Expert Opinion on Therapeutic Targets最新文献

Introduction: Pulmonary diseases impose a daunting burden on healthcare systems and societies. Current treatment approaches primarily address symptoms, underscoring the urgency for the development of innovative pharmaceutical solutions. A noteworthy focus lies in targeting enzymes recognizing oxidatively modified DNA bases within gene regulatory elements, given their pivotal role in governing gene expression.

Areas covered: This review delves into the intricate interplay between the substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) and epigenetic regulation, with a focal point on elucidating the molecular underpinnings and their biological implications. The absence of OGG1 distinctly attenuates the binding of transcription factors to cis elements, thereby modulating pro-inflammatory or pro-fibrotic transcriptional activity. Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges. These investigations underscore the absence of cytotoxicity and the establishment of a favorable tolerance profile for these OGG1 inhibitors.

Expert opinion: Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management.

Introduction: The pathways like Wingless-related integration (Wnt/β-catenin) and PI3K play an important role in colorectal cancer (CRC) development; however, their roles are distinct in the process of oncogenesis. Despite their differences, these pathways interact through feedback mechanisms and regulate the common effectors both in the upstream and the downstream processes in normal and pathological conditions. Their ability to reciprocally control each other is a primary resistance mechanism for the selective inhibitors in CRC.

Area covered: This review highlights the Wnt/β-catenin and PI3K pathways that are interrelated in CRC, recent advances and some key perspectives in developing inhibitors that could target the tankyrase enzyme and PI3K, apart from a brief description of the potential of dual inhibitors of PI3K and Tankyrases (TNKS).

Expert opinion: Recent research has focused on overcoming the challenges particularly relating to the resistance and efficacy of dual inhibitors targeting PI3K and tankyrase proteins. Despite these challenges, PI3K as well as tankyrases remain promising therapeutic targets for the treatment of solid tumors. The design of potent inhibitors is crucial to effectively block these protein signaling pathways. Moreover, it is essential to explore the potential of dual-target inhibition of other signaling pathways in conjunction with PI3K and tankyrase.

Introduction: Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy.

Areas covered: A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the β1 subunit of integrin receptors. The hERG1/β1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-β1), which specifically targets the hERG1/β1 integrin complex and exerts antineoplastic effects in preclinical experiments.

Expert opinion: Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/β1 integrin complex through the bispecific antibody scDb-hERG1-β1 can overcome such hindrances.

Background: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors.

Methods: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection.

Results: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin.

Conclusion: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.

Background: The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer.

Research design and methods: Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation.

Results: In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice.

Conclusions: We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.

Introduction: Inflammatory bowel disease (IBD) is an umbrella term that includes different chronic inflammatory diseases of the gastrointestinal tract, most commonly Crohn's disease and ulcerative colitis. IBD affects more than 6 million people worldwide and constitutes not only a debilitating disease for the patients, but also a significant factor for society due to costs for health care and reduced working capacity. Despite the introduction of biologicals for the treatment of IBD, the identification of novel targets that could lead to novel therapeutics is still needed.

Areas covered: In this review, we summarize current knowledge about the interleukin-6 family of cytokines as potential therapeutic targets for improving the therapy of patients with IBD. We discuss cytokines like IL-6 itself for which therapeutics such as inhibitory monoclonal antibodies have already entered the clinics, but also focus on other family members whose therapeutic potential has not been explored yet.

Expert opinion: The different cytokines of the IL-6 family offer multiple therapeutic targets that can potentially be used to treat patients with inflammatory bowel disease, but unwanted side effects like inhibition of epithelial regeneration have to be considered.

Introduction: Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results.

Areas covered: This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies.

Expert opinion: EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.

Introduction: Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation - the modification of gene expression/function without DNA sequence variation - has emerged as a key player both in sarcomagenesis and sarcoma progression.

Areas covered: Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas.

Expert opinion: Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.