantially limit the depth and durability of response. Polo-like kinase 1 (PLK1) is a key mitotic regulator implicated in resistance to taxanes and ET/CDK4/6i. We evaluated whether PLK1 inhibition with onvansertib enhances paclitaxel activity in HR+ breast cancer models with intrinsic or acquired ET/CDK4/6i resistance, testing across six cell lines and eight patient-derived xenograft models, including paclitaxel-resistant tumors. The combination synergistically inhibited cell viability in vitro and improved antitumor efficacy in xenograft models. Notably, the combination induced tumor regression across all paclitaxel-resistant models, with complete responses in more than half of treated animals in three of five models, and deep, durable regressions in paclitaxel-sensitive models, markedly outperforming either agent alone. Mechanistically, the combination exacerbated mitotic stress, disrupted spindle architecture, suppressed proliferative and cell-cycle-associated transcriptional programs, and promoted proteasome-dependent c-MYC degradation, resulting in enhanced apoptotic cell death in vitro and in vivo. Importantly, genetic modulation of c-MYC expression altered the apoptotic response, establishing c-MYC downregulation as a key mediator of the observed antitumor efficacy. Collectively, these findings support PLK1 inhibition as a mechanistically rational strategy to potentiate taxane efficacy and overcome resistance in advanced HR+/HER2-negative breast cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137902","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":"Preclinical Characterization of ADCT-241, an Exatecan-Based Antibody-Drug Conjugate Against PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.","authors":"Asma Jabeen, Ben Leatherdale, Rebecca Martin, Valenti Gomez, Danilo Cucchi, Banusha Rajeenthira, Hafsah Omar, Alison Faid, Pedro L Alves, Kristina Zaitseva, Nicolas Veillard, Narinder Janghra, Veronica Ilkow, Elizabeth Horsley, Lina Baxter, Christopher Gallagher, Cecile Oblette, Paul W Hogg, Monika Lamba Saini, Lolke de Haan, Charles Britten, Chris Pickford, Patrick H van Berkel","doi":"10.1158/1535-7163.MCT-25-1241","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1241","url":null,"abstract":"<p><p>Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with elevated expression in primary and metastatic prostate cancer (PCa) compared with normal prostate tissues; with low levels in renal proximal tubules, small intestine, and the brain. PSMA is a clinically validated target and is associated with progression and aggressiveness of disease. ADCT-241 is a novel antibody-drug conjugate (ADC) composed of the fully human monoclonal antibody (mAb) 2A10, directed against PSMA, to which the exatecan-containing PL2202 payload was stochastically conjugated with a drug-to-antibody ratio of 4. 2A10 was selected over J591, as it showed good binding affinity, a better half-life, and superior internalization properties and antitumor activity compared with a J591-based ADC. ADCT-241 showed specific, potent killing of PCa cell lines in vitro and antitumor efficacy in vivo in PCa cell line and patient-derived xenografts. ADCT-241 showed target-dependent internalization, topoisomerase 1 (TOP1) inhibition, cell cycle arrest at G2/M phase followed by apoptosis-induced cell death, and in vitro bystander activity. In rats and cynomolgus monkeys, ADCT-241 was well tolerated at dose levels ≤150 and 75 mg/kg, respectively, following dosing on day 1 and 22. Circulating serum total antibody, total ADC, and free exatecan concentrations showed good in vivo stability and a half-life of 8 to 10 days in cynomolgus monkeys. ADCT-241 demonstrated potent, specific in vitro and in vivo antitumor activity and it was stable and well tolerated in rats and cynomolgus monkeys, warranting progression of ADCT-241 into clinical trials in patients with metastatic castration-resistant PCa.