Expert Opinion on Therapeutic Targets最新文献

Introduction: Hypertension is a major health problem worldwide, yet fewer than half of patients maintain adequate blood-pressure control, pointing to hidden pathogenic drivers and therapeutic gaps. Normal pressure regulation depends on seamless cross-talk among the kidney, vasculature, brain, and gut; once this dialogue falters, low-grade, T cell-centered inflammation sustains disease.

Areas covered: In the kidney, CD8 ⁺ T cells bearing the purinergic receptor P2X7sense extracellular ATP and hypertonicity, upregulate renal sodium transporters, and lock in salt. Perivascular adipose tissue mobilizes monocytes, γδ T cells, and B cells that, through CCL5-guided trafficking and IFN-γ/IL-17A release, heighten oxidative stress and endothelial dysfunction - defects reversible by regulatory T-cell transfer. In the central nervous system, angiotensin II and dietary salt skew microglia toward a pro-inflammatory state, breach the blood-brain barrier and attract Th17 and γδ T cells, establishing a sympathetic feed-forward loop. Concurrent gut dysbiosis - marked by excess short-chain fatty acids and dwindling aryl-hydrocarbon metabolites - reprograms macrophage and T-cell phenotypes, reinforcing systemic inflammation.

Expert opinion: Targeting these inter-organ immune circuits, especially activation and infiltration of T cells and inflammasome, will provide precise immunomodulatory strategies poised to deliver enduring blood-pressure control and cardiovascular protection.

Introduction: erb-b2 receptor tyrosine kinase 3 (ERBB3/HER3) a kinase-inactive HER family receptor, significantly influences breast cancer by enhancing oncogenic signaling mainly via HER2 heterodimerization. Its role in therapy resistance marks it as a key target across subtypes, tackling a critical oncology challenge.

Areas covered: This review delves into HER3's molecular structure, with its ligand-binding extracellular domain and tyrosine-rich tail activating PI3K/AKT and MAPK/ERK pathways. It examines HER3's impact on tumor progression - like invasion and metastasis - and resistance to therapies such as trastuzumab, endocrine treatments, and chemotherapy across HER2- positive, hormone receptor-positive, and triple-negative subtypes, based on extensive literature. Clinically, it assesses HER3's prognostic role, with overexpression in 30-50% of cases, and therapeutic advances, notably antibody-drug conjugates (ADCs) like patritumab deruxtecan, promising in trials.

Expert opinion: HER3's therapeutic potential is transformative, with ADCs and combinations poised to redefine personalized care by improving survival in resistant cases. Its overexpression offers a strategic leverage point, yet inconsistent detection and adaptive resistance pose barriers. These demand innovative solutions, such as refined diagnostics and multi-target therapies. Given its demonstrated efficacy, HER3-targeted therapies, supported by novel therapeutic combinations and bioengineering innovations, are expected to become integral to routine clinical practice in the coming years, advancing precision oncology.

Introduction: Human neuregulins (NRG) are small epidermal growth factor ligands involved in the activation of ErbBs receptors. Among genomic aberrations, NRG fusions are one of the most intriguing genetic markers reported in the latest years, due to their agnostic and potentially predictive features. Mucinous carcinoma showed a higher rate of mutations in downstream effectors of NRG/ErbB activation, thus suggesting that RAS/MAPK and PIK3K/AKT pathway are involved in mucinous phenotype development and aggressiveness.

Areas covered: Epidemiological data on the spectrum of all NRG/ErbBs and downstream effectors alterations in mucinous carcinoma of digestive tract, ovary, lung, and pancreato-biliary tract, as well as their correlation with respective immunological and molecular background are discussed. Peer-reviewed publications on high-quality international from PubMed and data from scientific official sites were used to update the current literature.

Expert opinion: Recent scientific advances highlight the predictive and prognostic role of the NRGs/ErbBs network deregulation in cancer; anyhow its role is not well investigated in solid tumors with mucinous features. Although the mucin-rich cancers have a considerably greater rate of mutations in therapeutically critical pathways than non-mucinous ones, common mucinous pathways have not yet been found.

Introduction: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine involved in immune regulation, inflammation, and tissue homeostasis. Elevated MIF levels contribute to the progression of various cardiovascular diseases (CVDs), making it an attractive therapeutic target. However, the pleiotropic nature and complexity of MIF context-dependent effects pose significant challenges for clinical translation, but also offer unique opportunities to develop new precision medicine-based tools.

Areas covered: This review summarizes the biological functions of MIF and its homolog MIF-2 in CVD pathogenesis, along with the current landscape of therapies targeting MIF. We highlight recent preclinical findings, discuss ongoing controversies surrounding MIF's dual roles, and explore the potential of personalized approaches.

