OncotargetPub Date : 2025-10-16DOI: 10.18632/oncotarget.28772
Ashley C Dodd, Nitin R Wadhwani, Alison Lehane, Rom Brown, Kyle L MacQuarrie, Seth D Goldstein, Timothy B Lautz
{"title":"Widespread folate receptor expression in pediatric and adolescent solid tumors - opportunity for intraoperative visualization with the novel fluorescent agent pafolacianine.","authors":"Ashley C Dodd, Nitin R Wadhwani, Alison Lehane, Rom Brown, Kyle L MacQuarrie, Seth D Goldstein, Timothy B Lautz","doi":"10.18632/oncotarget.28772","DOIUrl":"10.18632/oncotarget.28772","url":null,"abstract":"<p><p>Contemporary fluorescence-guided surgery has evolved principally based on the uses and limitations of the contrast agent indocyanine green (ICG). A second generation of novel fluorescent agents are under development to target specific molecular markers on tumor cells and/or the tumor micro-environment. Pafolacianine, a molecular agent targeting the folate receptor (FR), is the first of these approved for use in adults, but its potential utility in pediatric cancers is unknown. In this study, we performed immunohistochemistry staining on slides obtained from a range of pediatric patients with solid tumors. Slides were stained with antibodies to FRα and FRβ, and fluorescence was quantified. Separately, publicly available RNA sequencing data were queried for both FRα and FRβ expression in various pediatric tumors.</p>","PeriodicalId":19499,"journal":{"name":"Oncotarget","volume":"16 ","pages":"759-767"},"PeriodicalIF":0.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncotargetPub Date : 2025-10-13DOI: 10.18632/oncotarget.28770
Hugo Jimenez, Denise Gibo, Sambad Sharma, Michael Pennison, Lance D Miller, Minghui Wang, Kimberly Sheffield, Liyue Zhang, Allan Johansen, Preeya Achari, Callum Mcgrath, Sean Lester, Jason Tang, Kojo Agyemang, Annette Johnson, Christopher T Whitlow, Michael Chan, Kounosuke Watabe, Ralph D'Agostino, Janaka Liyanage, Asfar Azmi, Geoffrey Barger, Alexandre Barbault, Glenn J Lesser, Waldemar Debinski, Boris C Pasche
{"title":"Treatment of glioblastoma with tumor-specific amplitude-modulated radiofrequency electromagnetic fields.","authors":"Hugo Jimenez, Denise Gibo, Sambad Sharma, Michael Pennison, Lance D Miller, Minghui Wang, Kimberly Sheffield, Liyue Zhang, Allan Johansen, Preeya Achari, Callum Mcgrath, Sean Lester, Jason Tang, Kojo Agyemang, Annette Johnson, Christopher T Whitlow, Michael Chan, Kounosuke Watabe, Ralph D'Agostino, Janaka Liyanage, Asfar Azmi, Geoffrey Barger, Alexandre Barbault, Glenn J Lesser, Waldemar Debinski, Boris C Pasche","doi":"10.18632/oncotarget.28770","DOIUrl":"10.18632/oncotarget.28770","url":null,"abstract":"<p><strong>Background: </strong>Intrabuccal administration of amplitude-modulated 27.12 MHz radiofrequency electromagnetic fields (AM RF EMF) resulting in the systemic delivery of low and safe levels of AM RF EMF has shown activity in several forms of cancer.</p><p><strong>Methods: </strong>Glioblastoma (GB) cell lines were exposed to GB-specific AM RF EMF (GBMF) three hours per day at a level of exposure identical to patients during treatment. Cellular assays and agnostic genomic approaches were used to characterize the mechanism-of-action. One patient with therapy refractory GB received compassionate use treatment with GBMF as well as a second patient with refractory oligodendroglioma.</p><p><strong>Results: </strong>Treatment with GBMF inhibited the proliferation of several GB cell lines. CACNA1H mediates the effect of GBMF. GBMF modulates the \"Mitotic Roles of Polo-Like Kinase\" pathway resulting in the disruption of GB mitotic spindle. There was evidence of clinical and radiological benefit in a 38-year-old patient with recurrent GB and evidence of safety and feasibility in a 47-year-old patient with oligodendroglioma.</p><p><strong>Conclusions: </strong>This is the first report showing <i>in vitro</i> antitumor activity, disruption of the mitotic spindle, activation of the Mitotic Roles of Polo-like kinase pathway in GB. This is also the first report showing feasibility and clinical activity in patients with brain tumor.</p>","PeriodicalId":19499,"journal":{"name":"Oncotarget","volume":"16 ","pages":"741-757"},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12517218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncotargetPub Date : 2025-10-06DOI: 10.18632/oncotarget.28769
Kyle R Cron, Ping Fang, Oanh Pham, Julie Janes, John Brandenburg, William Lu, Jonathan Zhu, Bret Peterson, Sara Tribble, Haixing Kehoe, Anastasia Makarova, Alex Iannello, Jean Chan, Justin Skoble, Hailey He, Chris Rae, Christopher D Thanos, Akshata R Udyavar
