Molecular Cancer Therapeutics最新文献

{"title":"Moxidectin Unravels the Role of the Hippo-YAP Pathway in Maintaining Immunity of Glioblastoma Multiforme.","authors":"Itishree Kaushik, Robin Rajan, Shreyas Gaikwad, Mohamed A Eltokhy, Sanjay K Srivastava","doi":"10.1158/1535-7163.MCT-24-0594","DOIUrl":"10.1158/1535-7163.MCT-24-0594","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a lethal and aggressive cancer with an extremely poor prognosis. Recent preclinical, clinical, and genomic studies have highlighted the role of the Hippo-Yap pathway in the progression of GBM. In addition, it has been identified that YAP plays a major role in creating an immunosuppressive tumor microenvironment, facilitating drug resistance, recurrence, and metastasis of GBM tumors. In this study, we report that \"moxidectin\", an antihelminthic drug, inhibits the proliferation of SF268, SF295, SF188, and CT-2A-Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence data show that moxidectin mediates its effects by inhibiting the MEK-ERK pathway, a regulator of Hippo-YAP signaling. Inhibition of MEK-ERK by moxidectin ultimately led to blockade of the nuclear translocation and transcriptional activity of the YAP/TAZ-TEAD complex in various GBM cells. Oral administration of 3.5 mg/kg moxidectin suppressed the growth of GBM tumors by 90% in an intracranial tumor model. Ex vivo analysis of excised tumors confirmed the observations made in in vitro studies. Interestingly, moxidectin enhanced antigen presentation in the tumor-draining lymph nodes and reduced the pro-tumorigenic macrophage population in the brain, indicating that it might play a role in modulating the immune response. Chronic moxidectin treatment did not cause any toxicity in mice based on our toxicologic evaluation. Moxidectin is an FDA-approved drug, and findings from our study will promote its clinical investigation as a potential therapeutic agent for patients with GBM.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1156-1170"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063118","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":"Epigenetic Regulation of Cellular Senescence in Gastrointestinal Cancer.","authors":"Ting Ye, Hang Gao, Zheng-Rong Zhang, Yang Ge, Yi-Ke Liu, Jing-Yuan Yan, De-Yi Li, Feng-Yuan Chen, Hang Song","doi":"10.1158/1535-7163.MCT-24-0949","DOIUrl":"10.1158/1535-7163.MCT-24-0949","url":null,"abstract":"<p><p>Gastrointestinal (GI) cancers, encompassing malignancies of the digestive tract, are significant contributors to global cancer morbidity and mortality. Despite advancements in molecular insights and therapeutic approaches, the prognosis remains dismal because of persistent treatment resistance and metastasis. Cellular senescence, a permanent halt in the cell cycle due to various stressors, plays dual roles in tumor suppression and promotion. Interestingly, epigenetic modifications, heritable shifts in gene level without altering the DNA sequence, are identified as key regulators of cellular senescence. These modifications, such as DNA methylation, histone alterations, chromatin remodeling, and noncoding RNA interactions, shape the senescence phenotype and influence cancer progression and therapy resistance. Recent research underscores the potential of \"pro-senescence\" therapies, leveraging epigenetic modulators and senescence-inducing agents to counteract GI cancer progression. This review explores the relationship between cellular senescence and epigenetic regulation in the context of GI cancer by highlighting the characteristics of senescence, the epigenetic mechanisms at play, their impact on GI cancer senescence, and the promising horizon of anti-senescence therapies. Through a detailed examination of current research, we propose that understanding the intricacies of epigenetic regulation in cellular senescence offers a novel vista for therapeutic intervention in GI cancers, potentially paving the way for improved clinical outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1145-1155"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700610","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":"Target-Specific Locked Nucleic Acid Gapmer Decreases Growth and Metastases of Pancreatic Cancer.","authors":"Jill P Smith, Narayan Shivapurkar, Wenqiang Chen, Godhanjali Chekuri, Amani Dabney, Kyle Holmes, Hong Cao, Ruvanthi N Kularatne, Stephan T