{"title":"IRAK signaling in cancers: <i>mechanisms, targeting, and clinical implications</i>.","authors":"Eric J Vick, Daniel T Starczynowski","doi":"10.1080/13543784.2025.2573646","DOIUrl":"https://doi.org/10.1080/13543784.2025.2573646","url":null,"abstract":"<p><strong>Introduction: </strong>All human cells have the capacity to respond to damage or danger through conserved signaling pathways that converge on interleukin-1 receptor-associated kinases (IRAKs). IRAKs are a family of kinases that play central roles in innate immunity and inflammation and are increasingly implicated in the development and progression of cancer.</p><p><strong>Areas covered: </strong>IRAKs are tightly regulated by multiple mechanisms to prevent aberrant activation, dysregulated IRAK function has been increasingly recognized for its role in cancer initiation, progression, and therapy resistance, extending beyond its canonical function in inflammatory signaling. While much of the research to date has focused on IRAK signaling in hematologic malignancies, emerging evidence suggests that IRAKs are also activated and therapeutically relevant in solid tumors. As a result, several small-molecule inhibitors targeting one or more IRAK family members are now approved, in clinical trials, or under preclinical development. In this review, we summarize the current understanding of IRAK biology in cancer, with a particular focus on therapeutic strategies and the translational potential of IRAK-targeted therapies.</p><p><strong>Expert opinion: </strong>IRAK inhibitors and degraders are promising treatments for a variety of cancers. Future clinical success will depend on optimizing kinase selectivity profiles and identifying biomarkers to guide patient selection and combination strategies.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Bleve, Pier Vitale Nuzzo, Abdul Baseet Arham, Aaron Holmes, Scott T Tagawa
{"title":"Androgen receptor pathway signaling inhibitors in development for prostate cancer therapy.","authors":"Sara Bleve, Pier Vitale Nuzzo, Abdul Baseet Arham, Aaron Holmes, Scott T Tagawa","doi":"10.1080/13543784.2025.2573647","DOIUrl":"https://doi.org/10.1080/13543784.2025.2573647","url":null,"abstract":"<p><strong>Introduction: </strong>Prostate cancer (PC), including castration-resistant disease (CRPC), remains largely driven by dysregulated androgen receptor (AR) signaling. While androgen deprivation therapy (ADT) combined with next-generation AR inhibitors improves survival, resistance inevitably arises through mechanisms such as AR amplification, mutations, and splice variants. Additionally, chronic AR suppression induces significant metabolic, musculoskeletal, and cardiovascular toxicities, highlighting the need for novel therapies that overcome resistance while minimizing systemic adverse effects.</p><p><strong>Areas covered: </strong>This review outlines the pivotal role of AR signaling in PC pathogenesis and evaluates the clinical impact and limitations of current AR-targeted therapies. In addition, it examines emerging therapeutic strategies aimed at modulating AR activity, disrupting androgen biosynthesis, and degrading the AR protein itself. Finally, we explore novel approaches targeting alternative oncogenic pathways involved in resistance and lineage plasticity, with the goal of advancing more effective and durable treatment paradigms.</p><p><strong>Expert opinion: </strong>Novel strategies such as bipolar androgen therapy (BAT), selective androgen receptor modulators (SARMs), and AR degraders like PROTACs offer context-specific or mechanistically distinct ways to overcome resistance to traditional AR antagonism in prostate cancer. These approaches, along with CYP11A1 inhibitors and resistance pathway targeting (e.g. PI3K/AKT, EZH2), mark a shift toward more personalized therapies aimed at improving efficacy while minimizing toxicity.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda J Hooper, Thusyanthy Parameswaran, John R Burnett
{"title":"Emerging ANGPTL3-directed therapies for hyperlipidemia: insights from two recent phase II trials.","authors":"Amanda J Hooper, Thusyanthy Parameswaran, John R Burnett","doi":"10.1080/13543784.2025.2571213","DOIUrl":"10.1080/13543784.2025.2571213","url":null,"abstract":"","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"1-4"},"PeriodicalIF":4.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jie Ding, Qian Zhang, Qin Yang, Qin Zhang, Sihui Tu, Yangyang Zuo, Zhiwei Yao, Peng Deng, Lin Tao, Liang Zheng, Hu Wei
