Expert Opinion on Therapeutic Targets最新文献

Introduction: p21-activated kinase 1 (PAK1) is a critical serine/threonine kinase involved in regulating key cellular processes driving cancer progression. While PAK1 is well-known for its contributions to the hallmarks of cancer - such as sustained proliferation, evasion of apoptosis, and metastasis - emerging evidence highlights its pivotal role in cancer metabolism, particularly in orchestrating the Warburg effect.

Areas covered: This review focuses on the multifaceted influence of PAK1 in metabolic reprogramming, emphasizing both its direct and indirect regulation of aerobic glycolysis, a hallmark metabolic adaptation in tumor cells. We explore how PAK1 modulates signaling pathways and metabolic enzymes to shift glucose metabolism toward glycolysis, supporting the biosynthetic and energetic demands of rapidly proliferating cancer cells. By bridging oncogenic signaling and metabolic remodeling, PAK1 acts as a central integrator that facilitates tumor growth and survival. Elucidating the mechanistic links between PAK1 and the Warburg effect unveils novel opportunities for targeted cancer therapies aimed at disrupting metabolic vulnerabilities.

Expert opinion: An ideal biodegradable drug delivery system and an appropriately representative pre-clinical model exploiting the Warburg effect could enhance targeted delivery and therapeutic efficacy, and could help advance tumor targeted therapies in aggressive cancers like TNBC and pancreatic cancer.

Introduction: Major depressive disorder (MDD) is a neuro-immune-metabolic-oxidative stress (NIMETOX) disorder. A significant proportion (50%) of individuals with MDD experience recurrence of episodes and suicidal behaviors. Recurrent MDD is characterized by greater severity of depression and increased functional impairments. Recently, the recurrence of illness (ROI) index was introduced as a quantitative metric for assessing this recurrence.

Area covered: This paper reviews how ROI should be calculated based on the number of lifetime depressive episodes, suicidal attempts, and ideation. This paper examines the associations between ROI and neuroimmune pathways (e.g. increased M1 macrophage activity, T helper (Th)1/Th17 polarization), metabolic pathways (e.g. reduced reverse cholesterol transport), and oxidative pathways (e.g. diminished lipid-associated antioxidant defenses, increased lipid peroxidation), as well as gut dysbiosis and abnormalities in neurotrophic factors, brain structure, and function. This study investigates potential interventions that could be employed to normalize each of the ROI-associated NIMETOX pathways.

Expert opinion: The future of recurrent MDD therapeutics resides in multi-targeting the ROI-associated pathways with NIMETOX-guided interventions aimed at attenuating immune sensitization, rectifying metabolic dysfunction, reducing oxidative toxicity, and concurrently restoring neuroplasticity. The development of such integrative therapies is an urgent imperative if we are to alter the natural trajectory of recurrent depression.

Introduction: Mismatch-repair deficiency (MMRd) is a pan-cancer mechanism resulting in high tumor mutation and microsatellite burden, leading to remarkable therapeutic success using immune checkpoint inhibition (ICI). However, efficacy remains variable. Our goal is to review the existing and emerging literature that provide mechanistic insights on how MMRd diversely impacts the current landscape of cancer therapeutics.

Areas covered: We summarize the biological impact of MMRd, highlight how variable etiologies and different MMRd cancer-types have significant diversity in genomic and immune profiles, how this drives primary and acquired ICI-resistance, and highlight the clinical trial landscape and preclinical efforts to harness these distinct mechanistic vulnerabilities into new therapeutic strategies.

Expert opinion: MMRd is currently recognized a tumor-agnostic biomarker for ICI treatment. However, differences in the MMRd etio-biology impact the immune microenvironment, contributing to significant response heterogeneity. Some patients show dramatic response to neoadjuvant ICI monotherapy and don't even need surgery, while most will need biologically rational combination approaches. Additionally, MMRd-driven genomic instability can make this a 'moving target,' mandating an ongoing effort to track and adapt to MMRd-driven cancer and microenvironment evolution. The next decade will focus on how best to effectively tailor immune-directed therapies for different MMRd cancers.

