Exploration of targeted anti-tumor therapy最新文献

{"title":"<i>L3MBTL4</i> methylation is a sensitive marker of DNA-PK inhibitor in pancreatic cancer.","authors":"Yuanxin Yao, Yuan Li, Aiai Gao, Cheng Zhu, Ruijie Wang, Yazhuo Li, Xiaomo Su, Meiying Zhang, Mingzhou Guo","doi":"10.37349/etat.2026.1002382","DOIUrl":"10.37349/etat.2026.1002382","url":null,"abstract":"<p><strong>Aim: </strong>The purpose is to explore the mechanism and new therapeutic strategy of lethal 3 malignant brain tumor like 4 (<i>L3MBTL4</i>) gene in pancreatic ductal adenocarcinoma (PDAC).</p><p><strong>Methods: </strong>Immunoprecipitation, siRNA knockdown, immunohistochemistry, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter assays, comet assays, and a xenograft mouse model were employed.</p><p><strong>Results: </strong><i>L3MBTL4</i> was methylated in 16.3% (7/43) of intraductal papillary mucinous neoplasms, 19.0% (4/21) of mucinous cystic neoplasm, and 28.2% (84/298) of PDAC, and its expression was regulated by promoter region methylation. <i>L3MBTL4</i> methylation was significantly associated with tumor differentiation and tumor size. The expression of <i>L3MBTL4</i> inhibited cell proliferation, colony formation, and induced apoptosis and G1/S phase arrest. L3MBTL4 activated ATM/CHK2 and inhibited NHEJ signaling by interacting with Ku70. Loss of <i>L3MBTL4</i> increased the sensitivity of PDAC cells to NU7441 both in vitro and in vivo.</p><p><strong>Conclusions: </strong><i>L3MBTL4</i> is a new component of NHEJ signaling and epigenetic silencing of <i>L3MBTL4</i> sensitizes PDAC cells to DNA-PK inhibitors, providing a potential new therapeutic strategy.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002382"},"PeriodicalIF":0.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13406882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148610798","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":"Predictive biomarkers for immunotherapy response in endometrial cancer: current insights and future directions.","authors":"Giuliana Pavone, Alessandra Spata, Marialuisa Puglisi, Vincenza Ricco, Ilaria Colombo","doi":"10.37349/etat.2026.1002381","DOIUrl":"10.37349/etat.2026.1002381","url":null,"abstract":"<p><p>In recent years, immunotherapy has modified the treatment landscape of advanced and recurrent endometrial cancer (a/rEC), particularly for patients with defective mismatch repair and microsatellite instability-high (dMMR/MSI-H), significantly improving their outcomes. Its success in later treatment lines has led to its investigation and adoption as a first-line therapy, alone or with chemotherapy. However, despite the high and long-lasting efficacy of immune checkpoint inhibitors (ICIs) in dMMR/MSI-H EC, not all patients benefit from this treatment, and reasons underscoring primary resistance in this setting remain poorly understood and are not yet incorporated into clinical decision-making. Additionally, the correlation between ICI response, tumor mutational burden (TMB), and PD-L1 expression, well-documented in other tumors, appears inconsistent in EC. While proficient mismatch repair and microsatellite stable (MMRp/MSS) EC remain an unmet medical need, some patients within this group still respond to ICIs. Although several biomarkers, including <i>TP53</i>, <i>BRCA</i>, and homologous recombination deficiency (HRD), have been investigated, none have proven to be definitively predictive. This review examines the relevant trials with ICIs as a single agent or in combination in EC and explores the available evidence on potential predictive biomarkers.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002381"},"PeriodicalIF":0.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13392825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148581394","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":"Can we now save the neck of OSCC T1-T2 patients? A narrative review of whether experimental techniques are on the way to clinical application.","authors":"Vincenzo Cuccurullo, Graziella Di Grezia, Gianluca Gatta, Giuseppe Lucio Cascini","doi":"10.37349/etat.2026.1002384","DOIUrl":"10.37349/etat.2026.1002384","url":null,"abstract":"<p><p>The molecular pathogenesis of oral squamous cell carcinoma (OSCC) is a complex process involving genetic alterations that accumulate over time. The clinical presentation and management of patients