{"title":"Pharmacokinetics, pharmacodynamics, and safety of HE009, a novel selective S1P1 receptor modulator, in healthy Chinese subjects.","authors":"Jie Ding, Qian Zhang, Qin Yang, Qin Zhang, Sihui Tu, Yangyang Zuo, Zhiwei Yao, Peng Deng, Lin Tao, Liang Zheng, Hu Wei","doi":"10.1080/13543784.2025.2570244","DOIUrl":"https://doi.org/10.1080/13543784.2025.2570244","url":null,"abstract":"<p><strong>Objective: </strong>HE009,a novel selective sphingosine-1-phosphate receptor-1(S1P1) modulator, was evaluated in healthy Chinese subjects to assess itspharmacokinetics, pharmacodynamics, and safety profile.</p><p><strong>Research design and methods: </strong>This randomized, placebo-controlled phase I studycomprised single ascending dose (SAD, 0.05-4.0 mg), multiple ascending dose(MAD, 0.5-3.0 mg), dose titration, and food effect components.</p><p><strong>Results: </strong>HE009 exhibited dose-proportional exposure, with T<sub>max</sub>of 4-6 hours and t<sub>1/2</sub> of 16-24 hours, supporting once-daily dosing.Steady-state was achieved by day 7 with minimal accumulation (1.7-2.0 fold). Aclear concentration-effect relationship was observed, with maximum lymphocytecount reductions of 58% (SAD) and 70-80% (MAD). Notably, HE009 demonstrated afavorable cardiac safety profile, with transient, asymptomatic bradycardiamitigated by dose titration. No events related to hypertension were observedduring the study period.</p><p><strong>Conclusion: </strong>Thesefindings suggest HE009 offers potential advantages in efficacy, safety, anddosing flexibility compared to existing S1P receptor modulators for treatingautoimmune disorders like systemic lupus erythematosus.</p><p><strong>Trial registration: </strong>The trial was registered on the ChineseClinical Trial Registry, (Identifier No. ChiCTR2200066345), Registered December1, 2022.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuhao Shi, Sravya Koduri, Jonathan T Yang, Brandon S Imber
{"title":"Development of investigational radiotherapeutics for the diagnosis and treatment of glioma.","authors":"Yuhao Shi, Sravya Koduri, Jonathan T Yang, Brandon S Imber","doi":"10.1080/13543784.2025.2564966","DOIUrl":"10.1080/13543784.2025.2564966","url":null,"abstract":"<p><strong>Introduction: </strong>Gliomas are tumors that arise from glial cells in the central nervous system. Radiation provides local control for low-grade gliomas and improves survival for patients with high-grade gliomas; however, recurrence is common and treatment can be associated with long-term toxicities. Several strategies are under development to improve the anti-tumor efficacy of radiation and limit possible side effects. Novel molecular imaging agents can help diagnose new gliomas, delineate tumors for more accurate radiation planning, and differentiate tumor recurrence from treatment response changes on imaging. Radiotherapeutics provide an alternative method of delivering targeted radiation to tumors by leveraging molecular targets. New generation of radiosensitizers that target DNA damage response and cell cycle pathways aim to enhance radiation-induced cytotoxicity.</p><p><strong>Areas covered: </strong>This review summarizes emerging molecular imaging agents, radiotherapeutics, and radiosensitizers in glioma with a focus on agents currently in the early phase of clinical trials.</p><p><strong>Expert opinion: </strong>The development of new diagnostic and therapeutic agents has the potential of improving outcomes for glioma patients. As new agents are tested in clinical trials, it will be critical to consider questions regarding standardization of methodology in use/interpretation of molecular imaging techniques, appropriate dosimetry of radiotherapeutics, and cumulative toxicities with radiosensitizers.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"1-10"},"PeriodicalIF":4.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olivia Triplett, Nicole Varda, Boris Decourt, Marwan N Sabbagh
