Expert Opinion on Therapeutic Targets最新文献

Introduction: The four members of the p90 ribosomal S6 kinase (RSK) family are serine/threonine protein kinases, which are phosphorylated and activated by ERK1/2. RSK1/2/3 are further phosphorylated by PDK1. Receiving inputs from two major signaling pathways places RSK as a key signaling node in numerous pathologies. A plethora of RSK1/2 substrates have been identified, and in the majority of cases the causative roles these RSK substrates play in the pathology are unknown.

Areas covered: The majority of studies have focused on RSK1/2 and their functions in a diverse group of cancers. However, RSK1/2 are known to have important functions in cardiovascular disease and neurobiological disorders. Based on the literature, we identified substrates that are common in these pathologies with the goal of identifying fundamental physiological responses to RSK1/2.

Expert opinion: The core group of targets in pathologies driven by RSK1/2 are associated with the immune response. However, there is a paucity of the literature addressing RSK function in inflammation, which is critical to know as the pan RSK inhibitor, PMD-026, is entering phase II clinical trials for metastatic breast cancer. A RSK inhibitor has the potential to be used in numerous diverse diseases and disorders.

Introduction: Leukemia is typically categorized into myeloid leukemia and lymphoblastic leukemia based on the origins of leukemic cells. Myeloid leukemia is a group of clonal malignancies characterized by the presence of increased immature myeloid cells in both the bone marrow and peripheral blood. Of note, the aberrant expression of specific proteins or the generation of fusion proteins due to chromosomal abnormalities are well established drivers in various forms of myeloid leukemia. Therefore, these oncoproteins represent promising targets for drug development.

Areas covered: In this review, we comprehensively discussed the pathogenesis of typical leukemia oncoproteins and the current landscape of small molecule drugs targeting these oncogenic proteins. Additionally, we elucidated novel strategies, including proteolysis-targeting chimeras (PROTACs), hyperthermia, and genomic editing, which specifically degrade oncogenic proteins in myeloid malignancies.

Expert opinion: Although small molecule drugs have significantly improved the prognosis of oncoprotein-driven myeloid leukemia patients, drug resistance due to the mutations in oncoproteins is still a great challenge in the clinic. New approaches such as PROTACs, hyperthermia, and genomic editing are considered promising approaches for the treatment of oncoprotein-driven leukemia, especially for drug-resistant mutants.

Introduction: microRNA-181a (miR-181a) is a crucial post-transcriptional regulator of many mRNA transcripts and noncoding-RNAs, influencing cell proliferation, cancer cell stemness, apoptosis, and immune responses. Its abnormal expression is well-characterized in numerous cancers, establishing it as a significant genomic vulnerability and biomarker in cancer research.

Areas covered: Here, we summarize miR-181a's correlation with poor patient outcomes across numerous cancers and the mechanisms governing miR-181a's activity and processing. We comprehensively describe miR-181a's involvement in multiple regulatory cancer signaling pathways, cellular processes, and the tumor microenvironment. We also discuss current therapeutic approaches to targeting miR-181a, highlighting their limitations and future potential.

Expert opinion: miR-181a is a clinically relevant pan-cancer biomarker with potential as a therapeutic target. Its regulatory control of tumorigenic signaling pathways and immune responses positions it as a promising candidate for personalized treatments. The success of miR-181a as a target relies on the development of specific therapeutics platforms. Future research on miR-181a's role in the tumor microenvironment and the RNA binding proteins that regulate its stability will help uncover new techniques to targeting miR-181a. Further research into miR-181a serum levels in patients undergoing therapy will help to better stratify patients and enhance therapeutic success.

Introduction: Ischemic stroke (IS), a major cause of mortality and disability worldwide, remains a significant healthcare challenge due to limited therapeutic options. Ferroptosis, a distinct iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress, has emerged as a crucial mechanism in IS pathophysiology. This review explores the role of ferroptosis in IS and its potential for driving innovative therapeutic strategies.

Area covered: This review delves into the practical implications of ferroptosis in IS, focusing on molecular mechanisms like lipid peroxidation, iron accumulation, and their interplay with inflammation, reactive oxygen species (ROS), and the Nrf2-ARE antioxidant system. It highlights ferroptotic proteins, small-molecule inhibitors, and non-coding RNA modulators as emerging therapeutic targets to mitigate neuroinflammation and neuronal cell death. Studies from PubMed (1982-2024) were identified using MeSH terms such as 'Ferroptosis' and 'Ischemic Stroke,' and only rigorously screened articles were included.

Expert opinion: Despite preclinical evidence supporting the neuroprotective effects of ferroptosis inhibitors, clinical translation faces hurdles such as suboptimal pharmacokinetics and safety concerns. Advances in drug delivery systems, bioinformatics, and AI-driven drug discovery may optimize ferroptosis-targeting strategies, develop biomarkers, and improve therapeutic outcomes for IS patients.