Stern","doi":"10.1158/1535-7163.MCT-24-1059","DOIUrl":"10.1158/1535-7163.MCT-24-1059","url":null,"abstract":"<p><p>Precision medicine and genomic profiling with target-specific therapy directed to cancer cell receptors have improved the outcome of many recalcitrant cancers. Strategies to deliver gene therapy to downregulate cancer driver genes have been challenging in vivo. Pancreatic cancer has the poorest survival of all solid tumors due to the lack of target-specific therapies and its characteristic tumor microenvironment with dense fibrosis and abundant immunosuppressive M2-polarized macrophages. In this study, we designed a panel of locked nucleic acid gapmer antisense oligonucleotides directed to human gastrin mRNA. We tested their efficacy by downregulation of mRNA and growth inhibition in vitro. The most effective gapmer, gapmer-90, was modified for in vivo therapeutics by thiol-maleimide click chemistry to render it target-specific to the cholecystokinin-B receptor. This G-protein-coupled receptor is overexpressed in pancreatic cancers. Mice bearing orthotopic human pancreatic tumors were treated with PBS (control), an untargeted gapmer, or receptor-targeted gapmers at low (60 nmol/L) and high (120 nmol/L) concentrations. Uptake of the gapmer was measured in tissues using a complementary probe. We found that the receptor-targeted gapmer significantly enhanced uptake in vivo and decreased growth and metastases of human pancreatic tumors in a dose-related fashion without off-target toxicity. The target-specific gapmer also altered the tumor microenvironment by decreasing fibrosis and reducing M2-polarized macrophages. Collectively, our results provide evidence that locked nucleic acid gapmers are a unique tool to deliver antisense oligonucleotides for therapy to recalcitrant cancers. Rendering the gapmers target-specific allows for selective uptake by receptor internalization, improving efficacy and decreasing off-target toxicity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1277-1288"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772589","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":"Development and Application of Radioactive Ligands Targeting Fibroblasts with Albumin-Binding Sites.","authors":"Tongtong Wu, Zhicong Yang, Sufan Tang, Hongmei Yuan, Yang Liu, Haiyang Li, Nan Liu, Zhanwen Huang, Yue Chen, Zhijun Zhou","doi":"10.1158/1535-7163.MCT-24-1108","DOIUrl":"10.1158/1535-7163.MCT-24-1108","url":null,"abstract":"<p><p>Fibroblast activation protein (FAP) is overexpressed on cancer-associated fibroblasts, making it an important target for cancer diagnosis and treatment, but limited tumor retention hinders late-stage diagnosis and radionuclide therapy. In this study, three albumin-bound FAP inhibitor (FAPI) radioligands, 68Ga/177Lu-DOTA-ALB-01, 68Ga/177Lu-DOTA-ALB-02, and 68Ga/177Lu-DOTA-ALB-03, were synthesized and evaluated for their in vitro stability, binding affinity, in vivo biodistribution, and tumor uptake using 68Ga and 177Lu labeling. All radioligands are stable in saline and plasma and exhibit high FAP-binding affinity. 177Lu-DOTA-ALB-02 has longer retention in circulation than 177Lu-FAPI-46 and other radioligands. Continuous tumor accumulation was observed during imaging with both 177Lu-DOTA-ALB-01 and 177Lu-DOTA-ALB-02. Notably, 177Lu-DOTA-ALB-02 had a significant tumor/nontarget ratio as indicated by biodistribution data. The outstanding tumor retention properties of 177Lu-DOTA-ALB-02 have been demonstrated in small-animal single-photon emission computed tomography imaging and biodistribution studies; therefore, it is considered the albumin-binding FAPI with the most favorable pharmacokinetic and imaging properties, worthy of further clinical investigation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1186-1196"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772588","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":"A PD-L1/CD3 Bispecific Antibody Enhances the Antitumor Effects of Regorafenib against Colon Cancer.","authors":"Izuchukwu F Okpalanwaka, Elizabeth A Daugherity, Amanda L McCormick, Trevor S Anderson, Savanna L Smith, Caryn Lawrence, Duke Appiah, Devin B Lowe","doi":"10.1158/1535-7163.MCT-24-1015","DOIUrl":"10.1158/1535-7163.MCT-24-1015","url":null,"abstract":"<p><p>Colorectal cancer is a leading cause of cancer-related deaths worldwide. The current standard of care for patients may involve surgery, chemotherapy, and immune checkpoint inhibitors, but these approaches typically