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128230","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":"Variant-selective and pan-RAS inhibitors enhance targeted agent activity in patient-derived multi-cell type tumor spheroids.","authors":"Thomas S Dexheimer, Zahra Davoudi, Nathan P Coussens, Thomas Silvers, Eric M Jones, Naoko Takebe, James H Doroshow, Beverly A Teicher","doi":"10.1158/1535-7163.MCT-26-0200","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0200","url":null,"abstract":"<p><p>RAS genes are among the most frequently altered oncogenes in cancer. Recently developed agents selectively target specific RAS variants or broadly inhibit multiple RAS alterations, including oncogenic variants and amplifications. Four RAS-targeted inhibitors were evaluated in combination with pathway-directed agents across twenty-nine solid tumor models, including twenty-six patient-derived lines from the NCI Patient-Derived Models Repository and three established cell lines. Multi-cell type tumor spheroids were generated using malignant (60%), endothelial (25%), and mesenchymal stem cells (15%). Drug response was assessed by seven-day viability and longitudinal volumetric imaging. As single agents, the KRAS G12C inhibitors elironrasib (RMC-6291) and divarasib, and the KRAS G12D inhibitor MRTX1133, demonstrated variant-selective activity. The pan-RAS(ON) inhibitor daraxonrasib (RMC-6236) suppressed growth across models harboring diverse RAS alterations and wild-type RAS, consistent with broader RAS pathway dependence. All four RAS inhibitors produced positive Bliss scores with SHP2 inhibition and reductions in viability and spheroid volume, consistent with vertical blockade of RAS-MAPK signaling. Daraxonrasib with the MEK inhibitor cobimetinib produced predominantly additive responses with localized Bliss-defined synergy. In addition, daraxonrasib and MRTX1133 combinations with PI3K-AKT-mTOR inhibitors reduced viability and localized positive Bliss scores, with many matrices remaining predominantly additive. MRTX1133 combinations reduced viability and produced the highest positive Bliss scores in KRAS G12D models, whereas daraxonrasib exhibited broader activity across RAS genotypes. These findings provide mechanistic support for rational combination strategies targeting convergent RAS effector pathways and inform the design of genotype-directed clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128146","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":"GNTbm-38, a Novel Epigenetic Modulator, Performs Immune Activation and Reprogramming of the Tumor Microenvironment.","authors":"Chia-Nan Chen, Cheng-Han Chou, Yi-Hong Wu, Mu-Hsuan Yang, Sz-Hao Chu, Ye-Su Chao, Jia-Shiong Chen","doi":"10.1158/1535-7163.MCT-25-1441","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1441","url":null,"abstract":"<p><p>The efficacy of immunotherapy depends on the composition of immune cells, including cytotoxic T cells (CTLs), etc., in the tumor microenvironment (TME). However, a significant proportion of patients with pre-existing immunity fail to respond to current immunotherapy, indicating the search of drugs/combinations with therapeutic potential for unmet medical needs for patients with CTL-low immune phenotypes is an urgent task, and the exploring of strategies by combining different agents like vascular endothelial growth factor receptor (VEGFR) inhibitors with additional immunomodulatory agents is still under extensive studies. Here, by using murine colon carcinoma (CT26) allograft and xenograft models, we examined the efficacy of a novel epigenetic immunomodulator (GNTbm-38) combined with regorafenib. TME reprogramming was assessed using flow cytometry and RNA sequencing to elucidate the novel mechanisms and their correlation with therapeutic effects in mice with significant treatment responses. Notably, CT26-bearing mice treated with GNTbm-38 plus regorafenib showed significant objective response rates (ORRs) and overall survival (OS). After treatment, analyses of immunohistochemistry (IHC) and flow cytometry revealed increased infiltration of activated CD8+ T cells in the TME, triggering a reprogramming mechanism by attenuating immunosuppressive cells and restoring T-cell activation to enhance ORR and OS. This result suggests that GNTbm-38-mediated TME reprogramming, combined with regorafenib, produces a synergistic effect, making it advantageous for achieving high ORR and maintaining long-lasting anti-tumor activity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128218","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":"Oncolytic Herpes Virus G47Δ Potentiates ADCC-Inducing Molecular Targeted Therapy via Coordinated Activation of Innate and Adaptive Immune Responses.","authors":"Takafumi Nagatomo, Miwako Iwai, Minoru Tanaka, Hiroshi Nishino, Tomoki