{"title":"Nonamyloid-beta active immunization for the treatment of Alzheimer's disease.","authors":"Olivia Triplett, Nicole Varda, Boris Decourt, Marwan N Sabbagh","doi":"10.1080/13543784.2025.2551352","DOIUrl":"10.1080/13543784.2025.2551352","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) is characterized by the formation of senile plaques composed of amyloid-beta (Aβ) peptides and the intraneuronal accumulation of neurofibrillary tangles composed of abnormal, hyperphosphorylated tau proteins. These act in concert to drive cognitive decline, but it is widely held that tau spread correlates better with cognitive decline than does amyloid burden. Control of AD neuropathologies with active immunizations is studied as a potential therapeutic avenue because it could build innate immunity. Although most active immunization studies have focused on Aβ targets, tau and other targets continue to be explored.</p><p><strong>Areas covered: </strong>This study aimed to identify and describe non-Aβ active immunization trials for AD treatment. A narrative review was conducted to analyze the current status of non-Aβ active immunization for AD using PubMed as the research database.</p><p><strong>Expert opinion: </strong>The potential of active immunization beyond Aβ was explored as a therapeutic strategy for AD with a focus that targets tau and provides insights into its effectiveness, associated challenges, and limitations. Results from preclinical and clinical studies were examined, highlighting the progress and the hurdles that exist. Active immunization against non-Aβ targets, such as tau, for the treatment of AD remains a promising and expanding field.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"685-693"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tirzepatide for metabolic dysfunction-associated steatohepatitis: results from phase II clinical trials and perspectives.","authors":"Stefano Fiorucci, Ginevra Urbani","doi":"10.1080/13543784.2025.2546812","DOIUrl":"10.1080/13543784.2025.2546812","url":null,"abstract":"<p><strong>Introduction: </strong>Tirzepatide is a once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. GIP and GLP-1 are incretins promoting insulin release from pancreatic β-cells. Results from clinical trials have confirmed that tirzepatide exerts favorable effects on glucose metabolism and insulin resistance, reduces food intake and has been approved for the treatment of adults with type 2 diabetes, and who are overweight/obese or who have weight-related comorbidities.</p><p><strong>Areas covered: </strong>Results from SYNERGY-NASH, a phase 2 study involving patients with biopsy-proven MASH and stage 2 or 3 fibrosis, have shown that tirzepatide achieved MASH resolution with no worsening of fibrosis in a significantly higher percentage of patients than placebo. Additionally, more patients in the tirzepatide group in comparison to placebo achieved a 1-stage or greater fibrosis improvement without worsening of MASH, but the study was not powered to detect this change, and noninvasive biomarkers of fibrosis were not significantly improved.</p><p><strong>Expert opinion: </strong>While these results suggest a potential role for tirzepatide in MASH treatment given its ability to improve insulin sensitivity and reduce food intake, factors already shown to be beneficial in reducing livers steatosis and fibrosis, larger clinical trials are needed.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"655-663"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Acute chest syndrome (ACS) in sickle cell disease (SCD): pathogenesis and pharmacotherapies in early clinical development.","authors":"Subarna Chakravorty, Anne Greenough","doi":"10.1080/13543784.2025.2551353","DOIUrl":"10.1080/13543784.2025.2551353","url":null,"abstract":"<p><strong>Introduction: </strong>Sickle cell disease (SCD) is a monogenic disorder caused by a point mutation in the <i>HBB</i> gene, leading to the production of sickle hemoglobin (HbS). Under hypoxic or acidic conditions, HbS polymerizes within erythrocytes, leading to a series of downstream events resulting in tissue ischemia. Acute chest syndrome (ACS) is a severe and often life-threatening complication of SCD and the leading cause of intensive care unit admission and mortality in children.</p><p><strong>Areas covered: </strong>This review covers the latest understanding of ACS pathology involving infectious triggers, pulmonary fat embolism, endothelial activation, hypercoagulability, and sterile inflammation. We discuss the role of neutrophil extracellular traps, inflammasomes, and platelet - leukocyte aggregates in pulmonary microvasculature causing tissue infarction, ventilation perfusion mismatch, and respiratory failure. We explore the emergence of targeted therapies in preventing and treating ACS.