Cancer Innovation最新文献

{"title":"Molecular Mechanisms and Therapeutic Advances in KRAS G12C-Mutant Non-Small Cell Lung Cancer: Toward Mechanism-Guided Longitudinal Management","authors":"Haiying Wang,&nbsp;Hanxiao Chen,&nbsp;Sheng Li,&nbsp;Jun Zhao","doi":"10.1002/cai2.70082","DOIUrl":"https://doi.org/10.1002/cai2.70082","url":null,"abstract":"<p>KRAS G12C-mutant non-small cell lung cancer (NSCLC) has become a clinically actionable molecular subtype. Discovery of the switch-II pocket enabled the development of covalent KRAS G12C(OFF)-state inhibitors, transforming a historically “undruggable” target into a therapeutic vulnerability. Drugging KRAS, however, proved to be a problem of chemistry, whereas sustaining its inhibition has proved to be a problem of biology. KRAS G12C-mutant NSCLC is biologically heterogeneous, and the magnitude and durability of clinical benefit are shaped by co-mutations, the tumor microenvironment, brain metastases status, pharmacologic differences between agents, and the dynamic evolution of resistance. Randomized trials have demonstrated that sotorasib and adagrasib improve progression-free survival (PFS) and objective response rates (ORR) over docetaxel in previously treated disease, yet these gains have not translated consistently into a definitive overall survival (OS) advantage. This review synthesizes the epidemiology, molecular biology, diagnostic strategies, first- and later-line treatment evidence, resistance mechanisms, and emerging KRAS/RAS-directed approaches. We distinguish randomized or guideline-supported practice from early-phase and translational signals, and propose an implementable framework that combines PD-L1, tumor mutational burden, STK11/KEAP1/TP53 status, TTF-1 expression, brain metastases, and circulating tumor DNA (ctDNA) for risk stratification and mechanism-guided management. At disease progression, oligoprogression should be distinguished from systemic progression, and tissue re-biopsy together with plasma profiling should be considered when feasible. In China, several domestically developed KRAS G12C inhibitors have been approved, and reimbursement coverage is expanding; the cost of molecular testing, uneven institutional access, regional disparities and limited confirmatory and real-world evidence nonetheless continue to constrain implementation. Future priorities include randomized first-line comparisons, biomarker-defined combination strategies, improved central nervous system activity and mechanism-matched treatment after resistance.</p>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 5","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205929","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":"Measure of Innovation: From Clinical Questions to Actionable Evidence","authors":"Shouzheng Wang,&nbsp;Fei Ma","doi":"10.1002/cai2.70086","DOIUrl":"10.1002/cai2.70086","url":null,"abstract":"&lt;p&gt;Anticancer drug development has entered an age of abundance, but also one of unfinished promises. New targets, mechanisms, therapeutic agents, and treatment modalities are emerging at a remarkable pace. However, their scientific promise does not always translate into durable clinical benefits. Many patients still experience inadequate responses, treatment-related toxicities, or limited treatment options after disease progression, while clinically important patient subgroups remain underserved by current care. The clinical relevance of a development program therefore does not begin with how novel an intervention appears, but with the unmet need it seeks to address in a defined patient population.&lt;/p&gt;&lt;p&gt;Novelty has its allure. A first-in-class agent may open a field or reveal previously inaccessible vulnerabilities. However, scientific distinction and clinical value are not the same achievement. First-in-class status marks innovation but does not, by itself, demonstrate added benefit for patients [&lt;span&gt;1&lt;/span&gt;]. Drug development begins to matter when scientific possibility is directed toward a clinical problem worth solving.&lt;/p&gt;&lt;p&gt;A meaningful development program begins with a question that matters to patients. Why does an effective therapy fail too soon? Why does a particular subgroup derive little benefit? Can efficacy be preserved with less toxicity or recovered once resistance appears? Such questions give direction to discovery and determine what evidence will ultimately matter.&lt;/p&gt;&lt;p&gt;The challenge lies in turning a clinical problem into a testable therapeutic hypothesis. A detectable molecular alteration may suggest a target, but does not make that target clinically actionable. A mechanistically appealing combination may justify investigation, but does not establish synergy. A new modality may broaden what is technically possible without yet indicating whom it should treat or whether it improves the balance of benefit and harm.&lt;/p&gt;&lt;p&gt;Therefore, a more useful discipline would be to ask what uncertainty must be reduced before a clinical decision can reasonably change. That uncertainty may involve patient selection, mechanism, resistance, dose, treatment sequence, or combination strategy. The question should come first. Technology and novelty should serve it.