Introduction: Despite the fact that the progress in developing new antibiotics with novel mechanism of action is limited owing to the considerable challenges involved and the modest financial returns, we are urgently needing new molecules with new mode of actions to overcome the increasing burden of multidrug resistance. Half of all antibiotics prescribed for human use target the bacterial cell wall. Targeting the cell wall has many advantages as it is essential for bacterial survival, with many steps readily accessible from the environment to small molecules and despite the success of beta-lactams, the pathway still has many underexploited targets.

Areas covered: Here, we review the limitations and the gaps that remain to be filled and the latest developments in new targets, strategies and drugs aimed at inhibiting the assembly of a viable cell wall, as this pathway remains a formidable and accessible source of new targets.

Expert opinion: The future of the field should benefit immensely from computational and AI-driven methodologies, combinatorial therapies reducing the risk of development of resistance and acknowledging that we have been screening poorly adapted chemical spaces for antibiotic discovery.

Introduction: Oxidative phosphorylation (OXPHOS) is essential for the progression of tumors and their resistance to therapy. Conventional inhibitors of OXPHOS that directly target the electron transport chain (ETC) activity often lack tumor selectivity and demonstrate limited efficacy. Inhibiting mitochondrial gene expression to block the de novo biogenesis of OXPHOS complexes, rather than inhibiting pre-existing OXPHOS complexes, represents a more potent and tumor-selective strategy. This strategy highlights leucine-rich pentatricopeptide repeat-containing (LRPPRC) as a promising anticancer target.

Areas covered: Extensive evidence confirms that LRPPRC is commonly overexpressed in various cancer types and is indispensable for maintaining malignant phenotypes. Mechanistically, LRPPRC binds mitochondrial mRNAs (mt-mRNAs) via its pentatricopeptide repeat (PPR) motif-rich RNA-binding domain. By stabilizing mt-mRNA and enhancing its translational efficiency, LRPPRC facilitates OXPHOS complex biogenesis and OXPHOS in tumors. We have developed the first small-molecule screening platform targeting LRPPRC. Using this platform, we identified dual-function compounds that both inhibit LRPPRC's RNA-binding function and trigger its proteolytic degradation. These agents demonstrate potent suppression of OXPHOS and exhibit favorable safety profiles across multiple preclinical models.

Expert opinion: Current LRPPRC inhibitors often suffer from suboptimal specificity and binding affinity. Advancing clinical translation requires co-crystal structures of LRPPRC for rational drug design and novel delivery strategies to enhance mitochondrial enrichment of inhibitors.

Background: Tumor stemness contributes to therapeutic resistance and malignant progression in lung adenocarcinoma (LUAD), yet its molecular basis remains unclear. This study investigated the tumor stemness index (mRNAsi) to identify key regulators and potential therapeutic targets in LUAD.

Research design and methods: Transcriptomic data from TCGA and PCBC datasets were analyzed to evaluate mRNAsi in LUAD. Weighted gene co-expression network analysis was used to identify stemness-related genes, and the tumor immune microenvironment was characterized. Core regulatory genes were screened using machine learning analyses and validated using independent datasets and experimental approaches.

Results: Higher mRNAsi was associated with aggressive clinicopathological features and an immune-cold subtype. Budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) was identified as a key regulator of LUAD stemness and was significantly correlated with enhanced proliferation, migration, invasion, and stemness marker expression. Mechanistic analyses indicated that BUB1B promotes LUAD progression by activating the Ca²⁺/PI3K/AKT signaling pathway.

Conclusions: BUB1B is a pivotal regulator linking tumor stemness with malignant progression and immune context in LUAD, highlighting its potential as a diagnostic, prognostic, and therapeutic biomarker.

Introduction: Proteases are essential enzymes that regulate protein turnover and activate signaling pathways through targeted peptide bond cleavage. While traditionally regarded as degradative agents, proteases are now recognized for their diverse roles in health and disease, particularly in cancer and viral infections. Advances in high-throughput, mass spectrometry-based technologies have enabled proteome-wide identification of protease substrates, revealing numerous potential therapeutic targets. As large-scale approaches yield expansive substrate lists, it is increasingly important to understand the roles of disease-related proteases within their specific biological contexts.

Areas covered: Peptide-level chemical libraries have provided more practical insights, facilitating the development of protease-targeted interventions. However, early efforts to derive inhibitors from these substrates faced challenges due to enzymatic redundancy and substrate promiscuity. Consequently, emerging research has shifted toward harnessing proteolytic activity for conditional activation of therapeutics. Since proteolytic activation can amplify therapeutic effects, protease-activated strategies, such as protease-cleavable linkers in antibody-drug conjugates, have gained interest and are now being applied to other therapeutic modalities.