vary according to several pathological factors, but lymph node involvement is a key consideration in this context. Accurate lymph node staging in the neck is challenging because metastases may be present at an early stage of oral cancer. This narrative review assesses the evolution of imaging techniques over the last five years, distinguishing between research and established methods in order to address specific clinical questions. Conventional imaging techniques, including ultrasonography, contrast-enhanced computed tomography, contrast-enhanced magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography, are reviewed and compared with several noteworthy developments in optical and fluorescence imaging. In this scenario, various position papers and guidelines strongly suggest using scintigraphy for sentinel node biopsy. However, its use in clinical practice is not widespread. This is a direct result of unrelenting advances in imaging accuracy, treatment options and new diagnostic approaches. All these approaches are considered here, but none emerges as a universal solution. Overall, no single technique currently emerges as a universal solution. The most realistic strategy is an integrated, multidisciplinary pathway. Multimodal imaging integration framework and AI-assisted diagnostic strategy could provide a novel clinical decision-making pathway for cervical lymph node staging in T1-T2 stage OSCC patients.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002384"},"PeriodicalIF":0.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148655177","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":"Reactive oxygen species (ROS) in cancer: from redox signaling and metabolic plasticity to therapeutic vulnerabilities.","authors":"Taslim Uddin, Tajmin Khanam, Afia Asma, Mayesha Tasnim, Tanbin Sultana, Nafisa Parvez Aruba, Mohammad Hasan, Anika Zaheen, Anika Tabassum Aziz, Abhishek Karmaker Joy, Nazifa Anjum, Nusrat Jahan, Rhea Sarkar Nipun, Sushmita Sharma, Maisha Maliha Misha, Most Tamanna Haque, Shubhro Saha","doi":"10.37349/etat.2026.1002383","DOIUrl":"10.37349/etat.2026.1002383","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2-Keap1 axis to adapt to these conditions, leading to redox plasticity and \"Nrf2 addiction\" in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc^-, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002383"},"PeriodicalIF":0.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13392827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148581423","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":"More than alternative estrogen receptors: the emerging role of GPER-1 and ERα36 in breast cancer.","authors":"Luis Molina Calistro, Rodrigo Flavio Torres, Johana Spies, Sonia Sánchez Meneses, María Soto, Joaquín Carrasco, Javiera Gálvez, Dayanara Muñoz, Javiera Soto, Yennyfer Arancibia","doi":"10.37349/etat.2026.1002377","DOIUrl":"10.37349/etat.2026.1002377","url":null,"abstract":"<p><p>Breast cancer classification and therapeutic decision-making have traditionally relied on the evaluation of estrogen receptor alpha (ERα), PR, and HER2, yet this framework does not fully explain tumor heterogeneity, endocrine resistance, or estrogen responsiveness in ERα-negative contexts. Emerging evidence implicates non-genomic estrogen signaling mediated by membrane-associated receptors such as G protein-coupled estrogen receptor 1 (GPER-1) and ERα36. Acting as interconnected signaling nodes, these receptors activate MAPK/ERK and PI3K/AKT pathways and engage in crosstalk with receptors such as EGFR, promoting proliferation, cellular plasticity, and adaptive responses. Here, we propose an integrative framework based on three axes: endocrine resistance in ERα-positive tumors, estrogen responsiveness in ERα-negative subtypes, and environmental modulation of signaling. Within this model, GPER-1 and ERα36 form a coordinated network that extends beyond genomic mechanisms and converges on shared downstream effectors. These pathways also intersect with post-transcriptional regulation, tumor-microenvironment interactions, and extracellular vesicle-mediated communication, contributing to tumor progression and metastasis. Environmental ligands, such as bisphenol A, may further modulate signaling intensity, reinforcing plasticity and resistance phenotypes. Collectively, GPER-1 and ERα36 emerge as candidate biomarkers with diagnostic and therapeutic relevance. Their integration into multi-omics and functional classification strategies may refine breast cancer stratification and support more precise therapeutic approaches.