Expert Opinion on Therapeutic Targets最新文献

Introduction: Epilepsy is a chronic neurological disorder leading to repeateduncontrollable seizures. The available armamentarium of ~ 30 antiseizure drugsis unable to control seizures in a third of the patients, which signifies the need to look for novel therapeutic targets with alternative mechanisms of action.

Areas covered: Fibronectin, an extracellular matrix (ECM) glycoprotein,is involved in epileptogenesis as shown by several clinical and preclinicalstudies. There is ample evidence supporting fibronectin's role in modulatingkey pathognomonic events during epileptogenesis. This review presents a conciseoverview of fibronectin's contribution to the initiation and progression ofepilepsy. Additionally, we highlight the potential of fibronectin to betargeted for developing novel anti-epileptogenic therapeutics.

Expert opinion: Epileptogenesis involves aberrant angiogenesis,blood-brain barrier (BBB) perturbation, neuroinflammation, synaptic remodeling,and neuronal hyperexcitability, all of which are significantly regulated byfibronectin. Small-molecule inhibitors against fibronectin could disrupt the signaling pathways that influence hyperexcitability, BBB disruption, andaberrant neurogenesis during epileptogenesis. Alternatively, delivering fibronectin/nanomedicine complex to the brain could help target neuroinflammation, as demonstrated in other diseases. However, current evidence supporting fibronectin as a therapeutic target in epilepsy remains limited,highlighting the need for further research to better understand its role in epileptogenesis.

Introduction: Recent advances in cancer immunotherapy have improved patient outcomes, even in advanced stages of the disease. However, the effectiveness of current cancer immunotherapies remains limited to a small subset of patients because of resistance and an immunosuppressive tumor microenvironment.

Areas covered: Research performed during the last years have identified immunosuppressive interactions between sialic acid-containing glycans and sialic acid-binding immunoglobulin-like lectin (Siglec) receptors as a potential new, targetable pathway to overcome resistance to immunotherapy. In addition, activatory Siglecs could be engaged to enhance anti-tumor immunity. In this review, we summarize accumulating preclinical evidence demonstrating the immunosuppressive role of sialoglycan-Siglec interactions in cancer. Additionally, we provide an overview of potential therapeutic strategies aimed at disrupting this immunosuppressive axis, including interventions currently being evaluated in early-phase clinical trials.

Expert opinion: Preclinical data strongly suggests that disrupting sialic acid-Siglec interactions could significantly improve cancer immunotherapy, in particular by changing the immunosuppressive microenvironment. Further biological understanding is needed to successfully develop new therapeutics. First trials are running that target these interactions and will hopefully inform, which patients are benefitting from this treatment.

Introduction: Osteosarcoma, a highly aggressive bone tumor, continues to pose significant treatment challenges despite advances in molecular research. Traditional therapeutic strategies have largely relied on targeting genetic alterations of tumor genes or signaling pathways, but these approaches have been less effective in clinical settings due to the complex biology.

Areas covered: Recent insights into the molecular landscape of osteosarcoma have revealed key mechanisms of therapeutic resistance, including tumor plasticity, immune evasion, and metabolic reprogramming. The interaction between the tumor and its microenvironment, such as mechanical stress, hypoxia, and extracellular matrix composition, leads to spatially distinct regions with varying drug sensitivities.

Expert opinion: We highlight three key shifts in understanding osteosarcoma biology: 'target plasticity' driven by evolving tumor dynamics, the importance of mechanical signaling at the tumor-bone interface, and the potential of multi-omics platforms for real-time monitoring and personalized treatment. We propose a new therapeutic framework that integrates these advances to overcome resistance mechanisms. By focusing on epigenetic reprogramming, immune resetting, and mechanopharmacological approaches, we envision a more comprehensive strategy for osteosarcoma treatment that goes beyond traditional single-target therapies. The success of these strategies will depend on integrating spatially informed, time-resolved treatment regimens, guided by advanced molecular and computational technologies.

