Exploration of targeted anti-tumor therapy最新文献

{"title":"The evolution of chemotherapy in brain tumors: from historical milestones to precision medicine in glioblastoma.","authors":"Alessia Ciafarone, Paola Palumbo","doi":"10.37349/etat.2026.1002374","DOIUrl":"10.37349/etat.2026.1002374","url":null,"abstract":"<p><p>Chemotherapy has profoundly shaped modern oncology, evolving from early cytotoxic approaches to biologically informed strategies. In glioblastoma (GBM), the highly aggressive primary brain tumor, precision medicine does not rely on the identification of a single crucial oncogenic driver but integrates biologically informed stratification strategies to predict treatment response, resistance, and therapy-induced adaptation. This review recapitulates the historical milestones of chemotherapeutic development in neuro-oncology, with particular emphasis on GBM. As the main chemotherapeutic agent currently used in GBM, temozolomide (TMZ) initially represented a major therapeutic breakthrough; however, its clinical use has progressively unveiled the biological and clinical limitations of conventional cytotoxic paradigms. While TMZ exerts antitumor activity through DNA damage-induced apoptosis, accumulating experimental evidence indicates that it may also elicit adaptive responses, ultimately supporting tumor progression and therapy resistance. By integrating historical milestones with recent molecular understanding, this review highlights how improved knowledge of therapy-induced adaptations may inform emerging precision medicine strategies in GBM, underscoring the need for tailored treatments to overcome tumor heterogeneity and adaptive responses.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002374"},"PeriodicalIF":0.0,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139952","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}

{"title":"Triple-negative breast cancer: current understanding and future perspectives.","authors":"Alhasan Alobaidi, Vikrant Rai","doi":"10.37349/etat.2026.1002372","DOIUrl":"10.37349/etat.2026.1002372","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype defined by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. Consequently, standard hormone and HER2-targeted therapies are ineffective, necessitating reliance on chemotherapy, immunotherapy, antibody-drug conjugates (ADCs), and poly(ADP-ribose) polymerase (PARP) inhibitors for <i>BRCA</i>-mutated cases. TNBC exhibits rapid growth, a high risk of early recurrence, and disproportionately affects younger women, Black women, and <i>BRCA1</i> mutation carriers. Standard management typically involves neoadjuvant chemotherapy followed by surgery and potential radiation. However, TNBC treatment remains challenging due to its severe biological heterogeneity, high metastatic potential, and the toxicity associated with systemic therapies. This review discusses the current understanding of TNBC biology, highlighting the urgent need for advanced diagnostics, integrated molecular subtyping, and personalized targeted therapies.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002372"},"PeriodicalIF":0.0,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147966111","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}

{"title":"Oligometastatic versus polymetastatic colon cancer: functional and genomic determinants of divergent metastatic trajectories.","authors":"Roberto Sirica, Carmine Picone, Francesco Sabbatino, Nadia Petrillo, Marco Cascella, Mariachiara Santorsola, Vincenza Granata, Monica Ianniello, Raffaella Ruggiero, Luisa Circelli, Giuliana Ciappina, Massimiliano Berretta, Giovanni Savarese, Alessandro Ottaiano","doi":"10.37349/etat.2026.1002371","DOIUrl":"10.37349/etat.2026.1002371","url":null,"abstract":"<p><strong>Aim: </strong>The aim of this study is to investigate the molecular and functional features underlying the clinical heterogeneity between oligometastatic (OM) and polymetastatic (PM) colon cancer.</p><p><strong>Methods: </strong>We performed a genotype-phenotype analysis in a homogeneous cohort of 127 patients with metastatic colon cancer (mCC) profiled using the same next-generation sequencing platform (TruSight Oncology^® 500). OM disease was defined as the presence of one to three metastatic lesions per involved organ, involving no more than two organs overall, with all lesions measuring < 70 mm in maximum diameter and no single lesion > 25 mm. Molecular alterations, microsatellite instability (MSI), tumor mutational burden (TMB), and overall survival (OS) were analyzed. Gene Ontology (GO) enrichment and Phenolyzer network analyses were applied to explore functional differences between prognostically distinct molecular subgroups.</p><p><strong>Results: </strong>OM patients showed a striking survival advantage compared with PM patients [median OS not reached versus 29 months; hazard ratio (HR): 0.20, <i>P</i> < 0.0001], validating the clinical distinction between the two phenotypes. PM disease was significantly enriched for <i>RAS</i> mutations, whereas OM disease was associated with MSI-high status and elevated TMB. Canonical driver alterations were largely shared between groups, and Phenolyzer analysis revealed similar core oncogenic networks centered on adenomatous polyposis coli (<i>APC</i>), tumor protein p53 (<i>TP53</i>), and epidermal growth factor receptor (<i>EGFR</i>). In contrast, GO analysis demonstrated selective enrichment in PM tumors for molecular functions related to ATP binding, nucleotide binding, and protein kinase activity, consistent with enhanced bioenergetic demand and signaling intensity.</p><p><strong>Conclusions: </strong>These findings support refined biological stratification of mCC and the exploration of personalized, metastasis-directed strategies, potentially incorporating immunological modulation in OM disease.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002371"},"PeriodicalIF":0.0,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147966124","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}