Expert opinion: MIF represents a promising yet complex target in cardiovascular medicine. Future success in clinical application will depend on the development of highly selective modulators, integration of patient stratification strategies and MIF-based interventions as part of multimodal cardiovascular care.

Introduction: The dysregulation of cyclin-dependent kinases (CDKs) is a key driver of cancer progression, making them attractive therapeutic targets. In CDK4/6 inhibitor (CDK4/6i)-resistant breast cancer, targeting CDK2 offers a promising approach. CDK2 is frequently hyperactivated due to cyclin E1 overexpression or retinoblastoma protein loss, acting as a mechanism that sustains proliferation despite CDK4/6 inhibition. CDK2 inhibitors (CDK2i) show strong anti-tumor activity, particularly in combination with CDK4/6i or immune checkpoint inhibitors.

Areas covered: This review explores the biological roles of CDK2 and its regulatory mechanisms. The review highlights the latest advancements in CDK2i, their mechanisms of action, and their potential in combination strategies with CDK4/6i, chemotherapy, and immunotherapies. Additionally, it examines other emerging targets, such as CDK7 and CDK5, which contribute to transcriptional regulation and immune evasion, respectively.

Expert opinion: Future research should focus on biomarker-driven patient selection, optimizing CDK2i combinations, and expanding CDK7 inhibitor applications. Integrating multi-omics profiling can refine patient stratification, while combination strategies with chemotherapy, DNA damaging agents, and immunotherapies may enhance efficacy. CDK7 inhibitors could also complement CDK2 targeting by modulating resistance mechanisms. Personalized, adaptive treatment approaches will be key to maximizing the clinical impact of CDK2 and CDK7 inhibitors in breast cancer therapy.

Background: Paclitaxel (PTX) is a standard treatment for triple-negative breast cancer (TNBC), but its effectiveness is often compromised by toxicity at therapeutic doses. Dyskerin pseudouridine synthase 1 (DKC1), a telomerase subunit, is overexpressed in TNBC and associated with poor prognosis. This study investigates whether combining PTX with R1D2-10, a novel DKC1 inhibitor developed by our group, enhances cytotoxicity while reducing required PTX dosages.

Research design and methods: In vitro assays were conducted using MDA-MB-231 and MDA-MB-468 TNBC cell lines, treated with R1D2-10, PTX or their combination. Cytotoxicity, drug synergy, clonogenic capacity, cell cycle distribution, apoptosis, and DNA damage markers were evaluated to assess efficacy and mechanism of action.

Results: The combination demonstrated synergistic effects, showing dose-dependent cytotoxicity and achieving a Dose Reduction Index (DRI) exceeding 3. Furthermore, the treatment significantly reduced colony formation and induced a rise in cell cycle population, both at the G2/M and Sub-G1 phases. These effects are supported by increased apoptosis and gene expression markers for cell cycle arrest, without evidence of replication stress or DNA damage.

Conclusions: Combining R1D2-10 with PTX may provide an effective therapeutic strategy to reduce dose-related toxicity while enhancing chemotherapy effects in TNBC. Further, in vivo studies are needed to validate these findings.

Introduction: The HER2-targeted monoclonal antibody trastuzumab has significantly improved the survival of patients with HER2-positive breast cancer (HER2+ BC) in both early and metastatic disease. Therapeutic resistance remains an inevitable challenge in the advanced setting, ultimately limiting the long-term efficacy of trastuzumab. Numerous mechanisms of trastuzumab resistance and response heterogeneity have been described, most involving alterations in HER2 receptor levels and reactivation of HER2 downstream signaling. However, the growing number of metabolic escape routes that allow HER2+ BC cells to evade HER2 inhibition have received little attention.

Areas covered: We comprehensively review the metabolic strategies that HER2+ BC cells adopt to enable trastuzumab resistance, grouping them into a structured classification that takes into account their functional nature, namely: (1) metabolic reprogramming - how cells maintain an adequate supply of energy and biosynthetic precursors to survive, grow and proliferate despite HER2 inhibition; (2) adaptive stress response - how cells increase their resilience to survive trastuzumab-induced stress and damage; and (3) metabolic-signaling crosstalk - how key survival pathways redirect metabolism to reinforce trastuzumab resistance feedback loops.

Expert opinion: The metabolic hallmarks of trastuzumab resistance may help to identify high-quality predictive biomarkers and to rationally develop optimized therapeutic strategies to counteract trastuzumab resistance metabolically.