{"title":"ACTM-838, a novel systemically delivered bacterial immunotherapy that enriches in solid tumors and delivers IL-15/IL-15Rα and STING payloads to engage innate and adaptive immunity in the TME and enable a durable anti-tumor immune response.","authors":"Kyle R Cron, Ping Fang, Oanh Pham, Julie Janes, John Brandenburg, William Lu, Jonathan Zhu, Bret Peterson, Sara Tribble, Haixing Kehoe, Anastasia Makarova, Alex Iannello, Jean Chan, Justin Skoble, Hailey He, Chris Rae, Christopher D Thanos, Akshata R Udyavar","doi":"10.18632/oncotarget.28769","DOIUrl":"https://doi.org/10.18632/oncotarget.28769","url":null,"abstract":"<p><p>STACT is a modular, genetically engineered live attenuated <i>S.</i> Typhimurium bacterial platform that enables tissue-specific localization and cell-targeted delivery of large, multiplexed payloads via systemic administration. It has been engineered to minimize systemic toxicity and to enrich in the tumor microenvironment (TME) via metabolic dependency and showed a decreased systemic inflammatory cytokine profile compared to its parent strain VNP20009. ACTM-838 utilizes the STACT platform to deliver IL-15/IL15Rα and a constitutively active STING to tumor-resident phagocytic antigen-presenting cells. Upon intravenous (IV) dosing to tumor-bearing mice, ACTM-838 distributed and enriched in the TME, exhibited specific uptake in tumor-resident phagocytic cells and led to expression of human IL-15/IL15Rα and murine IFNα in the tumor. ACTM-838 induced comprehensive TME changes to an immune permissive anti-tumor phenotype with a decrease in exhausted T-cells and Tregs and an increase in cytolytic T-cells and MHCII-high proliferating myeloid cells. ACTM-838-treated tumors exhibited upregulated anti-tumor innate and adaptive immunity expression profiles, T-, NK- and B-cell infiltration and downregulated cell cycle, DNA damage and TGFβ responses. Single-cell RNAseq and flow cytometry data confirmed activation and infiltration of both innate and adaptive immune cells. ACTM-838 showed durable anti-tumor efficacy in multiple murine tumor models and synergized with anti-PD1 therapy in combination.</p>","PeriodicalId":19499,"journal":{"name":"Oncotarget","volume":"16 ","pages":"721-740"},"PeriodicalIF":0.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncotargetPub Date : 2025-09-22DOI: 10.18632/oncotarget.28768
Jacob Haagsma, Yudith Ramos Valdes, Xuejin Ou, Rasheduzzaman Rashu, S M Mansour Haeryfar, Jim Petrik, Trevor G Shepherd
{"title":"Loss of <i>Trp53</i> results in a hypoactive T cell phenotype accompanied by reduced pro-inflammatory signaling in a syngeneic orthotopic mouse model of ovarian high-grade serous carcinoma.","authors":"Jacob Haagsma, Yudith Ramos Valdes, Xuejin Ou, Rasheduzzaman Rashu, S M Mansour Haeryfar, Jim Petrik, Trevor G Shepherd","doi":"10.18632/oncotarget.28768","DOIUrl":"10.18632/oncotarget.28768","url":null,"abstract":"<p><p>Ovarian high-grade serous carcinoma (HGSC) is an aggressive disease with an urgent need for improved therapies. Immunotherapies have proved useful for some cancers but have failed to provide benefits for HGSC. Improving our understanding of the mechanisms regulating the HGSC tumor microenvironment will facilitate the discovery of novel immunotherapies and help predict patient response. To this end, the development of syngeneic models is imperative to recapitulate immune responses observed in patients with HGSC. Yet, few syngeneic HGSC mouse models exist that accurately reflect the initiation and disease progression of human disease. In this study, we developed a syngeneic model reflecting both the site of origin and the genotype of early HGSC disease by deleting <i>Trp53</i> in mouse oviductal epithelial (OVE) cells. Orthotopic injection of OVE cells demonstrated advanced disease progression due to loss of <i>Trp53</i>, associated with a less active T cell phenotype. Molecular analyses uncovered altered inflammatory signaling in OVE4-<i>Trp53</i>ko cells. Further analysis on an ascites-derived cell line identified selection for decreased pro-inflammatory signaling. These results highlight potential mechanisms by which loss of p53 function contributes to an immunosuppressive microenvironment in HGSC, and provide insight into the role of ovarian and peritoneal microenvironments in regulating HGSC cell-intrinsic inflammatory signaling.</p>","PeriodicalId":19499,"journal":{"name":"Oncotarget","volume":"16 ","pages":"697-718"},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncotargetPub Date : 2025-08-29DOI: 10.18632/oncotarget.28764