{"title":"FDA 2025 Cancer Drug Approvals: targeted therapy dominates.","authors":"Jan Trøst Jørgensen","doi":"10.37349/etat.2026.1002369","DOIUrl":"10.37349/etat.2026.1002369","url":null,"abstract":"<p><p>This commentary discusses the FDA's drug approvals in 2025, with a particular focus on cancer therapies and the role of companion diagnostics (CDx). Cancer has emerged as the leading therapeutic area, accounting for 35% of all new drug approvals, largely driven by targeted therapies, with kinase inhibitors representing nearly half of these drugs. Many of the drugs have received orphan drug designations and/or have utilized the Accelerated Approval Program. A key finding was the widespread adoption of the drug-diagnostic co-development model, in which a CDx assay is developed along with the drug and used for patient selection in clinical trials. However, a significant challenge is the frequent lack of concurrent drug and CDx assay approvals. The absence of an analytically and clinically validated CDx assay may pose a challenge for healthcare providers in accurately identifying eligible patients, potentially delaying access to appropriate therapy. The FDA's cancer drug approvals for 2025 highlight an ongoing commitment to precision medicine, with several new targeted treatments, such as antibody-drug conjugates and kinase inhibitors, where CDx assays play an important role in identifying the appropriate patient population.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002369"},"PeriodicalIF":0.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824314","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}

{"title":"The evolving landscape of first-line and subsequent therapies in <i>EGFR</i>-mutated NSCLC: efficacy, resistance, and tolerability.","authors":"Carminia Maria Della Corte, Caterina De Rosa, Faiz Ul Haq, Floriana Morgillo","doi":"10.37349/etat.2026.1002370","DOIUrl":"10.37349/etat.2026.1002370","url":null,"abstract":"<p><p>The treatment paradigm for advanced non-small cell lung cancer (NSCLC) harboring <i>EGFR</i> mutations is undergoing a significant transition. While third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have long served as the frontline standard, the emergence of heterogeneous resistance mechanisms requires more robust therapeutic strategies. This review evaluates the clinical impact of the MARIPOSA trial, which demonstrated the superior efficacy of combining the bispecific antibody amivantamab with lazertinib. Beyond improving progression-free and overall survival, this dual-inhibition approach fundamentally alters the clonal evolution of the disease by suppressing common escape routes, such as <i>MET</i> amplifications and secondary <i>EGFR</i> mutations. Furthermore, we explore the diversifying landscape of second-line interventions, including the rise of antibody-drug conjugates (ADCs) like Sac-TMT and patritumab-deruxtecan, dual PD-1/VEGF inhibitors, and novel fourth-generation TKIs. By integrating preclinical insights on drug-tolerant persister cells with late-phase clinical data, this article outlines a future for <i>EGFR</i>-mutant NSCLC management defined by precision sequencing and the proactive mitigation of molecular resistance.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002370"},"PeriodicalIF":0.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824329","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}

{"title":"The evolving role of targeted radioligand therapy in small cell and non-small cell lung cancer: a systematic review.","authors":"Serin Moghrabi, Saad Ruzzeh, Kamal Al-Rabi, Ahmed Abdlkadir, Mohammed J Al-Jaghbeer, Nouraldeen Alzorgan, Ula Al Rasheed, Mohammad Alqudah, Akram Al-Ibraheem","doi":"10.37349/etat.2026.1002368","DOIUrl":"10.37349/etat.2026.1002368","url":null,"abstract":"<p><strong>Background: </strong>Targeted radioligand therapy (TRT) is an emerging theranostic modality in oncology. While well established in neuroendocrine and prostate cancers, its role in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) remains investigational. This systematic review summarizes current evidence evaluating TRT in lung cancer.</p><p><strong>Methods: </strong>A Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-guided systematic review of PubMed, Embase, and Scopus (2000-November 2025) was conducted. Original studies evaluating TRT in SCLC or NSCLC were included. Primary outcomes were tumor response, disease-control rate, and treatment-related toxicity. Secondary outcomes included progression-free survival, overall survival, and dosimetry. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool.</p><p><strong>Results: </strong>From 2,453 records, 15 studies were included, reporting 358 lung cancer patients, of whom 105 received TRT. Disease-control rates reached up to 78% in mixed NSCLC/SCLC cohorts. In SCLC, somatostatin receptor-targeted peptide receptor radionuclide therapy demonstrated heterogeneous disease control (0-50%), with [¹⁷⁷Lu]Lu-labeled agents showing more favorable outcomes than [⁹⁰Y]Y-based therapy. The most favorable outcomes were a median progression-free survival of 11.9 months and an overall survival of 16 months in responders. In NSCLC, fibroblast activation protein (FAP)-targeted agents such as [¹⁷⁷Lu]Lu-FAP-2286 demonstrated partial metabolic responses, including a 44.4% response rate and 78% disease control in a mixed cohort. Severe toxicities were infrequent.</p><p><strong>Discussion: </strong>TRT is a promising but experimental option for advanced lung cancer. Early efficacy signals exist for strong somatostatin receptor (SSTR)-targeted therapy in SCLC and FAP-targeted therapy in NSCLC, but evidence remains limited. Prospective trials with standardized protocols and dosimetry are needed to define TRT's role in lung cancer treatment.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002368"},"PeriodicalIF":0.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824373","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}