&lt;/p&gt;&lt;p&gt;Early clinical development is where biological possibility first faces clinical scrutiny. Mechanism, exposure, pharmacodynamic effects, safety, tolerability, and preliminary antitumor activity should be considered concurrently rather than as isolated signals.&lt;/p&gt;&lt;p&gt;The phase I development of pyrotinib in human epidermal growth factor receptor 2 -positive metastatic breast cancer illustrates this approach. Dose escalation, pharmacokinetics, safety, antitumor activity, and predictive biomarkers were all evaluated within the same clinical framework, with next-generation sequencing performed on circulating tumor DNA and tumor tissue [&lt;span&gt;2&lt;/span&gt;]. The study established a maximum to","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 5","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187194","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":"Nanoprobe-Enabled Precision Imaging and Panoramic Boundary Delineation in Retinoblastoma","authors":"Xuefei He,&nbsp;Precious Amarachi Ikwuagwu,&nbsp;Wenjing Pang,&nbsp;Aomen Chen,&nbsp;Lingchao Xiang,&nbsp;Feng Chen,&nbsp;Chen Xu,&nbsp;Aiguo Wu","doi":"10.1002/cai2.70083","DOIUrl":"10.1002/cai2.70083","url":null,"abstract":"<p>Retinoblastoma is the most common primary intraocular malignancy in children. Its prognosis depends critically on accurate delineation of the tumor and its margins, early detection of small lesions, and timely monitoring of therapeutic response. Traditional single-modality imaging techniques are inherently constrained by trade-offs among spatial resolution, molecular sensitivity, and dynamic imaging capability, making them insufficient for the demands of precision diagnosis and treatment. In recent years, nanomedicine-based imaging strategies have emerged as promising approaches to overcome these limitations. Through rational design of nanoprobes with tunable physicochemical properties, active targeting capabilities, and integrated multimodal signaling, researchers have achieved more comprehensive visualization and diagnostic evaluation of retinoblastoma lesions. In this review, we systematically summarize the major imaging modalities applied to retinoblastoma, including optical imaging, ultrasound (US), magnetic resonance imaging (MRI), and photoacoustic imaging (PAI). Subsequently, the corresponding imaging probes and targeting strategies were discussed, which were developed to enhance the imaging contrast and improve the spatiotemporal resolution of tumor visualization. Furthermore, we highlight the emerging role of artificial intelligence (AI) in the rational design of high-performance imaging nanoprobes and in multimodal image analysis, emphasizing its potential to enable quantitative tumor and boundary delineation. Finally, we outline the key challenges that must be addressed to advance the clinical translation of nanoprobes, including the identification of novel targeting strategies, AI-assisted image analysis, the development of models that more accurately recapitulate the human ocular microenvironment, and the application of new biocompatible materials. Overall, this review aims to provide comprehensive and insightful guidance for the development of next-generation nanoprobes for the precise visualization and boundary delineation of retinoblastoma.</p>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 5","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171861","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":"Not Whether, but in Whom: Reframing Antibody–Drug Conjugate Sequencing in Metastatic Breast Cancer","authors":"Armando Orlandi","doi":"10.1002/cai2.70085","DOIUrl":"https://doi.org/10.1002/cai2.70085","url":null,"abstract":"<p>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 5","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146122","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":"Evaluating the Performance of Covidence's Artificial Intelligence-Based Screening Function in Cancer Systematic Reviews","authors":"Ashirbani Saha,&nbsp;Xiaomei Yao,&nbsp;Sharan Saravanan,&nbsp;Aditya Misra,&nbsp;Ashley Low,&nbsp;Samya Ali,&nbsp;Mariam Abdelmalek,&nbsp;Shakil Ahmed,&nbsp;Sussman Jonathan","doi":"10.1002/cai2.70077","DOIUrl":"https://doi.org/10.1002/cai2.70077","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Systematic reviews (SRs), often conducted for evidence synthesis, require extensive multistage screening, with Stage-I title/abstract screening being especially time consuming. Covidence systematic review software, a widely used SR platform, has offered artificial intelligence (AI)-assisted Stage-I screening function since 2022. However, this function's performance has not yet been formally compared across heterogeneous, large-scale oncology-focused SRs.