</p><p><strong>Expert opinion: </strong>Although understanding of ACS pathogenesis has improved, current treatments are mainly supportive, with hydroxyurea as the primary preventive therapy. Newer treatments focus on specific mechanisms such as heme scavenging, P-selectin inhibition, toll-like receptor blockade, nitric oxide pathway modulation, and anti-thrombotic strategies. Given ACS's complex nature, a multi-drug targeted approach is likely needed. Scaling up hydroxyurea use remains essential to improving outcomes for millions affected globally by this life-threatening condition.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"695-703"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mirdametinib, an FDA-Approved MEK1/2 inhibitor for adult and pediatric NF1-associated plexiform neurofibromas.","authors":"Gorkem Oztosun, Amy Armstrong, Angela C Hirbe","doi":"10.1080/13543784.2025.2558656","DOIUrl":"10.1080/13543784.2025.2558656","url":null,"abstract":"<p><strong>Introduction: </strong>Neurofibromatosis type 1 (NF1) is an autosomal-dominant cancer predisposition syndrome that leads to the development of plexiform neurofibromas (PNs), which can cause significant morbidity and are at risk to transform into malignant peripheral nerve sheath tumors (MPNSTs). Targeted therapies such as mirdametinib, a selective oral MEK1/2 inhibitor, have offered new treatment options for patients with symptomatic, inoperable PNs.</p><p><strong>Areas covered: </strong>This review summarizes the pathophysiology of NF1, the role of MEK inhibition, and the development of mirdametinib as a treatment for NF1-associated plexiform neurofibromas. Relevant literature was identified through PubMed searches using keywords related to NF1, plexiform neurofibromas, MEK inhibition, and mirdametinib. Key aspects discussed include mirdametinib's pharmacologic properties, clinical efficacy, safety profile, and comparison with other MEK inhibitors.</p><p><strong>Expert opinion: </strong>Mirdametinib offers an effective, targeted, and orally available treatment for NF1-associated plexiform neurofibromas, with the added advantage of CNS penetration and durable clinical benefit. However, resistance and toxicity remain challenges, and future research should focus on optimizing patient selection and developing combination strategies to further expand its role in NF1-PN management.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"665-673"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dimitrios S Kontogiannis, Laura T Romanos, Iva D Tzvetanova, Georgios L Voulgaris, Matthew E Falagas
{"title":"Antibiotics and non-traditional antimicrobial agents for carbapenem-resistant <i>Acinetobacter baumannii</i> in Phase 1, 2, and 3 clinical trials.","authors":"Dimitrios S Kontogiannis, Laura T Romanos, Iva D Tzvetanova, Georgios L Voulgaris, Matthew E Falagas","doi":"10.1080/13543784.2025.2552846","DOIUrl":"10.1080/13543784.2025.2552846","url":null,"abstract":"<p><strong>Introduction: </strong>Carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infections have become common in healthcare settings worldwide, yet current therapeutic options are limited. A pipeline of new antibiotics and non-traditional antimicrobial agents is being developed to address the urgent need for efficacious therapeutic options for patients with CRAB infections.</p><p><strong>Areas covered: </strong>At the time of this writing, 13 traditional antibiotics are in clinical development for CRAB infections, some with a novel mechanism of action. Specifically, 9 antibiotics are in Phase 1 (<i>R</i>-327, xeruborbactam/QPX-7728, upleganan/SPR-206, MRX-8, QPX-9003, zifanocycline/KBP-7072, apramycin/EBL-1003, zosurabalpin/RG-6006, and ANT-3310), two in Phase 2 (BV-100, OMN-6), and two in Phase 3 (zidebactam/WCK-5222, funobactam/XNW-4107) clinical trials. Additionally, there are six non-traditional antimicrobial agents in Phase 1 or 2 clinical trials for treating CRAB infections. In particular, two monoclonal antibodies (TRL-1068, CMTX-101), a phage therapy (Phagebank), an immune-modulating agent (recombinant human plasma gelsolin/Rhu-pGSN), a microbiome-modulating agent (SER-155), and an engineered cationic antibiotic peptide (PLG-0206).</p><p><strong>Expert opinion: </strong>Several agents with promising characteristics against CRAB infections are in clinical development (Phases 1, 2, and 3). The urgent need for therapeutic options against CRAB infections necessitates optimizing efforts and time for introducing successfully studied agents into clinical practice.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"705-716"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}