fail to secure durable responses against late-stage disease. Regorafenib (REG) is an FDA-approved tyrosine kinase inhibitor with immunomodulating properties for patients with colorectal cancer who progress on standard care, but 5-year relative survival rates for individuals dosed with the drug as a monotherapy are poor. We hypothesize that REG may be more appropriately leveraged alongside immunotherapeutic agents that specifically stimulate T-cell infiltration and activation within the tumor microenvironment (TME). We engineered a PD-L1/CD3 bispecific antibody (bsAb) that simultaneously binds PD-L1-expressing colorectal cancer cells and stimulates activated T cells in order to investigate combination strategies with REG in preclinical models of colorectal cancer. Combined REG + bsAb therapy safely initiated and sustained inhibition against MC38 and CT26 progression in vivo, and these effects correlated to improved CD8+ T-cell infiltration and activity within a type 1-prone TME. Additionally, cytotoxic CD8+ T cells from REG + bsAb-sensitized mice exhibited heightened tumor cell reactivity compared with animals treated with either agent alone. Therefore, the immunomodulatory benefits of REG can be effectively paired with a bsAb that anchors to colorectal cancer cells, diminishes immunosuppression (through PD-L1 blockade), and activates/sustains antigen-specific CD8+ T cells within the TME. Our newly described REG + bsAb regimen led to improved antitumor outcomes preclinically and may represent a promising future approach for patients with colorectal cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1240-1251"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811909","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 Tumor-Infiltrating Immune Cells for Targeted Alpha Therapy in Gliomas: Optimization of [225Ac]Ac-DOTA-αCD11b Dosing through PET Imaging.","authors":"Ambika P Jaswal, Anders Josefsson, Angel G Cortez, Abhinav Bhise, Bo Li, Chaim T Sneiderman, Sarah R Vincze, Michal Nisnboym, Joseph D Latoche, Kathryn E Day, Robert S Edinger, Itay Raphael, Lora H Rigatti, Wilson B Edward, Gary Kohanbash, Jessie R Nedrow","doi":"10.1158/1535-7163.MCT-24-0996","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0996","url":null,"abstract":"<p><p>Myeloid cells are key mediators of immunosuppression and treatment resistance in primary brain tumors, including glioblastoma (GBM). This study aims to eradicate CD11b+ immunosuppressive cells at the tumor site to enhance overall survival in a model of GBM using an α-emitting radiopharmaceutical therapy targeted to tumor-associated myeloid cells as a monotherapy or in combination with immune checkpoint inhibitors. An anti-CD11b (αCD11b) antibody was modified for radiolabeling with diagnostic (zirconium-89) or therapeutic (actinium-225) radioisotopes. Initial PET imaging and biodistribution studies using 89Zr-αCD11b found that an antibody concentration of ∼5 mg/kg of αCD11b (100 μg) was effective in saturating on-target/off-site sinks, such as the spleen, but effective in increasing tumor accumulation. The estimated maximum tolerable activity of [225Ac]Ac-DOTA-αCD11b (225Ac-αCD11b) was determined by biodistribution and dosimetry studies, including the free in vivo-generated decay daughters. The dose-limiting tissue was the bone marrow, and an estimated maximum tolerable activity (∼0.55 kBq, 100 μg) was determined. The therapeutic efficacy of 225Ac-αCD11b was evaluated by survival studies, both as a monotherapy and in combination with immune checkpoint inhibitors. Combination therapy resulted in increased survival in the GBM model compared with the monotherapy and controls; in addition, long-term survival was observed in 50% of the mice receiving combination therapy as well as in a single mouse receiving 225Ac-αCD11b alone. No long-term surviving mice were observed in the control groups. Long-term surviving mice were rechallenged, and potential antitumor immunity was observed, as no tumors developed over 120 days after rechallenge. Overall, these results validate the preclinical relevance of CD11b-targeted image-guided α-emitting radiopharmaceutical therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":5.