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002377"},"PeriodicalIF":0.0,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148407216","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":"Why precision oncology works: lessons from gastrointestinal stromal tumours.","authors":"Si Ying Adelina Ho, Alwyn Hong Sheng Tok, Hui Qi Megan Kimberly Han, Jens Samol, Vishal G Shelat","doi":"10.37349/etat.2026.1002378","DOIUrl":"10.37349/etat.2026.1002378","url":null,"abstract":"<p><p>Gastrointestinal stromal tumours (GISTs) are the clearest solid-tumour model of precision oncology because diagnosis, prognosis, and treatment are strongly shaped by molecular genotype. The discovery of activating mutations in <i>KIT</i> proto-oncogene receptor tyrosine kinase (<i>KIT</i>) and platelet-derived growth factor receptor alpha (<i>PDGFRA</i>) transformed management by enabling genotype-directed use of tyrosine kinase inhibitors (TKIs) across localized and advanced disease. This review summarizes how molecular classification informs contemporary GIST care, from diagnostic work-up and risk stratification to neoadjuvant, adjuvant, and metastatic treatment planning. <i>KIT</i> exon 11 mutations generally predict sensitivity to standard-dose imatinib, whereas <i>KIT</i> exon 9 tumours may benefit from dose escalation. <i>PDGFRA</i> D842V confers primary resistance to imatinib but sensitivity to avapritinib, illustrating the clinical value of mutation-specific therapy. We also review <i>KIT</i>/<i>PDGFRA</i>-wild-type GISTs, including succinate dehydrogenase (<i>SDH</i>)-deficient, neurofibromin 1 (<i>NF1</i>)-associated, B-Raf proto-oncogene (<i>BRAF</i>)-mutant, and neurotrophic tyrosine receptor kinase (<i>NTRK</i>)-rearranged subtypes, where extended molecular testing is increasingly important. Surgery remains central in localized disease, but operative timing, extent of resection, and use of neoadjuvant therapy should be individualized according to tumour site, rupture risk, technical feasibility, and genotype. In advanced disease, sequential use of imatinib, sunitinib, regorafenib, ripretinib, and selected mutation-specific agents reflects evolving resistance biology and the need for ongoing molecular interpretation. Emerging tools such as broader genomic profiling and liquid biopsy may further refine treatment selection. GIST therefore demonstrates that precision oncology is most effective when molecular diagnostics, surgery, systemic therapy, and multidisciplinary decision-making are integrated across the full disease course.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002378"},"PeriodicalIF":0.0,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148407230","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":"Oncologic outcome and safety profile of first-line enfortumab vedotin plus pembrolizumab vs. conventional chemotherapy in advanced urothelial cancer.","authors":"Makito Miyake, Nobutaka Nishimura, Yuki Oda, Takuto Shimizu, Takeshi Inoue, Satoshi Anai, Keichi Sakamoto, Yoshiaki Matsumura, Yuta Toyoshima, Daiki Ichii, Kota Iida, Takashi Iwamoto, Norimi Takamatsu, Atsushi Tomioka, Hiroaki Yamamoto, Fumisato Maesaka, Kiyohide Fujimoto","doi":"10.37349/etat.2026.1002379","DOIUrl":"10.37349/etat.2026.1002379","url":null,"abstract":"<p><strong>Aim: </strong>The aim of this multicenter study was to assess patient characteristics and short-term survival outcomes of first-line (1L) enfortumab vedotin plus pembrolizumab (EVP) as compared with conventional chemotherapy in locally advanced or metastatic urothelial carcinoma (la/mUC).</p><p><strong>Methods: </strong>The database included 642 patients with la/mUC diagnosed between January 2008 and December 2025 at 12 collaborating hospitals. Baseline characteristics and follow-up data, including overall and organ-specific objective tumor response according to the RECIST v1.1, progression-free survival, and duration of response, were compared among the 1L regimens. Treatment-related adverse events (TRAEs) were graded according to the CTCAE v5.0 in patients treated with 1L EVP.