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We selected two completed SRs conducted by the Program in Evidence-based Care (PEBC), Ontario, Canada. The first SR (Axilla-BC, &lt;i&gt;N&lt;/i&gt; = 8774) supported a clinical practice guideline in breast cancer and the second SR (PET-utility, &lt;i&gt;N&lt;/i&gt; = 7267) informed the provincial Positron Emission Tomography (PET) steering committee in Ontario. Using each SR, we conducted a simulation-based study by drawing subsets of 500, 1000, and 2000 articles and running 30, 30, and 10 simulation trials, respectively, to emulate Covidence's AI-assisted Stage-I screening. For each trial, we calculated the workload and time savings at 95% and 100% sensitivity for relevant articles and at 100% sensitivity for finally included articles as primary outcomes. Secondary outcomes comprised missed finally included articles at 95% sensitivity for relevant articles. Wilcoxon rank-sum tests were used to compare outcomes between these two SRs.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;When pooling all subset sizes and the &lt;i&gt;N&lt;/i&gt; = 1000 subsets, workload savings at 95% sensitivity were significantly higher for Axilla-BC than for PET-utility (median = 37.4% &lt;i&gt;vs.&lt;/i&gt; 26.2%, &lt;i&gt;W&lt;/i&gt; = 3156.5, &lt;i&gt;p&lt;/i&gt; = 0.003 and median = 38.3% &lt;i&gt;vs.&lt;/i&gt; 20.5%, &lt;i&gt;W&lt;/i&gt; = 641.0, &lt;i&gt;p&lt;/i&gt; = 0.005, respectively). Corresponding time savings were also significantly higher for Axilla-BC (median = 6.0 &lt;i&gt;vs.&lt;/i&gt; 4.2 h, &lt;i&gt;W&lt;/i&gt; = 3089.5, &lt;i&gt;p&lt;/i&gt; = 0.008 and median = 9.6 &lt;i&gt;vs.&lt;/i&gt; 5.1 h, &lt;i&gt;W&lt;/i&gt; = 639.0, &lt;i&gt;p&lt;/i&gt; = 0.005). In Axilla-BC, 20% of the 70 trials missed a total of 18 finally included articles, but only one PET-utility trial missed one article.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In two large oncology-SRs, Covidence's AI-assisted Stage-I screening function demonstrated meaningful potential to reduce reviewer workload and screening time. Nonetheless, Covidence's performance varied notably between reviews, suggesting a possible association between the results and the characteristics of the SR, including topic, methodological complexity, re","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 5","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068530","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":"Radioiodine-Refractory Differentiated Thyroid Cancer: Definition, Molecular Mechanisms, and Advances in Precision Therapy","authors":"Yamin Li,&nbsp;Zuoxiang He","doi":"10.1002/cai2.70078","DOIUrl":"10.1002/cai2.70078","url":null,"abstract":"<p>Radioiodine-refractory differentiated thyroid cancer, defined by loss of responsiveness to ¹³¹I therapy or by heterogeneous iodine uptake, accounts for the majority of thyroid cancer-related deaths; 10-year survival is approximately 10% with distant metastases. Its definition is not uniform: the 2014 expert consensus and the 2015 American Thyroid Association guideline diverge on heterogeneous uptake and on progression despite substantial uptake, and the 2019 Martinique principles reframe these as risk-stratification triggers rather than absolute disqualifiers. Refractoriness reflects mitogen-activated protein kinase-driven silencing of the sodium iodide symporter; <i>TERT</i> promoter mutations, often co-occurring with <i>BRAF</i> V600E, are associated with dedifferentiation. The therapeutic landscape has changed over the past decade: antiangiogenic multikinase inhibitors (lenvatinib, sorafenib, and cabozantinib) are established first- and second-line options; molecular profiling supports genotype-driven and tumor-agnostic treatment of <i>RET</i>, <i>NTRK</i>, and <i>ALK</i> fusions and <i>BRAF</i> V600E mutations; redifferentiation with MEK or combined BRAF/MEK inhibition can restore radioiodine uptake in selected patients, with responses that vary by molecular subtype; and immune checkpoint inhibitors benefit the rare microsatellite instability-high or mismatch repair-deficient subset. Most syntheses organize these options by molecular driver and evidence level, whereas the patient's experience of therapy (toxicity, disruption of daily life, decisional preferences) is acknowledged but seldom carried into recommendations. This review compares those definitions, appraises the evidence for each therapeutic class, defines where ¹²⁴I lesional dosimetry can refine treatment timing, and adds the patient dimension as an explicit third axis, operationalized through two tables: a patient-centered agent comparison and a scenario-specific decision matrix. The evidence supports, without yet establishing, early broad molecular profiling, a selective inhibitor where an actionable alteration is present, a multikinase backbone otherwise, and redifferentiation only where tested. Randomized evidence is distinguished throughout from expert opinion. Head-to-head comparisons and sequencing data remain limited; circulating tumor DNA and imaging-derived biomarkers, so far supported only by small cohorts, and adaptive trial designs are the most plausible routes forward. By making treatment burden as explicit as genotype and evidence level, the framework is intended to make treatment selection and shared decision-making more reproducible.