Todo","doi":"10.1158/1535-7163.MCT-25-1350","DOIUrl":"10.1158/1535-7163.MCT-25-1350","url":null,"abstract":"<p><p>Antibody-dependent cellular cytotoxicity (ADCC) is a key player in the antitumor immunity elicited through molecular targeted therapy of oncogenic receptors using monoclonal antibodies (mAb). Oncolytic viruses represent an alternative therapeutic means that selectively replicate in and destroy tumor cells, as well as induce specific antitumor immune responses. This study investigates whether oncolytic virus therapy using G47Δ, a third-generation oncolytic herpes virus with enhanced induction of antitumor immunity, can augment the efficacy of molecular targeted therapy with ADCC using the anti-epidermal growth factor receptor (EGFR) mAb cetuximab. Due to the species specificity of cetuximab, we developed a human EGFR-expressing immunocompetent murine tumor model specific to the ADCC activity of cetuximab. Intratumoral G47Δ administration combined with systemic cetuximab treatment was significantly more effective in suppressing tumor growth than G47Δ monotherapy. This phenomenon was dependent upon the activation of both innate and adaptive immune cells, as antitumor responses were abrogated upon natural killer cell and CD8+ T-cell depletion. Further studies investigating the draining lymph node dendritic cells (DC) indicate that the destruction of cetuximab-coated tumor cells by G47Δ promotes uptake of tumor cells by DCs, enhances the priming of immune responses, and subsequently stimulates tumor-specific CD8+ T cells. These results suggest that the combination of G47Δ therapy and molecular targeted therapies with ADCC activity may represent a useful therapeutic strategy for enhancing antitumor immune responses, even after the emergence of acquired resistance.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1691-1701"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840536","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":"HDAC Inhibition Unlocks Tumor Plasticity and Enhances Immunotherapy Response in Myc-Driven Small Cell Lung Cancer.","authors":"Azam Ghafoor, Linying Zhu, Zoe Weaver Ohler, Rajaa El Meskini, Haoxuan Ying, Devon Atkinson, Amanda Day, Nathan Pate, Laura Bassel, Weixin Wang, Katherine R Calvo, Lorinc Pongor, Kanak Parmar, Yves Pommier, Anish Thomas, Yilun Sun","doi":"10.1158/1535-7163.MCT-25-1077","DOIUrl":"10.1158/1535-7163.MCT-25-1077","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is a highly aggressive malignancy, accounting for approximately 15% of all lung cancer cases. Characterized by low immunogenicity, SCLC may utilize epigenetic mechanisms to evade immune detection. In this study, we demonstrate that entinostat, a class I histone deacetylase inhibitor, upregulates immune-related genes in human SCLC cells. In vivo, we confirmed that entinostat treatment increased the expression of immune checkpoint ligands and antigen presentation machinery in Myc-driven tumors in a Rb1/Trp53/MycT58A (RPM) SCLC mouse model while shifting tumors from a neuroendocrine (NE)-high phenotype to a NE-low phenotype and was associated with increased T-cell infiltration. Notably, combining entinostat with anti-PD-1 immunotherapy suppresses tumor growth and significantly prolongs survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1664-1677"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817769","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":"TRPM4 Expression as a Predictive Biomarker and a Mechanistic Driver of Acetalax Activity in Prostate Cancer: Preclinical Efficacy Studies.","authors":"Yuka Hoshi-Kadonosawa, William C Reinhold, Daiki Taniyama, Yoshitaka Inoue, Augustin Luna, Suresh Kumar, Nai-Yun Sun, Yoo Sun Kim, Juan Juan Yin, Nitin Roper, Adam G Sowalsky, William D Figg, Naoko Takebe, Yves Pommier","doi":"10.1158/1535-7163.MCT-26-0011","DOIUrl":"10.1158/1535-7163.MCT-26-0011","url":null,"abstract":"<p><p>Advanced and treatment-refractory prostate cancer, including castration-resistant disease, requires new therapeutic strategies. Transient receptor potential melastatin 4 (TRPM4), a calcium-activated monovalent cation channel, regulates cell volume and promotes cancer progression. Acetalax induces oncosis-like death in TRPM4-positive triple-negative breast cancers, suggesting a TRPM4-dependent vulnerability. In this study, we investigated whether TRPM4 expression defines Acetalax sensitivity