</p><p><strong>Results: </strong>The objective response and disease control rate were higher with 1L EVP than with chemotherapy (66% vs. 42% and 83% vs. 68%, respectively). The organ-specific response rate for liver metastatic lesions was 85%. Median progression-free survival (95% confidence interval) for 1L EVP, gemcitabine plus cisplatin, and gemcitabine plus carboplatin was 14.5 months (10.5-not determined), 10.5 months (8.4-13.3), and 9.2 months (6.7-14.2), respectively. In the safety analysis set including 40 patients, all-grade TRAEs occurred in 36 (90%) patients, including grade 1-2 events in 30 (75%) and grade 3-4 toxicities in 6 (15%). Grade 3-4 TRAEs included skin toxicity (7.5%), anorexia (5.0%), anemia (5.0%), gastrointestinal disorders (2.5%), renal dysfunction (2.5%), and interstitial lung disease (2.5%). The median number of administered EV cycles was 4 (range, 1-13), 5 (2-13), and 10 (4-13) in the overall, responder, and complete-response populations, respectively. EV dose modifications and interruptions were frequent in the initial 2 months but rare thereafter.</p><p><strong>Conclusions: </strong>This multicenter study provides real-world evidence on short-term outcomes and safety with 1L EVP, highlighting its impact on the evolving treatment landscape for la/mUC.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002379"},"PeriodicalIF":0.0,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148407276","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":"Impact of smoking on subtypes and molecular profile of breast cancer: a systematic review.","authors":"Georgia Ntella, Anastasia Bothou, Giannoula Kyrkou, Anna Deltsidou, Vasiliki E Georgakopoulou, Maria Tzeli, Maria Vlachou, Athina Diamanti","doi":"10.37349/etat.2026.1002376","DOIUrl":"10.37349/etat.2026.1002376","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer encompasses heterogeneous pathological and molecular subtypes with distinct aetiologies and clinical outcomes. Although cigarette smoking is an established carcinogenic exposure, its subtype-specific associations and molecular effects in breast cancer remain insufficiently clarified. This systematic review synthesizes epidemiological, molecular, and prognostic evidence on how active cigarette smoking influences the risk of specific breast cancer subtypes.</p><p><strong>Methods: </strong>We conducted a systematic review, including observational and translational human studies that assessed active cigarette smoking in relation to breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, or by intrinsic molecular classifications. We also included studies evaluating smoking-associated molecular alterations within breast tumors.</p><p><strong>Results: </strong>Nineteen studies met the eligibility criteria. Epidemiological evidence suggested a possible modest increase in the risk of luminal/ER-positive breast cancer, particularly among women with longer smoking duration, heavier cumulative exposure, or smoking initiation before first full-term pregnancy; however, the pooled meta-analysis for current vs. never smoking was not statistically significant. No meaningful association was identified for triple-negative breast cancer (TNBC), and findings for HER2-positive breast cancer were heterogeneous. Molecular studies were associated with smoking-related changes in promoter DNA methylation, higher overall mutational burden, increased genomic instability, altered immune-cell infiltration within the tumor microenvironment, and conversion of receptor phenotype-especially toward HER2 positivity-suggesting a potential association with more aggressive tumor characteristics. Prognostic studies generally showed poorer overall survival and a higher risk of disease recurrence among smokers.</p><p><strong>Discussion: </strong>Active cigarette smoking may be associated with a possible modest increase in the risk of luminal/ER-positive breast cancer, while being associated with molecular alterations linked to more aggressive tumor phenotypes and poorer clinical outcomes.