Pharmacological Reviews最新文献

The hypoxia-inducible factors (HIFs)-HIF-1 and HIF-2-play critical roles in cancer progression by controlling the transcription of thousands of genes across the full range of human cell types. Inhibition of their activity blocks cancer growth, vascularization, and metastasis in mouse models. Small-molecule HIF inhibitors, with varying degrees of specificity and mechanism of action have been reported to have antitumor activity in mouse models. An HIF-2 inhibitor, belzutifan, has recently been approved for the treatment of renal cell carcinoma. Dual HIF-1/2 inhibitors are being developed and are likely to have utility as cancer therapeutics, particularly in combination with immune checkpoint blockade. SIGNIFICANCE STATEMENT: Hypoxia-inducible factor inhibitors represent a powerful new therapeutic approach that has the potential to improve patient survival in many types of cancer when administered in combination with existing therapies.

The locus coeruleus (LC), the brain's main source of noradrenaline, has received increased attention due to the recently unveiled heterogeneity of its cell types. Departing from the long-standing idea of molecular, anatomical, and functional uniformity of the structure, we now understand the LC as a multiplexed nucleus, capable of temporally precise and targeted neuromodulation of distinct brain regions and functions. The LC neuropeptidergic landscape provides a window into this remarkable neuronal diversity. Stemming from recent technological advances that have allowed for LC transcriptional profiling, a wealth of data on the (co)expression of LC neuropeptides and their cognate receptors has come to light. Peptidergic systems are ideally situated to exert neuromodulatory control over the LC noradrenergic system. This peptidergic control can occur both locally, within the LC and the neighboring peri-LC microcircuitry, and at distal LC terminal fields. The functional significance of LC neuropeptidergic signaling in physiological processes and pathological conditions is an emerging field. Here we compile existing literature on the expression, anatomical distribution, physiological effects, and, when available, behavioral role of the major neuropeptidergic populations of, and innervating, the LC and peri-LC. Furthermore, we highlight current methodologies that delineate LC peptidergic input/output, aiming at uncovering their functional role. Finally, we discuss how neuropeptidergic signaling enables LC modularity and thus sustains a multifaceted role of physiological noradrenaline release dynamics with a rich feature set of behavioral representations. SIGNIFICANCE STATEMENT: The locus coeruleus (LC) noradrenergic system influences a variety of neurophysiological processes to coordinate complex behaviors. These far-reaching neuromodulatory effects are not solely mediated by noradrenaline, but rather, by a variety of coreleased neuropeptides that can alter postsynaptic responses in LC terminal regions. In addition, the LC itself is regulated by a multitude of incoming peptidergic signals that drive wide-ranging changes in LC neuronal physiology and the subsequent patterns of noradrenaline release. It is important to understand how neuropeptide (co)transmitters and regulators of the LC can drive circuit-level plasticity and adaptive behavioral responses to changing environmental stimuli. This review compiles our current understanding of these processes, providing additionally crucial insights into the mechanisms underlying LC dysfunction and its many related neuropsychiatric conditions.

Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. SIGNIFICANCE STATEMENT: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and emerging new therapeutic strategies. A deeper understanding of these aspects is crucial for overcoming resistance and guiding the development of more effective and personalized cancer treatments.

Many species, including humans, rely on social interactions to thrive and survive. These life interactions engage many neural systems, including those used for learning, cognition, and innate behaviors that are fundamentally guided by rewarding processes. Dopamine, a neuromodulator critical for signaling natural rewards, orchestrates a variety of social functions in both health and disease states. Recent advances in tools to manipulate brain circuits and molecular biology in behaving animals have opened new paths to understanding dopamine's role in social functions. In this review, we will discuss recent cross-species studies that are beginning to uncover the role of dopamine and its substrates across 4 main social domains: reward, decision making, stress, and dominance. Finally, we consider the potential implications of this current body of literature for dopamine-associated dysfunctions in neuropsychiatric disorders that impact social interactions. SIGNIFICANCE STATEMENT: As the field of social neuroscience progresses, dopamine and its associated mechanisms emerge as central regulatory entities guiding diverse social behaviors and offer vital clues to their mechanistic processes at the molecular, cellular, and network levels. In this review, the dopamine correlates of social domains were framed in a timely and concise manner while highlighting the gaps in knowledge and future research opportunities in the biology of dopamine that are most relevant to our social world.

Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed "trained immunity" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guérin vaccine and β-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guérin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by β-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. SIGNIFICANCE STATEMENT: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitumor state. This review provides a comprehensive overview of myeloid cell populations in cancer and the mechanisms underlying microbial-induced trained immunity. It also highlights preclinical and clinical evidence demonstrating the efficacy of microbial-based strategies in overcoming immunosuppression and synergizing with existing immunotherapies, offering a promising approach to improve cancer treatment outcomes.

