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Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance. 靶向LKB1/ stk11突变型癌症：不同的代谢、微环境和治疗耐药性
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-22 DOI: 10.1016/j.tips.2025.06.008
Allegra C Minor, Evan Couser, Lillian J Eichner
{"title":"Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance.","authors":"Allegra C Minor, Evan Couser, Lillian J Eichner","doi":"10.1016/j.tips.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.tips.2025.06.008","url":null,"abstract":"<p><p>Despite the development of new classes of therapeutics in oncology, patients with tumors harboring mutations in the tumor suppressor gene STK11/LKB1 continue to exhibit poor clinical response and therapeutic resistance. Recent advances in the understanding of LKB1-mutant tumor biology have illuminated how metabolism and the tumor microenvironment (TME) function as effectors of the aggressive nature of this tumor type. New findings have revealed how metabolic reprogramming, a hallmark of LKB1-mutant tumor biology, can be exploited as a potential targetable liability in these tumors. Characterization of the distinctly immunosuppressive LKB1-mutant TME has motivated multiple discoveries of new approaches for rewiring the microenvironment to overcome immunotherapy resistance. Indeed, overcoming therapeutic resistance in LKB1-deficient tumors continues to be a major research focus, and some preclinical studies have advanced to clinical trials. In this review, we critically analyze these findings and discuss therapies in development that aim to leverage this new understanding for clinical benefit.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TREM2 and LAG-3 in cancer and Alzheimer's disease immunotherapy. TREM2和LAG-3在癌症和阿尔茨海默病免疫治疗中的作用。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-18 DOI: 10.1016/j.tips.2025.06.010
Shaoren Yuan, Natalie S Fuchs, Somaya A Abdel-Rahman, Baljit Kaur, Moustafa T Gabr
{"title":"TREM2 and LAG-3 in cancer and Alzheimer's disease immunotherapy.","authors":"Shaoren Yuan, Natalie S Fuchs, Somaya A Abdel-Rahman, Baljit Kaur, Moustafa T Gabr","doi":"10.1016/j.tips.2025.06.010","DOIUrl":"https://doi.org/10.1016/j.tips.2025.06.010","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and cancer are immune-mediated disorders characterized by chronic neuroinflammation and immune evasion, respectively. Recent studies implicate two key immune regulators in both diseases: LAG-3, an adaptive immune checkpoint receptor, and TREM2, an innate receptor expressed on microglia and tumor-associated macrophages (TAMs). LAG-3 inhibitors have demonstrated clinical efficacy in cancer and are being explored in AD research. TREM2 activation supports microglial function in AD, while its inhibition may counteract immunosuppressive macrophages in cancer. In this review we compare the roles, mechanisms, and therapeutic strategies targeting LAG-3 and TREM2 in both diseases. We highlight their distinct immune compartmentalization and the importance of context-specific modulation. Strategies include LAG-3 blockade in cancer and AD, and TREM2 agonism or antagonism depending on disease context. We discuss a framework integrating immune compartment, disease state, and therapeutic modality to guide cross-domain immunotherapy development in cancer and AD.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design and development of glucocorticoid receptor modulators. 糖皮质激素受体调节剂的设计与研制。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-17 DOI: 10.1016/j.tips.2025.06.005
Frank Buttgereit, Christian Elling, Florian Jakob
{"title":"Design and development of glucocorticoid receptor modulators.","authors":"Frank Buttgereit, Christian Elling, Florian Jakob","doi":"10.1016/j.tips.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.tips.2025.06.005","url":null,"abstract":"<p><p>Synthetic glucocorticoids (GCs) are effective anti-inflammatory drugs but cause serious adverse effects (AEs). Initially, anti-inflammatory efficacy and AEs were ascribed to GC receptor (GR)-mediated gene transrepression and transactivation, respectively. Although current evidence indicates greater mechanistic complexity of GC action, this proposed distinction in GR-mediated effects has led to the design of novel steroidal and nonsteroidal GR modulators (GRMs) using emerging technologies and new laboratory assays to reduce the AEs associated with synthetic GCs. These GRMs alter the balance between GR transrepression and transactivation. A novel GRM, the dissociated steroid vamorolone, received marketing approval in 2024, confirming that altering the transrepression-transactivation profile is a valid strategy. Here, we review GR-mediated gene regulation and the transrepression-transactivation profile of GCs in relation to their anti-inflammatory efficacy and AEs. We highlight technological advances driving the design/development of novel GRMs, such as selective GR agonists and modulators (SEGRAMs), and provide insights into their mechanism of action.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ion channels as therapeutic targets in osteoarthritis. 离子通道作为骨关节炎的治疗靶点。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-10 DOI: 10.1016/j.tips.2025.06.003