Kristen Kwong, Yue Pan, Jacqueline Morales, Matthew Watson, David V Allegakoen, Alex G Lee, Trever G Bivona, Peter Wipf, Christopher J Guerriero, Jeffrey L Brodsky, Amit J Sabnis
{"title":"<i>In vivo</i> manipulation of the protein homeostasis network in rhabdomyosarcoma.","authors":"Kristen Kwong, Yue Pan, Jacqueline Morales, Matthew Watson, David V Allegakoen, Alex G Lee, Trever G Bivona, Peter Wipf, Christopher J Guerriero, Jeffrey L Brodsky, Amit J Sabnis","doi":"10.18632/oncotarget.28764","DOIUrl":"https://doi.org/10.18632/oncotarget.28764","url":null,"abstract":"<p><p>The protein homeostasis (proteostasis) network includes quality control systems that coordinate protein synthesis, folding, localization, and degradation, and is deregulated in numerous diseases including cancer. Loss of proteostasis can activate lethal cellular stress responses, potentially opening a therapeutic window. Previous research demonstrated that MAL3-101, an inhibitor of heat shock protein 70-kD (HSP70) chaperones, selectively induces rhabdomyosarcoma (RMS) cell death via unfolded protein response (UPR) activation. RMS is the most common pediatric soft tissue sarcoma, and relapsed patients are rarely cured despite transient responses to DNA-damaging therapy. To examine whether MAL3-101 or more drug-like proteostasis inhibitors represent a new therapeutic strategy for RMS, we screened proteostasis components that might recapitulate the effects of MAL3-101 <i>in vivo</i>. We find that inhibition of <i>VCP</i>, which encodes the p97 ATPase that facilitates proteasome-dependent degradation, similarly activates the UPR and induces RMS apoptosis. In mouse models, a preclinical p97 inhibitor showed superior bioavailability and anti-tumor activity compared to MAL3-101. Patient-derived xenografts exhibited a spectrum of p97 inhibitor sensitivities, and RNA sequencing of resistant tumors revealed elevated autophagy, nominating a biomarker of proteostasis adaptability. Together, these findings confirm that proteostasis inhibition can slow RMS growth and suggest that targeting compensatory network components might yield synergistic outcomes.</p>","PeriodicalId":19499,"journal":{"name":"Oncotarget","volume":"16 ","pages":"681-696"},"PeriodicalIF":0.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncotargetPub Date : 2025-08-19DOI: 10.18632/oncotarget.28762
Laurence Booth, Michael R Booth, Jane L Roberts, Yang Yue, Emily Kinsey, Andrew Poklepovic, David Boone, L Ashley Cowhart, Allen Baharaff, Paul Dent
{"title":"The SCD1 inhibitor aramchol interacts with regorafenib to kill GI tumor cells <i>in vitro</i> and <i>in vivo</i>.","authors":"Laurence Booth, Michael R Booth, Jane L Roberts, Yang Yue, Emily Kinsey, Andrew Poklepovic, David Boone, L Ashley Cowhart, Allen Baharaff, Paul Dent","doi":"10.18632/oncotarget.28762","DOIUrl":"10.18632/oncotarget.28762","url":null,"abstract":"<p><p>The anti-tumor actions of the Stearoyl-CoA desaturase (SCD1) inhibitor aramchol in tumor cells remains poorly understood. Aramchol interacted with the multi-kinase inhibitors sorafenib, regorafenib or lenvatinib, to kill GI tumor cells, with regorafenib exhibiting the greatest effect. In HCT116 cells homozygous for the autophagy-regulatory protein ATG16L1 T300, aramchol and regorafenib interacted to activate ATM and the AMPK and to inactivate mTORC1 and mTORC2. As a single agent, regorafenib inactivated eIF2α and it combined with aramchol to elevate GRP78 expression. In HCT116 cells expressing the ATG16L1 A300 isoform the drug-induced dephosphorylation of mTORC1 S2448 and mTORC2 S2481 and the increased phosphorylation of eIF2α S51 were significantly lower than in T300 cells. In cells expressing ATG16L1 T300, but not A300, regorafenib and/or the drug combination inactivated AKT, ERK1/2 and p70 S6K. Regorafenib and aramchol interacted to cause formation of autophagosomes which was significantly greater in cells expressing ATG16L1 T300. Aramchol as a single agent did not stimulate autophagic flux but further enhanced both flux and autolysosome formation caused by regorafenib. Knock down of Beclin1 reduced the lethality of regorafenib and aramchol as single agents and when combined whereas knock down of LAMP2 or BID did not reduce killing caused by aramchol as a single agent but did reduce the lethality of regorafenib alone and regorafenib plus aramchol. <i>In vivo</i> using the HuH7 adult hepatoma cell line, regorafenib and aramchol interacted to suppress tumor growth without normal tissue toxicities.</p>","PeriodicalId":19499,"journal":{"name":"Oncotarget","volume":"16 ","pages":"662-678"},"PeriodicalIF":0.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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