{"title":"Solitary fibrous tumor of the lung: diagnostic challenges and surgical management.","authors":"Vasileios Leivaditis, Konstantinos Grapatsas, Francesk Mulita, Sofoklis Mitsos, Efstratios Koletsis, Athanasios Papatriantafyllou, Elias Liolis, Admir Mulita, Periklis Tomos, Manfred Dahm","doi":"10.37349/etat.2026.1002367","DOIUrl":"10.37349/etat.2026.1002367","url":null,"abstract":"<p><p>Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that typically arise from the pleura but may occur in various extrathoracic sites. Primary intraparenchymal pulmonary SFTs without pleural attachment are exceptionally uncommon and often pose diagnostic and therapeutic challenges. We report the case of a middle-aged female patient presenting with progressive dyspnea and a large mass in the left lower lobe on imaging. Computed tomography revealed a well-circumscribed, hypervascular mass occupying the left lower lobe. Bronchoscopic and percutaneous biopsies were nondiagnostic, and surgical resection was pursued. Intraoperatively, the tumor was found to arise from the lung parenchyma without pleural involvement. Histopathological examination demonstrated a spindle-cell neoplasm with the typical \"patternless pattern,\" and immunohistochemistry confirmed nuclear STAT6 positivity, establishing the diagnosis of SFT. The postoperative course was uneventful apart from a transient pulmonary embolism, which was successfully treated. The patient was discharged in good condition and is under regular radiologic surveillance. SFTs of the lung are rare and often mimic more common pulmonary tumors radiologically. Histologic confirmation with STAT6 immunohistochemistry is crucial for accurate diagnosis. Complete surgical excision remains the mainstay of treatment. Given the risk of late recurrence-especially in large tumors-long-term imaging follow-up is mandatory. This case highlights the importance of considering SFT in the differential diagnosis of large pulmonary masses, the critical role of STAT6-based histopathologic confirmation, and the necessity for prolonged surveillance even after complete resection.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002367"},"PeriodicalIF":0.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13106994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790786","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}

{"title":"Lorlatinib in advanced ALK-positive NSCLC after prior progression on ALK inhibitors: real-world experience in Russia.","authors":"Sergey V Orlov, Konstantin K Laktionov, Aram A Musaelyan, Elena V Reutova, Svetlana V Odintsova, Magaripa A Urtenova, Valeria A Kuzmina, Vladislav I Tiurin, Alexandra E Lomakova, Evgeny N Imyanitov","doi":"10.37349/etat.2026.1002366","DOIUrl":"10.37349/etat.2026.1002366","url":null,"abstract":"<p><strong>Aim: </strong>This study aimed to evaluate the real-world efficacy and safety of lorlatinib in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior ALK tyrosine kinase inhibitor (TKI).</p><p><strong>Methods: </strong>The dataset included 82 subjects with metastatic NSCLC, who received lorlatinib upon compassionate use program or routine treatment between January 2017 and May 2025. All patients involved in this study responded to a prior ALK inhibitor for at least 4 months and switched to the above drug due to disease progression.</p><p><strong>Results: </strong>The overall objective response rate (ORR) was 64.6%, with the disease control rate (DCR) of 96.3%. Among 65 patients with brain metastases, the intracranial ORR and DCR were 66.2% and 96.9%, respectively. After a median follow-up of 82.7 months, the median progression-free survival (PFS) was 66.7 months (95% CI, 40.5-75.0 months), while the median overall survival (OS) was not reached (NR) (95% CI, NR-NR). Patients who had benefited from prior ALK TKI for more than 12 months achieved significantly longer PFS (NR vs. 34.0 months; <i>p</i> = 0.013) and OS (NR vs. 39.4 months; <i>p</i> = 0.002). Multivariate analysis showed that prior response to ALK TKI of less than 12 months was an independent negative predictor of survival (PFS: <i>p</i> = 0.039, OS: <i>p</i> = 0.027). Treatment-related adverse events (AEs) were reported in 75.6% of patients, with 8.1% experiencing grade 3 or higher toxicity; no treatment-related AEs led to permanent discontinuation of lorlatinib.</p><p><strong>Conclusions: </strong>This real-world dataset demonstrates an unusually pronounced benefit from lorlatinib in selected patients who progressed on early-generation TKIs, especially in long-term responders to prior therapy. However, the observed outcomes should be interpreted within the context of patient selection. The enrichment for prior responders limits the generalizability to unselected post-TKI populations, including those with primary resistance.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002366"},"PeriodicalIF":0.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724709","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}