Renpeng Zhou, Wei Hu, Stephen G Waxman, Chuan-Ju Liu
{"title":"Ion channels as therapeutic targets in osteoarthritis.","authors":"Renpeng Zhou, Wei Hu, Stephen G Waxman, Chuan-Ju Liu","doi":"10.1016/j.tips.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.tips.2025.06.003","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a leading cause of disability worldwide and is characterized by cartilage loss, inflammation, and pain. Despite advances, effective disease-modifying treatments are lacking. Emerging evidence highlights ion channels as key regulators of OA that affect chondrocyte survival, mechanotransduction, inflammation, and nociception. This review discusses ion channel families - including sodium, potassium, TRP, Piezo, acid-sensing, and chloride channels, as well as ligand-gated receptors - and their roles in OA progression. We explore preclinical and clinical advances in ion channel-targeted therapies, such as small-molecule inhibitors, biologics, and gene therapies, as well as repurposing of existing drugs for symptom relief and disease modification. Challenges in selective targeting, pharmacological and drug delivery strategies, and patient stratification are also addressed. Continued research on ion channel biology is essential for developing targeted OA therapies to enable precision medicine via site-specific strategies that minimize systemic side effects.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144620731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nemolizumab (Nemluvio®) for prurigo nodularis. Nemolizumab (Nemluvio®)用于结节性皮炎。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-05 DOI: 10.1016/j.tips.2025.06.004
Svenja Royeck, Sonja Ständer
{"title":"Nemolizumab (Nemluvio®) for prurigo nodularis.","authors":"Svenja Royeck, Sonja Ständer","doi":"10.1016/j.tips.2025.06.004","DOIUrl":"https://doi.org/10.1016/j.tips.2025.06.004","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Shining light on parvalbumin interneuron plasticity. 照亮小白蛋白中间神经元的可塑性。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-05 DOI: 10.1016/j.tips.2025.06.006
Marina P Hommersom, Dirk Schubert, Nael Nadif Kasri
{"title":"Shining light on parvalbumin interneuron plasticity.","authors":"Marina P Hommersom, Dirk Schubert, Nael Nadif Kasri","doi":"10.1016/j.tips.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.tips.2025.06.006","url":null,"abstract":"<p><p>Neuronal networks rely on a balance between the activity of excitatory and inhibitory neurons, each having distinct roles in regulating the flow of activity across brain circuits and signal processing. Recent work by Selten et al. uncovers how parvalbumin (PV)-expressing interneurons adjust their inhibitory inputs in response to activity changes, revealing a neuropeptide-based mechanism.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PSA inhibitors for contraception: insights from prostate cancer. PSA抑制剂用于避孕：来自前列腺癌的见解。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-04 DOI: 10.1016/j.tips.2025.05.005
Wipawee Winuthayanon
{"title":"PSA inhibitors for contraception: insights from prostate cancer.","authors":"Wipawee Winuthayanon","doi":"10.1016/j.tips.2025.05.005","DOIUrl":"10.1016/j.tips.2025.05.005","url":null,"abstract":"<p><p>Despite the availability of effective hormonal contraceptive methods, nearly half of pregnancies worldwide remain unintended, highlighting the urgent need for innovative, nonhormonal options. Prostate-specific antigen (PSA) is a biomarker for prostate cancer and is well established for its role in liquefying semen by hydrolyzing gel-forming proteins. Liquefaction is essential for sperm motility and fertilization, making PSA inhibition a prime candidate for novel contraceptive strategies. Advances in prostate cancer research have led to the development of PSA inhibitors for cancer therapeutic purposes, including drugs that suppress PSA activity or selectively kill PSA-expressing cells. PSA presents a unique target as it is produced in men and acts in women, making it a promising contraceptive strategy for both sexes. This opinion explores the potential adaptation of existing PSA inhibitors from the oncology field for contraceptive applications. It also highlights emerging strategies to identify effective PSA-targeted contraceptive candidates, opening new avenues for next-generation nonhormonal contraception for men and women.