Introduction: Colorectal cancer (CRC) imposes a substantial worldwide health burden, necessitating innovative strategies to enhance therapeutic outcomes. T cell immunoglobulin-3 (Tim-3), an immune checkpoint, enhances immunological tolerance. Tim-3's role in CRC surpasses its conventional function as an indicator of dysfunction in T lymphocytes.

Areas covered: This review provides an all-inclusive summary of the structural and functional attributes of Tim-3's involvement in the case of CRC. It explores the implications of Tim-3 expression in CRC with regard to tumor progression, clinical characteristics, and therapeutic approaches. Furthermore, it delves into the intricate signaling pathways and molecular mechanisms through which Tim-3 exerts its dual function in both immunity against tumors and immune evasion.

Expert opinion: Understanding Tim-3's complicated network of interactions in CRC has significant consequences for the development of novel immunotherapeutic strategies targeted toward restoring anti-tumor immune responses and improving patient survival. Tim-3 is an important and valuable target for CRC patient risk classification and treatment because it regulates a complex network of strategies for suppressing immune responses, including causing T cell exhaustion, increasing Treg (regulatory T-cell) proliferation, and altering antigen-presenting cell activity.

Introduction: Dysregulation of the hepcidin-ferroportin axis is a hallmark in the pathogenesis of iron overload, ultimately leading to end-organ injury. Hereditary hemochromatosis and iron-loading anemias are characterized by a hepcidin deficiency, making hepcidin a novel therapeutic target for preventing and managing iron overload.

Areas covered: Modulators of hepcidin expression and molecules mimicking hepcidin are emerging as highly promising therapeutic strategies. We present a summary of results from preclinical and clinical trials of such therapies in models of iron overload.

Expert opinion: Current treatment alternatives in iron overload fail to address the underlying hepcidin deficiency - and may even exacerbate it. Until hepcidin-targeting therapies become available, several challenges remain, including the need to optimize dosing in order to manage the narrow treatment window and improving specificity in targeting iron metabolism pathways exclusively. Long-term studies are crucial to fully assess both the benefits and risks of these therapies and to explore their potential utility in combination with existing treatment guidelines. Furthermore, these therapies are expected to have applications, particularly in addressing other iron-maldistributed disorders, as seen in anemia of chronic disease and inflammation.

Introduction: Diabetes mellitus, a chronic disorder with persistent hyperglycemia, severely affects the quality of life through significant neurological impairments, including neuropathy and cognitive dysfunction. Inflammation and oxidative stress are key factors in these complications, and Lipocalin-2 (LCN2), which is involved in inflammation and iron homeostasis, is crucial in these processes.

Area covered: This review explores the potential of LCN2 as a therapeutic target for mitigating diabetes neurological complications. By examining the mechanisms by which LCN2 contributes to neuroinflammation, we discuss the therapeutic strategies that target LCN2 to alleviate diabetic neuropathy and cognitive dysfunction.

Expert opinion: To fully grasp the impact of LCN2 on neurological health, it is essential to understand its multifaceted role in metabolic regulation. Because effective LCN2-targeting drugs must penetrate the blood - brain barrier, various strategies are being developed to meet this requirement. Such therapeutics could treat various neurological complications, including diabetic encephalopathy, retinopathy, and peripheral neuropathy. While animal models offer insights into pathophysiology and potential treatments, their limitations must be acknowledged. Therefore, future research should bridge the gaps between animal findings, human studies, and clinical applications. Moreover, comprehensive personalized approaches, including LCN2-targeting drugs, lifestyle changes, and regularly monitoring individual patients, may be required to manage diabetic complications.

Introduction: Melanotransferrin (CD228), a cell membrane-anchored protein, has emerged as a significant cancer antigen due to its high expression in various solid tumors. This review synthesizes the current understanding and therapeutic potential of CD228.

Areas covered: We conducted a literature search using PubMed, Web of Science, and ClinicalTrials.gov with the keywords 'melanotransferrin' and 'CD228.' Our comprehensive review examines CD228 and its isoforms, membrane-bound CD228 (mMFI2) and soluble CD228 (sMFI2), their roles in tumorigenesis, angiogenesis, endothelial cell migration, plasminogen activation, and transendothelial transport across the BBB, as well as the current state of drug development efforts targeting CD228.

Expert opinion: Targeting CD228 represents a promising therapeutic strategy in oncology, with mMFI2 as a potential target for solid tumors and sMFI2 valuable for disease diagnosis in malignant tumors, Alzheimer's disease, and arthritis, and facilitating macromolecular drug delivery across the blood-brain barrier (BBB). Despite its potential to transform the treatment landscape for numerous solid cancers, further research into the precise mechanisms and clinical translation of CD228-directed treatments is needed to maximize its therapeutic utility.