Trends in pharmacological sciences最新文献

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematological cancers. However, achieving comparable success in solid tumors remains challenging. Factors contributing to these limitations include the scarcity of tumor-specific antigens (TSAs), insufficient CAR-T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Vaccine-based strategies are emerging as potential approaches to address these challenges, enhancing CAR-T cell expansion, persistence, and antitumor efficacy. In this review, we explore diverse vaccine modalities, including mRNA, peptide, viral vector, and dendritic cell (DC)-based vaccines, and their roles in augmenting CAR-T cell responses. Special focus is given to recent clinical advancements combining mRNA-based vaccines with CAR-T therapy for the treatment of genitourinary cancers. In addition, we discuss crucial considerations for optimizing vaccine dosing, scheduling, and delivery to maximize CAR-T synergy, aiming to refine this combination strategy to improve treatment efficacy and safety.

Synthetic binding proteins (SBPs) are a class of protein binders that are artificially created and do not exist naturally. Their broad applications in tackling challenges of research, diagnostics, and therapeutics have garnered significant interest. Traditional protein engineering is pivotal to the discovery of SBPs. Recently, this discovery has been significantly accelerated by computational approaches, such as molecular modeling and artificial intelligence (AI). Furthermore, while numerous bioinformatics databases offer a wealth of resources that fuel SBP discovery, the full potential of these data has not yet been fully exploited. In this review, we present a comprehensive overview of SBP data ecosystem and methodologies in SBP discovery, highlighting the critical role of high-quality data and AI technologies in accelerating the discovery of innovative SBPs with promising applications in pharmacological sciences.

Therapeutic drug monitoring (TDM) for biologic therapies in inflammatory bowel disease (IBD) primarily aims to optimize dosing. However, several unmet needs remain. These include the identification of optimal drug concentrations, accounting for variability in pharmacokinetics (PK) and pharmacodynamics (PD), and the frequent delays between sampling and clinical decision-making. Recent technical advances, such as population PK/PD modeling and model-informed precision dosing (MIPD) tools developed from such models, as well as point-of-care (POC) and self-sampling assays and novel software programs, offer potential solutions. Successful implementation of these innovations may help to establish MIPD for patients with IBD. This would enable personalized dosing, advancing a one-size-fits-all approach to TDM that currently is inadequate to fulfill the needs for every patient with IBD.

The human microbiome consists of diverse microorganisms that inhabit various body sites. As these microbes are increasingly recognized as key determinants of health, there is significant interest in leveraging individual microbiome profiles for early disease detection, prevention, and drug efficacy prediction. However, the complexity of microbiome data, coupled with conflicting study outcomes, has hindered its integration into clinical practice. This challenge is partially due to demographic and technological biases that impede the development of reliable disease classifiers. Here, we examine recent advances in 16S rRNA and shotgun-metagenomics sequencing, along with bioinformatics tools designed to enhance microbiome data integration for precision diagnostics and personalized treatments. We also highlight progress in microbiome-based therapies and address the challenges of establishing causality to ensure robust diagnostics and effective treatments for complex diseases.

Recent studies have highlighted the complexity of platelet biology, revealing their diverse roles beyond hemostasis. Pathological platelet activation is now recognized as a key contributor to thrombosis and inflammation that are both central to cardiovascular disease (CVD). Emerging research emphasizes the significant impact of demographic factors - such as age, sex, race, and ethnicity - on CVD risk and responses to antiplatelet therapies. These population-based differences, shaped by genetic and non-genetic factors, highlight the need for reevaluation of antiplatelet strategies. We address current knowledge and emphasize the pressing need for further research into platelet biology and cardiovascular outcomes across diverse populations. In this review we advocate for tailored therapeutic approaches in CVD based on the recent demographic-focused findings.

Exportin-1 (XPO1), also known as chromosome region maintenance 1 (CRM1), directly binds to and mediates the nuclear export of hundreds of cargo proteins. Blocking nuclear export by the selective inhibitors of nuclear export (SINEs) is a validated therapeutic axis in cancer and an active area of research. However, a growing body of evidence implicates XPO1 in biological functions beyond nuclear export that include the regulation of mitosis and the epigenome. Additionally, new pharmacological classes of small molecules have emerged that degrade XPO1 or induce distinct cellular activity profiles. Here, we discuss the canonical model of nuclear export and XPO1's emergence as an anticancer target. We also spotlight the key evidence for underappreciated XPO1 functions and discuss the use of chemical probes to uncover new cellular roles for XPO1. With these growing trends, the field is poised to extend XPO1 therapeutic targeting to indications beyond oncology.

The optic nerve, comprising axons from retinal ganglion cells (RGCs), is a component of the central nervous system (CNS) that generally exhibits a limited regeneration capacity following injury in mature mammals, resulting in permanent vision loss. Here, we summarize recent advances in interventions targeting cell-intrinsic and cell-extrinsic mechanisms to enhance RGC axon regeneration. Additionally, we summarize strategies for guiding the reconnection of regenerating axons with brain visual targets, aiming to restore partial visual function. Given the advent of high-throughput screening techniques and multiomics analyses, we discuss how these emerging methodologies deepen our understanding of regenerative mechanisms and expedite the development of innovative therapeutic approaches. Lastly, we explore the translational potential of these strategies in achieving clinically meaningful vision recovery.

Activated CDC42-associated kinase 1 (ACK1), encoded by the TNK2 gene, is a cytoplasmic non-receptor tyrosine kinase whose aberrant activation correlates positively with cancer severity. Recent research has revealed the functional relevance of this oncokinase - it is an epigenetic regulator that drives cancer progression in multiple malignancies. Although ACK1 is an attractive target for therapeutic intervention, incomplete knowledge of its diverse signaling mechanisms and the lack of specific inhibitors have challenged its clinical success. We summarize recent breakthroughs in understanding ACK1 regulation and cellular signaling, and shed light on its immunomodulatory role in balancing T cell activation. We provide a comprehensive overview of preclinical, proof-of-concept studies of potent ACK1-targeting small-molecule inhibitors that are expected to enter clinical trials for cancer patients.

Most solid tumors are insensitive to single-agent immunotherapy, calling for the development of combinatorial treatment regimens. Recently, Lin and collaborators developed a pharmacological platform enabling the combination of different immunotherapies into a single chemical entity. This approach may effectively circumvent obstacles associated with the simultaneous delivery of multiple immunotherapeutic agents.