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690972","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":"Trametinib Thwarts Activation of Survival Pathways Induced by Pro-ferroptotic Drug Conjugate ACXT-3102 Resulting in Enhanced Pancreatic Cancer Cell Death.","authors":"Kumar S Bishnupuri, Kenneth F Newcomer, Qingqing Gong, Rony Takchi, Li Ye, Suwanna Vangveravong, Lauren Ross, Brian A Van Tine, William G Hawkins, Dirk Spitzer","doi":"10.1158/1535-7163.MCT-24-1032","DOIUrl":"10.1158/1535-7163.MCT-24-1032","url":null,"abstract":"<p><p>Ferroptosis has recently been described as an iron-dependent subroutine of programmed cell death. Cancers driven by oncogenic Ras mutations, such as pancreatic ductal adenocarcinoma, are particularly vulnerable to ferroptosis and are thus promising candidates for antineoplastic drugs targeting this unique form of programmed cell death. Our group has developed a cancer-specific drug conjugate (ACXT-3102), consisting of a proapoptotic sigma-2 ligand as a delivery moiety (SV119), linked to an inhibitor of the cystine antiporter xCT (dm-erastin), an established inducer of ferroptosis. We hypothesized that ACXT-3102 would trigger apoptosis and ferroptosis via its discrete chemical components, representing a new approach to clinical therapy for pancreatic ductal adenocarcinoma. In vitro cell viability assays corroborated our earlier findings that ACXT-3102 is a potent inducer of cancer cell death. The sigma-2 delivery component of ACXT-3102 induced canonical markers of apoptosis, including cleaved caspase-3/7 and PARP, whereas the dm-erastin cargo component induced canonical markers of ferroptosis, including lipid peroxidation and consumption of glutathione peroxidase 4. These changes resulted in the accumulation of reactive oxygen species. Subsequently, we found that ACXT-3102-mediated cell death was accompanied by the activation of MAPK/ERK signaling, presumably via the reactive oxygen species-dependent degradation of dual-specificity phosphatase 6, a negative regulator of MAPK/ERK phosphorylation. We suspected that this was a compensatory reaction and that ACXT-3102-induced cancer cell death would be augmented by inhibition of MAPK/ERK signaling. We successfully combined ACXT-3102 with trametinib (MEK inhibitor) to enhance the overall efficacy of treatment in vitro and in vivo, presumably by targeting ACXT-3102-induced upregulation of MAPK/ERK.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF12"},"PeriodicalIF":5.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659680","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":"TUB-040, a homogenous and hydrophilic NaPi2b-targeting ADC with stably linked exatecan, exhibits long-lasting anti-tumor activity and a well-tolerated safety profile.","authors":"Annette M Vogl, Saskia Schmitt, Isabelle Mai, Paul Machui, Sarah Herterich, Natascia Leonardi, Philipp Cyprys, Danila Hauswald, Philipp Ochtrop, Izabela Kozlowska, Annabel Kitowski, Marcus Gerlach, Florian Waldmann, Olivier Marcq, Pamela A Trail, Dominik Schumacher, Günter R Fingerle-Rowson, Björn Hock, Marc-André Kasper, Jonas Helma","doi":"10.1158/1535-7163.MCT-25-0254","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0254","url":null,"abstract":"<p><p>TUB-040 is a highly homogenous and hydrophilic antibody-drug conjugate (ADC) targeting NaPi2b, a surface receptor overexpressed in ovarian cancer and non-small cell lung adenocarcinoma. Previous NaPi2b-directed therapies have shown target-mediated and expression-dependent clinical activity. However, none of the previous tubulin inhibitor-based ADCs has been able to leverage the full therapeutic potential of the target. TUB-040 was constructed with a drug-to-antibody ratio (DAR) of 8 using the Tubutecan linker-payload technology based on ethynylphosphonamidates (P5 conjugation chemistry), a protease cleavage site and exatecan, a potent topoisomerase 1 (TOP1) inhibitor. TUB-040 induces potent antigen-specific cytotoxicity against NaPi2b-expressing cancer cells and demonstrates strong bystander activity. It displays a favorable pharmacokinetic behavior, showing dose-proportionality and superimposable total antibody and intact ADC curves and low free payload levels, reflecting the high stability of TUB-040 enabled by the P5 conjugation platform. This specific feature also ensures sustained delivery of exatecan to tumor sites which translates into excellent in vivo efficacy and tolerability. In cell line- and patient-derived xenograft models, including those with low target expression, single-dose TUB-040 administration leads to prolonged tumor growth inhibition and significant rates of complete remission, with a minimally effective dose (MED) level of 1 mg/kg in the OVCAR-3 model. Repeated-dose toxicological assessment in rats indicates that TUB-040 is well-tolerated, with no evidence of lung toxicity or thrombocytopenia. Taken together, TUB-040 is designed to enable long-lasting, durable tumor responses and to optimize both efficacy and tolerability, supporting the advancement of TUB-040 into clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642886","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":"The recycling collagen receptor uPARAP is a unique mediator of stromal drug delivery to carcinoma cells.","authors":"Kirstine S Nørregaard, Ida M E Larsen, Henrik J Jürgensen, Michaela Hansen Blomquist, Pınar Çakılkaya, Virginia Metrangolo, Alba Martinez Perlado, Oliver Krigslund, Henrik Gårdsvoll, Thomas T Poulsen, Dominik Mumberg, Eric Santoni-Rugiu, Lars H Engelholm, Niels Behrendt","doi":"10.1158/1535-7163.MCT-25-0051","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0051","url":null,"abstract":"<p><p>The genetic instability of cancer cells leads to cellular resistance against most targeted cancer drugs. Cancer-associated fibroblasts (CAFs) infiltrate all carcinomas and are genetically stable. Using antibody-drug conjugates (ADCs), we exploit the unique properties of a rapidly recycling endocytic receptor, uPARAP, to achieve a highly efficient CAF-mediated drug delivery and kill of carcinomas. This receptor is generally not present on carcinoma cells and is only expressed in a restricted group of mesenchymal cancer cell types which are sensitive to uPARAP-directed ADCs. However, we show that uPARAP is highly expressed in CAFs in all carcinoma types examined. This property is recapitulated in mouse xenograft carcinoma models. In these models, despite the absence of uPARAP on the carcinoma cells, uPARAP-targeting ADCs with clinically validated payloads MMAE and Dxd eradicated tumors with remarkable efficiency. Systemic treatment with anti-uPARAP ADC led to permanent eradication of tumors in mice carrying subcutaneous xenografts with human EBC-1 lung carcinoma cells. A pronounced repression of tumor growth and strongly increased mouse survival was also obtained with human HT29 colon adenocarcinoma cells, both when these tumors were growing subcutaneously and after homing of tumor cells to bone from the circulation. CAFs were largely refractory to ADC treatment and retained a high expression of uPARAP. uPARAP-expressing fibroblasts could also process an anti-uPARAP ADC in vitro and deliver the cytotoxic component to carcinoma cells. The current bystander mechanism may be exploited in the majority of the most prevalent solid cancers, thus making uPARAP an extraordinarily versatile target for ADC-based cancer treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642885","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 SUMOylation triggers interferon-ß-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia.","authors":"Rawan Hallal, Marion de Toledo, Denis Tempé, Rayane Berrahouane, Sara Zemiti, Loïs Coënon, Delphine Gitenay, Simon George, Moritz Schüssler, Nadine Laguette, Sarah Bonnet, Ludovic Gabellier, Guillaume Cartron, Mireia Pelegrin, Martin Villalba, Guillaume Bossis","doi":"10.1158/1535-7163.MCT-25-0504","DOIUrl":"10.1158/1535-7163.MCT-25-0504","url":null,"abstract":"<p><p>Natural Killer (NK) cells can play a significant role in the anti-tumoral immune response. In patients with Acute Myeloid Leukemia (AML), NK cells are however often found in low numbers and exhibit poor activity, contributing to leukemic progression. Allogenic NK cells are emerging as promising cellular therapies for hematological cancer treatment. New strategies are however required to both reactivate NK cells in AML patients and enhance the anti-tumor activity of transplanted NK cells. Here, we demonstrate that targeting SUMOylation, a protein post-translational modification, activates NK cells from both healthy donors and AML patients. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex-vivo expanded cord-blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of type I interferon (IFN-I) pathway genes and induce their transcription. TAK-981-induced secretion of interferon-ß, mostly by NK cells and myeloid cells, is required for NK cells activation. Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7618005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637671","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}