</p>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842707","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":"Global Burden and Temporal Trends of Brain and Central Nervous System Tumors in Children and Adolescents: A Systematic Analysis for the Global Burden of Disease Study 2021","authors":"Zhaoyang Feng,&nbsp;Yu Su,&nbsp;Lin Yang,&nbsp;Kaiwen Deng,&nbsp;Jianmin Wang,&nbsp;Jiao Zhang,&nbsp;Fei Liu,&nbsp;Dongyang Wang,&nbsp;Yuyan Liang,&nbsp;Wei Wang,&nbsp;Xiaoguang Qiu,&nbsp;Tao Jiang,&nbsp;Yu Tian,&nbsp;Hailong Liu","doi":"10.1002/cai2.70079","DOIUrl":"10.1002/cai2.70079","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Central nervous system (CNS) tumors pose major global health challenges. Previous studies often assessed all-age populations without focusing on children and adolescents. We analyzed the burden and temporal trends of CNS tumors among individuals aged &lt; 20 years from 1990 to 2021, with projections to 2036.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data were obtained from the Global Burden of Disease Study 2021, including annual incidence, mortality, and disability-adjusted life years (DALYs) for brain and CNS tumors. Regions were classified by Socio-demographic Index (SDI) to examine associations between burden and development. Temporal trends were analyzed using the age-period-cohort (APC) model and future projections via the Bayesian APC model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In 2021, an estimated 40,534.53 (95% uncertainty interval [UI]: 33,345.94–49,609.04) new cases of brain and CNS tumors occurred worldwide. The global age-standardized incidence rate (ASIR) was 1.54 (95% UI: 1.27–1.88), and the death rate (ASDR) was 0.76 (0.61–0.93) per 100,000. High-SDI regions showed the highest ASIR and ASDR, while lower-SDI regions faced growing burdens. Mortality and DALYs improved most in Greenland, Serbia, and China. The APC model showed a mild global decline in incidence (<i>p</i> = 0.099) and significant mortality reduction (−1.16% annually, <i>p</i> &lt; 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Global CNS tumor burden declined but remains uneven. Enhanced prevention and healthcare access are needed, especially in low-SDI regions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13499956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809655","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":"Clinical Advances in Breast Cancer: A Comprehensive Overview of Full-Course Disease Management","authors":"Xuenan Peng,&nbsp;Yujing Tan,&nbsp;Fei Ma","doi":"10.1002/cai2.70076","DOIUrl":"https://doi.org/10.1002/cai2.70076","url":null,"abstract":"<p>The landscape of breast cancer (BC) treatment has reached a pivotal turning point in recent years, marked by a succession of breakthrough findings from landmark international clinical trials. These advances have fundamentally reshaped treatment paradigms across distinct molecular subtypes. In the field of hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) BC, the introduction of novel targeted agents has continuously optimized therapeutic strategies. Meanwhile, the management of endocrine therapy resistance has evolved into an innovative framework characterized by multitarget therapeutic combination approaches. Concurrently, the extensive impact of the DESTINY-Breast series has constructed a stratified, precision medicine system covering the entire disease course of HER2-positive BC. In triple-negative breast cancer, the ASCENT-03 and ASCENT-04 trials have successfully positioned antibody-drug conjugates as a cornerstone of first-line treatment for advanced disease. This article focuses on the latest advances in BC, systematically reviewing recent clinical evidence and practical experience in medical oncology to provide a robust reference for clinical diagnosis and treatment.</p>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784173","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":"BACE2 Promotes Bladder Cancer Chemoresistance Through Proteolytic Activation of JAG1-Notch Signaling","authors":"Zekun Li,&nbsp;Sanxiang Li,&nbsp;Zhenyu Liu,&nbsp;Yulin Sun,&nbsp;Yun Zhang","doi":"10.1002/cai2.70073","DOIUrl":"https://doi.org/10.1002/cai2.70073","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Chemoresistance to platinum-based regimens, primarily gemcitabine plus cisplatin, remains a major obstacle in the treatment of advanced bladder cancer. Identifying the underlying molecular mechanisms is critical for developing effective therapeutic strategies to improve clinical outcomes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Integrative analysis of transcriptomic profiles from chemoresistant bladder cancer models and clinical data sets from The Cancer Genome Atlas was performed to identify candidate resistance drivers. The biological function of the candidate gene was evaluated in vitro using bladder cancer cell lines. Mechanistic investigations, including transcriptomic analyses and immunoprecipitation, were conducted to elucidate downstream signaling. The therapeutic potential of targeting this axis was assessed in vitro and in an in vivo xenograft model using a small-molecule inhibitor combined with chemotherapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We identified