Targeting the innate immune complement system has long been pursued as a promising strategy for treating a wide spectrum of acute and chronic immune-mediated disorders. Nearly 2 decades since the approval of the first complement inhibitor targeting C5, the field of complement therapeutics has flourished. In just the past 5 years, 8 new complement-targeting drugs have entered the market. Traditionally dominated by monoclonal antibodies, the approved drug arsenal now includes an ever-expanding selection of macrocyclic peptides, low molecular weight compounds, and aptamers. Other novel approaches in clinical development include recombinant proteins, nanobodies, oligonucleotide therapeutics, and gene therapies. Alongside this remarkable diversification of drug modalities, the complement field is advancing toward deciphering and precisely targeting all pathways of the complement network. Although current approved therapies primarily benefit patients with rare diseases, there is a nascent shift towards addressing more prevalent conditions. In line with this unprecedented expansion in the field, we aim to provide a comprehensive overview of the complement system, its activation pathways, key effector mechanisms, and regulation. We discuss the consequences of unchecked complement activation leading to disease pathologies and highlight therapeutic intervention points within the cascade. We review the discovery and molecular pharmacology of clinically approved and late-phase complement therapeutics, bridging to their clinical pharmacokinetics, safety, and regulatory status for clinical indications. We particularly focus on the diversifying modalities of complement-targeting drugs and evaluate the unique opportunities and challenges these new developments present. With this knowledge, we forecast potential short-term and long-term development trends in the field. SIGNIFICANCE STATEMENT: Therapeutic targeting of the complement system has been widely pursued for treating autoimmune and inflammatory disorders, with the field recently seeing an exponential increase in clinical approvals (8 new drugs during 2022-2024). This timely comprehensive review presents an overview of the complement cascade, its effector mechanisms, and the molecular pharmacology and clinical utility of currently approved and late-phase complement-targeting drugs. We thus provide a valuable one-stop guide for existing and upcoming researchers working in the complement field.

More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.

Bile acids (BAs), the end products of cholesterol catabolism, play a crucial role in various physiological and pathological processes. Defects in BA synthetic enzymes and transporters cause rare monogenic diseases. Dysregulation of BA homeostasis contributes to the pathogenesis and progression of various liver diseases, including hepatocellular carcinoma (HCC), the most common form of liver cancer. BA profiles are altered in patients with HCC and in mouse models of HCC, and their diagnostic potential is currently under clinical investigation. Growing evidence suggests that BA metabolism and signaling regulate key processes involved in HCC development. Recent advances in understanding the complex interactions between the gut microbiota and BAs have provided new insights into HCC. In this review, we summarize the current literature on BA quantification, detoxification, synthesis, transport, signaling functions, and the interplay between BAs and bacteria in the pathogenesis and progression of HCC, particularly in patients with HCC and mouse models. Furthermore, we discuss potential therapeutic strategies targeting BA metabolism and signaling as promising approaches for HCC treatment. SIGNIFICANCE STATEMENT: Bile acids hold promise as potential biomarkers for the diagnosis and prognosis of hepatocellular carcinoma. Modulating bile acid metabolism and signaling pathways represents a promising novel strategy for hepatocellular carcinoma treatment.

Vascular remodeling is a complex process involving the coordinated actions of multiple cellular signaling pathways in various cell types, leading to structural and functional changes in blood vessels. These changes can be adaptive, as in wound healing, or maladaptive, as seen in chronic vascular diseases such as atherosclerosis, hypertension, and retinopathy. Exchange proteins directly activated by cAMP (EPACs) are key players in cAMP-mediated cell signaling, distinct from the more traditionally studied protein kinase A pathway. EPAC proteins are guanine nucleotide exchange factors for the small G proteins Rap1 and Rap2. Recent studies have also revealed noncanonical functions of EPAC1 involving the formation of biomolecular condensates. EPAC proteins regulate various cellular processes, including cell adhesion, migration, proliferation, and differentiation. In this review, we discuss the roles of EPACs in vascular remodeling and diseases associated with the process, as well as the potential of EPACs as therapeutic targets for proliferative vascular diseases. SIGNIFICANCE STATEMENT: Vascular remodeling is associated with various human diseases, such as atherosclerosis, stroke, and retinopathy. Understanding the roles of exchange proteins directly activated by cAMP signaling in vascular remodeling provides insights into the mechanisms underlying vascular diseases and facilitates the development of targeted therapies.

Epilepsy affects over 80 million people worldwide, with approximately 40% experiencing refractory seizures. Despite some progress in deciphering the complex process of epileptogenesis, which transforms a healthy brain into one susceptible to epilepsy, there are still no therapies available to prevent this condition. Traumatic brain injury (TBI) is a leading cause of epilepsy in both military and civilian populations, often leading to the complex condition of posttraumatic epilepsy (PTE). Defined as recurrent seizures following TBI, PTE lacks effective treatment options, highlighting the need for improved experimental models and translational interventions. Unveiling disease-modifying therapeutics for epilepsy is a top priority in the field of neurology research. One major obstacle in PTE research is the lack of robust models that accurately reflect the multifaceted and heterogeneous nature of human PTE. Hence, developing disease-modifying treatments requires innovative models that facilitate the identification of novel therapeutic approaches. Establishing clinically relevant animal models is critical for elucidating the pathophysiological mechanisms of epileptogenesis and identifying effective therapies for PTE management. This article describes the opportunities and challenges associated with advances in PTE experimental models, including the call for common data elements to be developed for PTE. Inspired by insights from a 2023 workshop supported by the American Epilepsy Society, this review explores progress in animal models, experimental protocols, biomarkers, and principles of therapeutic interventions for TBI-induced seizures and posttraumatic epileptogenesis. It evaluates the PTE research landscape and critically discusses current strategies, innovations, hurdles and future directions for establishing models that ultimately lead to the development of disease-modifying agents and targeted therapeutic approaches for PTE prevention. SIGNIFICANCE STATEMENT: Posttraumatic epilepsy (PTE) lacks specific therapies due to limited experimental models. Here, we outline the proceedings of the 2023 American Epilepsy Society-supported National Workshop on PTE, covering small and large animal models for PTE research. This article provides insights into recent advancements in experimental paradigms and analyzes the validity and application of these models in identifying interventions to prevent epileptogenesis following traumatic brain injury. We address challenges and obstacles in discovering PTE therapies, offering clinical data context and common themes.