{"title":"Changes of urinary immunity and microbiome after intravesical BCG therapy and their association with outcomes in NMIBC.","authors":"Yuki Oda, Makito Miyake, Nobutaka Nishimura, Takuto Shimizu, Takuya Owari, Kota Iida, Yasushi Nakai, Nobumichi Tanaka, Kiyohide Fujimoto","doi":"10.37349/etat.2026.1002365","DOIUrl":"10.37349/etat.2026.1002365","url":null,"abstract":"<p><strong>Aim: </strong>Intravesical <i>Bacillus</i> Calmette-Guérin (BCG) is the standard therapy for non-muscle invasive bladder cancer (NMIBC); however, many patients experience recurrence or progression. We examined how urinary immune signals and the urinary microbiome change across BCG and are related to outcomes.</p><p><strong>Methods: </strong>In this single-center prospective cohort study, adults with NMIBC underwent transurethral resection of bladder tumor (TURBT), followed by BCG induction. Urine was collected before TURBT, before BCG, after BCG induction, and three months later. Urine sediment mRNA (PD-L1, PD-L2, CD33, and CD204) was quantified using TaqMan ΔCt. The urinary microbiome was profiled using 16S rRNA gene sequencing, and diversity, composition, and taxon balance were evaluated using nonparametric tests, PERMANOVA, repeated-measures correlations, and mixed-effects models. We analyzed the relationship between the urinary microbiome and prognosis.</p><p><strong>Results: </strong>Twenty-three patients were analyzed; ten recurrences, eight progressions, and three deaths were observed. Relative to baseline, CD33 increased after BCG and after three months; PD-L2 increased immediately after BCG and returned to baseline by three months; PD-L1 and CD204 increased after BCG. Shannon alpha-diversity was unchanged, but total read count was higher at three months, with stable beta-diversity and dispersion. Higher PD-L1 expression was associated with lower Actinobacteria abundance in the bladder cancer microenvironment. A higher post-BCG Firmicutes/Bacteroidetes ratio was associated with worse prognosis, with the clearest signal for progression-free survival (PFS) observed in the univariate Cox models. Higher post-BCG <i>Corynebacterium</i> and Enterobacteriaceae abundance was associated with better PFS.</p><p><strong>Conclusions: </strong>BCG was associated with higher urinary PD-L1/PD-L2 and myeloid marker transcripts, while overall community structure remained stable. These exploratory data support that pre-BCG microbial features may be related to early response, and post-BCG profiles may reflect durability and survival. Urine immune-microbiome profiling could be a feasible, noninvasive adjunct for monitoring and risk stratification in NMIBC.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002365"},"PeriodicalIF":0.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724945","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}

{"title":"Disrupting the TGF-β-regulated epithelial-mesenchymal transition, apoptotic and autophagic phenotypes of 3D glioblastoma spheroids via glycolytic inhibition.","authors":"Maellis Payet-Desruisseaux, Alain Zgheib, Bogdan Alexandru Danalache, Michel Desjarlais, Borhane Annabi","doi":"10.37349/etat.2026.1002364","DOIUrl":"10.37349/etat.2026.1002364","url":null,"abstract":"<p><strong>Aim: </strong>Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes.</p><p><strong>Methods: </strong>3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels.</p><p><strong>Results: </strong>3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy-<i>D</i>-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30-300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib. Transcriptomic profiling revealed shared upregulation of apoptosis-related (<i>BCL2</i>, <i>CASP7</i>, <i>FAS</i>, <i>FASLG</i>, <i>GADD45A</i>) and autophagy-related (<i>ATG7</i>, <i>ATG16L1</i>, <i>IRGM</i>, <i>PIK3C3</i>, <i>ULK1</i>) genes in response to TGF-β or upon 3D spheroid formation. 2DG, transient silencing of TGF-β, or galunisertib treatment prevented these increases.</p><p><strong>Conclusions: </strong>3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002364"},"PeriodicalIF":0.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724209","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}