Introduction: Neuroblastoma, a sympathetic nervous system tumor, is known for its remarkable biological heterogeneity. Unlike other neurogenic malignancies driven by mutations, neuroblastoma carries a significant 'transcriptional burden.' Deregulation of transcription unveils in the course of the tumor's natural history, making the advanced stages of the disease intractable.

Areas covered: Recent research investigated the molecular profiles of key neuroblastoma states: adrenergic (ADRN) and mesenchymal (MES). These categories are defined by core regulatory circuit (CRC) genes whose products (transcription factors) modulate a variety of malignant properties. This review analyzes fundamental mechanisms of regulation of CRC in neuroblastoma, focusing on transcriptional alterations as tentative therapeutic targets. We dissect differential CRC patterns in ADRN and MES states and discuss opportunities for therapeutic combinations targeting CRC along with other survival mechanisms.

Expert opinion: We emphasize the critical importance of combined CRC inactivation as a promising therapeutic avenue. This approach is substantiated by basic biological mechanisms largely demonstrated in experimental models. Although the detailed roles of CRC in individual clinical situations remain to be elucidated, interference with the subtype-specific patterns of CRC-dependent gene expression, together with inactivation of an additional survival factor(s), offers new opportunities for mechanism-based, personalized treatment.

Introduction: Rhabdomyosarcoma (RMS), predominantly diagnosed in children, represents 3% of the pediatric solid tumors. RMS has characteristics of skeletal muscle, although the cell of origin remains controversial. Cytotoxic therapeutics, radiation treatment and surgery remain the standard of care; however, outcomes for advanced disease have not changed for several decades. Major research advances over the past two decades have defined molecular subtypes and driver mutations that could provide new therapeutic targets.

Areas covered: Due to the small number of patients diagnosed with RMS, progress in testing novel agents has been slow and, although many drugs with 'molecular targets' have been identified as 'active' in preclinical models, there remains a lack of standardization for evaluating efficacy. Molecular therapeutics identified in model systems include kinase inhibitors, antibody-drug conjugates (ADCs), chimeric antigen receptor T-cells (CAR T-cells), and drugs that target the genetic/epigenetic drivers of RMS. More recently, immune checkpoint inhibitors have entered clinical trials.

Expert opinion: RMS represents a set of diseases with unique molecular drivers that will each necessitate the development of targeted therapeutics. For efficient development of effective treatments, novel approaches to preclinical testing and standardization of efficacy assessments need to be developed in conjunction with molecularly guided clinical trials in patients earlier in their disease before drug resistance develops.

Introduction: The most prevalent solid cancer in young adult males is testicular germ cell tumors (TGCTs), which are becoming more and more common globally. Approximately 20% of patients with metastatic disease relapse or develop resistance to cisplatin-based chemotherapy, despite its high effectiveness, underscoring the need for alternative therapies.

Areas covered: With an emphasis on new molecular targets and biomarkers, this review describes developments in TGCT pathophysiology and treatment. Tyrosine kinase receptors, transcription factors, elements of the DNA damage response, and cell cycle regulators are important oncogenic drivers. CDK inhibitors, PARP inhibitors, and Aurora kinase antagonists are promising early-stage agents. Meanwhile, noninvasive liquid biopsy techniques are being made possible by biomarkers like CLDN6, cfDNA/ctDNA, and the miR-371 ~ 373 cluster, which may enhance disease monitoring, risk assessment, and diagnosis.

Expert opinion: Although the majority of TGCT cases have positive results, cisplatin-refractory disease continues to be a significant therapeutic challenge. A route to precision medicine is provided by molecular profiling and biomarker-driven approaches. However, implementation requires clinical validation, patient selection, and standardization. The landscape of TGCT treatment may change over the next 10 years as a result of the integration of targeted therapies and molecular diagnostics, which may greatly increase survival rates while lowering long-term toxicity.