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002376"},"PeriodicalIF":0.0,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13341265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413804","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":"<i>ESR1</i> mutations in ER-positive breast cancer: from endocrine resistance to ctDNA-guided therapeutic interception.","authors":"Thais Martinez, Samantha Wegner, Hisham F Bahmad","doi":"10.37349/etat.2026.1002375","DOIUrl":"10.37349/etat.2026.1002375","url":null,"abstract":"<p><p>Endocrine resistance in estrogen receptor-positive (ER+) breast cancer has undergone a fundamental reconceptualization over the past decade. The discovery that activating mutations in the <i>ESR1</i> gene encoding ERα emerge under aromatase inhibitor (AI) selection pressure and drive ligand-independent receptor activation established a shift from empirical treatment sequencing to molecularly guided intervention. This review provides a synopsis of the structural biology underlying constitutive ER activation, the evolutionary dynamics of <i>ESR1</i>-mutant clones detectable through circulating tumor DNA (ctDNA), and the clinical evidence demonstrating that early molecular detection can trigger therapeutic switches that alter disease trajectory. The regulatory approval of elacestrant for <i>ESR1</i>-mutant disease and randomized trial data showing progression-free survival (PFS) benefit from ctDNA-guided endocrine switching (PADA-1, SERENA-6) position <i>ESR1</i> genotyping as a dynamic biomarker with direct therapeutic implications. We examine the integration of oral selective ER degraders (SERDs) into treatment algorithms, the role of co-occurring alterations in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and emerging directions, including machine learning approaches to ctDNA kinetics and adaptive trial designs that treat clonal evolution as an actionable target. The convergence of structural mechanisms, liquid biopsy technology, and biomarker-driven drug development provides a framework for precision oncology in endocrine-resistant breast cancer. While these advances are substantial, important challenges remain, including the lack of mature overall survival (OS) data from interception trials, cost and accessibility barriers to serial ctDNA monitoring in diverse global healthcare settings, the unresolved question of optimal therapeutic sequencing in patients with concurrent <i>ESR1</i> and PI3K pathway alterations, and the need to distinguish clinically actionable low-variant allele frequency (VAF) <i>ESR1</i> calls from background noise in liquid biopsies.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002375"},"PeriodicalIF":0.0,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139919","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":"RNA therapeutic targeting of recalcitrant and rare cancers.","authors":"Afeez Adekunle Ishola, Nalini Devi Verusingam, Bashir Lawal","doi":"10.37349/etat.2026.1002373","DOIUrl":"10.37349/etat.2026.1002373","url":null,"abstract":"<p><p>In 2013, more than a decade ago, the \"Recalcitrant Cancer Research Act of 2012\" was signed into law in the USA. Recalcitrant cancers are among the leading causes of global cancer morbidity and mortality. At the inception of the act, priority was placed on lungs and pancreatic cancers. Despite the tremendous advancement achieved in the research and treatment of said 'recalcitrant cancers' in the form of developing novel or modified small molecule and antibody drugs, modest improvement has been recorded for patients' survival. Also, current mortality and morbidity for recalcitrant cancers keep increasing. Similarly, rare cancers only enjoy very meager research and drug development efforts globally. Consequently, very limited advancement has been made towards therapeutic development targeting rare cancers. Hence, the current situation calls for re-strategizing research efforts and exploring different treatment modalities towards combating recalcitrant and rare cancers. On this note, RNA therapeutics strategy holds a unique and vital prospect because of its propensity to target coding and non-coding RNA transcripts in the biological system. Moreover, RNA therapeutics such as lncRNAs and circRNAs have been established to even modulate protein expressions and biological phenotypic activity through RNA-protein interactions. Therefore, the current review aimed at summarizing existing literature, clinical trials, and elucidating the important prospect of RNA therapeutics in mitigating the recalcitrant and rare cancers menace.</p>","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":"7 ","pages":"1002373"},"PeriodicalIF":0.0,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139923","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}