β-secretase 2 (BACE2) as a candidate mediator of cisplatin resistance. &lt;i&gt;BACE2&lt;/i&gt; is significantly upregulated in gemcitabine- and cisplatin-resistant models, including patient-derived organoids. Its elevated baseline expression correlates with advanced pathologic stage, poor prognosis, and diminished clinical benefit from platinum-based therapy. Functionally, BACE2 promotes resistance to both gemcitabine and cisplatin. Mechanistically, BACE2 interacts with Jagged1 (JAG1) and promotes the generation of a soluble JAG1 fragment in a catalytic activity-dependent manner. Mutation of the catalytic Asp303 residue markedly reduced JAG1 fragment generation and restored gemcitabine sensitivity, supporting a functional requirement for BACE2 enzymatic activity in this process. This fragment is associated with Notch signaling activation through autocrine and paracrine mechanisms, which concomitantly induces endogenous JAG1 expression, establishing a positive feedback loop that sustains chemoresistance. Pharmacologic inhibition of β-secretase activity with verubecestat disrupted JAG1 cleavage, reduced downstream Notch signaling and enhanced chemotherapy efficacy in vitro without inducing apparent cytotoxicity alone. Furthermore, combination treatment with verubecestat and gemcitabine produced stronger tumor growth inhibition than either monotherapy in vivo.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These results define a novel BACE2-JAG1-Notch signaling axis that contributes to bladder cancer chemoresistance. Importantly, our findin","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783778","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":"Safeguarding the Right to a Whole Life","authors":"Jie Qiao,&nbsp;Fei Ma","doi":"10.1002/cai2.70080","DOIUrl":"https://doi.org/10.1002/cai2.70080","url":null,"abstract":"&lt;p&gt;The ultimate concern of medicine transcends the mere eradication of disease; more profoundly, it resides in the preservation of human dignity and the intergenerational continuity of life's hope. From the ancient maxim of the &lt;i&gt;Zhouyi&lt;/i&gt; (&lt;i&gt;Book of Changes&lt;/i&gt;)—“The greatest virtue of Heaven and Earth is the giving of life”—to the contemporary advances in assisted reproductive technology that repeatedly render the impossible possible, the continuity and full flourishing of life have remained among medicine's deepest aspirations. As precision oncology continues to continually improve survival outcomes, we are increasingly cognizant that a truly curative path must not only draw patients back from the abyss of illness but also preserve their right to embrace a fulfilling life—of which safeguarding reproductive potential stands as an indispensable dimension that must not be overlooked [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;With the remarkable advance in tumor diagnosis and treatment, a growing number of young patients have moved beyond the threshold of mere survival to reclaim the fullness of life. As long-term survival becomes achievable for an increasing proportion of patients, a central consideration in redefining quality of life lies in the ability to “nurture the future” and to reclaim familial and societal identities. Taking breast cancer as an example, 50% of young patients have not yet completed their families at the time of diagnosis, yet the actual pregnancy rate remains below 5% [&lt;span&gt;2, 3&lt;/span&gt;]. Cytotoxic chemotherapy may exert substantial gonadotoxic effects, whereas prolonged endocrine therapy may defer childbearing during the reproductive years; the reproductive effects of many targeted therapies remain incompletely characterized [&lt;span&gt;4, 5&lt;/span&gt;]. Consequently, some patients who survive cancer may still face premature ovarian insufficiency and fertility loss. Reassuringly, existing evidence indicates that timely and appropriately selected interventions can preserve reproductive potential without sacrificing anticancer efficacy in many clinical settings, encompassing fertility preservation strategies like cryopreservation techniques and pharmacological protection [&lt;span&gt;5-7&lt;/span&gt;]. Between oncology and reproductive medicine, an interdisciplinary frontier demanding systematic cultivation has thus emerged. Oncofertility stands as the nascent cross-disciplinary practice that responds to this pressing clinical need [&lt;span&gt;1&lt;/span&gt;]. We advocate a clinical philosophy wherein anticancer treatment and fertility preservation are considered in parallel, so that disease control and preservation of reproductive potential need not become mutually exclusive goals, thereby moving fertility preservation from an exploratory practice confined to selected centers toward routine clinical care, and from post-treatment remediation toward proactive and safeguarding planning [&lt;span&gt;7&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Since its inception, &lt;i&gt;Cancer Innovation&lt;/i&gt; has steadfastly ch","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"5 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783653","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}