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"599-609"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12227279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emerging approaches for antagonizing the aryl hydrocarbon receptor. 拮抗芳烃受体的新方法。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-05 DOI: 10.1016/j.tips.2025.05.003
Zdeněk Dvořák, Sridhar Mani, Jan Vondráček
{"title":"Emerging approaches for antagonizing the aryl hydrocarbon receptor.","authors":"Zdeněk Dvořák, Sridhar Mani, Jan Vondráček","doi":"10.1016/j.tips.2025.05.003","DOIUrl":"10.1016/j.tips.2025.05.003","url":null,"abstract":"<p><p>Antagonizing the aryl hydrocarbon receptor (AhR) is a highly pertinent pharmacotherapeutic strategy. To overcome the drawbacks of existing AhR antagonists, novel molecules that can selectively target canonical and noncanonical AhR pathways are urgently needed. Recent reports on the structures and functions of cytosolic and nuclear AhR-protein complexes have allowed for understanding structural determinants for intrinsic activity and functional selectivity of AhR ligands. This new information regarding AhR surface interactions has opened new avenues for the development of novel AhR antagonists. Achievable strategies include the negative allosteric modulation of AhR and the disruption of AhR-protein and AhR-DNA interfaces using peptidomimetics or small molecules. Here, we discuss such novel approaches that may lead to new AhR-targeted therapeutics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"629-637"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Protein acylations in cancer immunity: effects and therapeutic opportunities. 蛋白质酰化在癌症免疫中的作用和治疗机会。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-20 DOI: 10.1016/j.tips.2025.05.011
Jia-Cheng Lai, Yi-Ting Jiang, Shougeng Liu, Simeng Wang, Wei Cui, Lihui Wang
{"title":"Protein acylations in cancer immunity: effects and therapeutic opportunities.","authors":"Jia-Cheng Lai, Yi-Ting Jiang, Shougeng Liu, Simeng Wang, Wei Cui, Lihui Wang","doi":"10.1016/j.tips.2025.05.011","DOIUrl":"10.1016/j.tips.2025.05.011","url":null,"abstract":"<p><p>Acylations are conserved and dynamic modifications that control various biological processes, including gene transcription and protein biology, and have been tied to diseases, such as cancers. Due to their reversible characteristic, acylations exhibit great therapeutic potential through targeting of their regulatory enzymes and proteins. Recent studies have improved our understanding of the close interplay between acylations and the tumor immune microenvironment (TIME), showing the potential to improve antitumor immune responses via acylation manipulation. Herein, we review the effects of acylations, including acetylation, lactylation, palmitoylation, and some less well-known acylations on cancer immunity, and corresponding therapeutic opportunities. Specifically, we bring into focus diverse roles of different acylation-related enzymes, metabolites, or substrates to provide insights into targeting acylations to increase antitumor immunity and generate broader research enthusiasm.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"653-673"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bright sorting yields drug-like anti-amyloid antibodies. 明亮分选产生类似药物的抗淀粉样抗体。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-16 DOI: 10.1016/j.tips.2025.05.013
Bingqian Li, Pietro Sormanni
{"title":"Bright sorting yields drug-like anti-amyloid antibodies.","authors":"Bingqian Li, Pietro Sormanni","doi":"10.1016/j.tips.2025.05.013","DOIUrl":"10.1016/j.tips.2025.05.013","url":null,"abstract":"<p><p>Conformation-specific antibodies represent powerful tools for targeting pathogenic amyloid aggregates. However, the discovery of aggregate-selective antibodies with drug-like developability properties has been slow, inefficient, and difficult to generalise across different amyloid targets. The Tessier lab has developed a yeast-display screening pipeline that enables conformation-specific antibody discovery against diverse aggregated proteins.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"587-589"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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