in prostate cancer. We compared Acetalax sensitivity in TRPM4-high and -low prostate cancer cell lines, including androgen-dependent (LNCaP), castration-resistant (22Rv1), and androgen-independent (PC3 and DU145) models. We evaluated TRPM4 dynamics and oncosis-associated phenotypes using Western blotting and immunofluorescence. Resistant clones were developed through continuous drug exposure. TRPM4 expression in patient samples was analyzed using prostate cancer tissue microarray and The Cancer Genome Atlas. Transcriptional changes following TRPM4 loss were examined by RNA sequencing (RNA-seq). Antitumor activity and tolerability were evaluated in TRPM4-positive patient-derived xenograft (PDX) models. TRPM4-high cells (PC3, LNCaP, and 22Rv1) underwent oncosis-like swelling and TRPM4 degradation upon Acetalax exposure, whereas TRPM4-low cell and resistant clones (DU145 and chronic exposure cells) remained insensitive and lacked TRPM4 expression. RNA-seq revealed transcriptomic remodeling associated with TRPM4 loss. TRPM4 was significantly increased in tumors compared with normal tissues and was unchanged across stages or Gleason scores. In TRPM4-positive PDX models, Acetalax (300 mg/kg) significantly suppressed tumor growth without body weight loss, indicating antitumor efficacy without overt toxicity. TRPM4 is a mechanistic driver and predictive biomarker of Acetalax response in prostate cancer, supporting TRPM4-dependent targeting and providing a rationale for the clinical development of Acetalax for TRPM4-expressing and treatment-refractory prostate cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1755-1770"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776591","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":"NAPRT Expression and Epigenetic Regulation in Pediatric Rhabdomyosarcoma as a Potential Biomarker for NAMPT Inhibition.","authors":"Angela Kim, Prateek Bhardwaj, Shahyan Rehman, Sophia J Zhao, Karlie N Lucas, Katelyn J Noronha, Deepti Bhatt, Sam Friedman, Raffaella Morotti, Ranjini K Sundaram, Filemon S Dela Cruz, Tamar Y Feinberg, Subhash Ramakrishnan, Wei Xue, Donald A Barkauskas, David Hall, Jack F Shern, Wenyue Sun, Frederic G Barr, Jae-Sung Yi, Josh Spurrier, Amy Yu, Charles Brenner, Collin D Heer, Christine M Heske, Juan C Vasquez","doi":"10.1158/1535-7163.MCT-25-0619","DOIUrl":"10.1158/1535-7163.MCT-25-0619","url":null,"abstract":"<p><p>New treatments are needed to improve survival in children with rhabdomyosarcoma (RMS). Nicotinamide adenine dinucleotide (NAD+) biosynthesis, regulated by the enzymes nicotinic acid phosphoribosyltransferase (NAPRT) and nicotinamide phosphoribosyltransferase (NAMPT), represents a metabolic vulnerability due to high NAD+ turnover in cancers. Although NAMPT inhibitors (NAMPTi) show preclinical promise, clinical translation has been limited by toxicity and the lack of predictive biomarkers. In this study, we evaluated NAPRT expression in RMS and its potential as an actionable biomarker to guide NAMPTi therapy. NAPRT promoter methylation, transcript levels, and protein expression were assessed in RMS cells, patient-derived xenografts (PDX), and primary tumors (n = 109) from the Children's Oncology Group. In vitro sensitivity to NAMPTi was tested in isogenic RMS cell lines, examining the role of NAPRT expression in mediating cytotoxicity and the ability of nicotinic acid (NA) to rescue viability. In vivo efficacy was assessed using cell-derived, NAPRT-isogenic, and orthotopic PDX models. NAPRT promoter hypermethylation was found in a subset of RMS models and patient samples. Immunohistochemistry showed loss of NAPRT protein in 30% to 40% of tumors, defined as <1% tumor cell staining. Methylation modestly correlated with protein expression. NAPRT-deficient cells were highly sensitive to NAMPTi, driven by NAD+ depletion and not reversible with NA. In vivo, NAMPTi induced significant tumor regression, which was not abrogated with NA administration in NAPRT-deficient models. NAPRT loss occurs in a subset of RMS and may offer a biomarker-driven strategy to expand the therapeutic window of NAMPTi. Further research is needed to understand NAPRT regulation and optimize biomarker assays in future clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1771-1784"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776458","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}