Expert opinion: We believe that identifying substrates activated by disease-associated proteases, enabled by recent technological advances, will lead to deeper biological insights. When combined with peptide-level techniques, these discoveries can drive the development of efficient therapeutic interventions with amplified effects.

Introduction: The Growth Arrest and DNA Damage-Inducible 45 (GADD45) proteins, including GADD45α, GADD45β, and GADD45γ, play a crucial role in the cellular stress response and maintaining genome stability. These proteins are involved in various biological processes, including cell cycle arrest, DNA repair, apoptosis, and senescence, particularly when cells encounter genotoxic stress.

Areas covered: This review outlines the isoform-specific functions of GADD45 proteins in controlling DNA repair, apoptosis, and stress responses, emphasizing their context-dependent effects on cancer progression. We analyze emerging evidence highlighting their dual roles and discuss the potential of targeting GADD45 pathways in cancer therapy. This review was created through an extensive literature search and critical analysis of peer-reviewed articles obtained from PubMed, Scopus, Web of Science, and Google Scholar databases. The search covered literature published from 1994 to 2024, with a focus on recent studies (2018-2024) that examined molecular mechanisms, clinical correlations, and therapeutic implications of GADD45 signaling.

Expert opinion: In summary, the GADD45 family serves as a crucial link between stress signaling, genomic stability, and immune regulation. Gaining a clearer understanding of their isoform-specific and context-dependent functions will be vital to fully leverage their potential as biomarkers and therapeutic targets in precision oncology.

Introduction: Autophagy, from Greek auto, meaning self and phagein to eat, is a highly conserved cellular pathway responsible for the degradation and recycling of long-lived proteins. A functional autophagy pathway, characterized by cell- and tissue-specific basal autophagy activity, is crucial for the cell's successful response to aging and the mitigation of age-related pathologies. However, comprehensive understanding of underlying mechanisms and spatiotemporal profiling of autophagy flux across tissues remain largely elusive.

Areas covered: Here, we attempt to dissect how to better discern key metrics that may inform autophagy failure. By reporting evidence for tissue-inherent autophagy activities, their flux responses in magnitude and capacity, we provide a new perspective on existing data of species-specific autophagy in age. By evaluating the connection between autophagy activity in peripheral blood mononuclear cells (PBMCs) relative to tissue associated autophagy failure, new concepts are provided that may assist in accelerating targeted development of therapeutic interventions.

Expert opinion: Despite major progress in understanding the molecular mechanisms of autophagy in aging, knowledge gaps remain in standardizing methods to accurately monitor tissue-specific autophagy activity and cargo clearance. Building comprehensive databases, integrating multi-scale imaging, multi-omics, and AI-driven analyses will be essential for developing effective autophagy-targeted therapies for age-related diseases.

Introduction: Epilepsy often presents numerous comorbidities, including anxiety, depression, and cognitive deficits. Epilepsy is not only restricted to GABA/glutamate imbalance, as researchers are delving more into finding the possible causal inference between other factors; one such recognized interplay is between seizures, stress, and inflammation. Stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation increases corticosteroid release, which binds to mineralocorticoid receptors (MR), intensifies the release of neuroinflammatory markers, lowers seizure threshold, and worsens seizure susceptibility.

Areas covered: Recent studies have demonstrated the potential advantages of MR antagonists in lowering seizure susceptibility. MR antagonists reestablish the equilibrium between MRs and GRs by inhibiting corticosteroid binding on MRs, thereby maintaining the balance between pro- and anti-inflammatory mediators. MR antagonists have been undergoing clinical trials as adjuvant therapy for management of psychological disorders by reducing neuroinflammation and altering body's reaction to stress. In addition to assessing the possible contribution of MR antagonists in the reduction of comorbidities linked to epilepsy, this review also elucidates mechanisms that underlie the connection between seizures, stress, and inflammation.

Expert opinion: By addressing these gaps, future research can provide a more comprehensive understanding of MR signaling in epilepsy, ultimately leading to personalized treatment strategies and novel therapeutic targets.