MedComm – Oncology最新文献

Owing to the limitations of conventional cancer therapies, including chemotherapy, radiotherapy, and surgery, gene therapy has become a prominent strategy for cancer treatment over the past few decades. Gene therapy is a medical approach for targeting and destroying cancer cells by delivering exogenous genes into the target cancerous cells or surrounding tissues. However, successful delivery of foreign genes into target cells and tissues remains a key issue in such therapy. Efficient gene delivery systems would undoubtedly be important for improving the medical outcomes of gene therapy. With genetic modifications, viral vectors can target specific cells with high gene transduction efficiency, thus, the use of viral vectors is a promising technology for improving foreign gene delivery. Currently, four viral vectors—adenovirus, adeno-associated virus, herpes simplex virus, and retrovirus—are dominantly being investigated and used in preclinical and clinical trials. In this review, we provide an overview of the mechanisms and latest applications of the four above-mentioned viral vectors, and summarize the current development of several other viral vectors. In addition, we discuss the challenges and provide insights into future development of viral vectors in cancer treatment.

The Hippo pathway is crucial to organ size control and its dysregulation contributes to tumorigenesis. The aberrant activation of YAP1 was identified in gallbladder cancer (GBC). However, the underlying mechanism and role in GBC remains unclear. The C terminal fragment of Mucin16, also known as carbohydrate antigen 125 (CA125) encoded product, MUC16c, plays extensive roles in tumor initiation and development. Our study showed that MUC16c binding with 14-3-3ε disrupted the interaction of 14-3-3ε and phosphorylated yes-associated protein 1 (YAP1), which led to the activation of YAP1 in GBC. Furthermore, MUC16c decreased the phosphorylation of YAP1 at serine 397 (ser397) by inhibiting LATS1, which upregulated YAP1 protein stability. Interestingly, there was a potential Src kinase site in the MUC16c fragment. The MUC16c_del15Y polypeptides with the deletion of the Src kinase site promoted the interaction of YAP1 with 14-3-3ε and downregulated the YAP1 protein levels. Consistently, SU6656, a Src kinase inhibitor also blocked the activation of YAP1 by MUC16c. The MUC16c_del15Y polypeptides decreased GBC cell proliferation in vitro and the growth of xenograft tumors in vivo. Our study revealed the underlying mechanism of the activation of MUC16c on YAP1 mediated by Src signaling and the antitumor effect of MUC16c_del15Y, providing a potential target for GBC therapy.

P38 mitogen-activated protein kinase (p38MAPK) is a multifunctional protein kinase that plays an important role in human normal physiological activities and a variety of major diseases, and its signaling pathway affects a variety of regulatory factors in vivo, which is related to cell cycle, survival, metabolism, and differentiation. The four subtypes of p38MAPK have significant differences in their distribution, content, and effects in the body. The inhibitors of the four subtypes play potential roles in regulating cancer, neurodegenerative diseases, inflammation, and cardiovascular diseases, making it an attractive target for drug development. So far, an increasing number of p38MAPK inhibitors have been developed for targeted therapy in diseases, among which some representative compounds have entered clinical trials. Therefore, this review aims to provide a summary of the structural characteristics, signaling pathways of P38MAPK and the relationship between p38MAPK and disease, along with an overview of the binding modes and structure–activity relationships of small molecule inhibitors targeting four p38MAPK subtypes, and summarizes the challenges about the development of p38MAPK inhibitors, hoping to provide a valuable reference for the development and application of novel inhibitors.

Lymphocyte Antigen 96 (LY96) was identified as an oncogene in several tumors. However, its role in renal cancer has not been explored. In the study, LY96 is identified abnormally expressed using several public kidney cancer sequencing data. The expression level of LY96 is validated using paired clinical samples. Survival analyses and ROC curves are used to examine its prognostic and diagnostic value. Gene sets enrichment analyses (GSEA) show LY96 might influence immune processes. Then immune infiltration analyses results suggest that LY96 is positively correlated with M2 macrophages infiltration in RCC. Single-cell data are used to verify its association with macrophages. Moreover, LY96 is positively with various immune scores and might affect the efficacy of immunotherapy. Drug screening results show LY96 might be the target of vemurafenib and etoposide. Further experiments confirm the spatial co-localization of LY96 and M2, and knocking down LY96 can inhibit M2 polarization. Cell viability experiments indicate that knocking down LY96 would result in a decrease in the resistance of M2 macrophages to etoposide. The study shows LY96 could act as an unfavorable biomarker for RCC and possibly contribute to cancer progression by promoting the infiltration of M2 macrophage. LY96 could be a novel therapeutic target for RCC.

Cancer is a worldwide leading cause of cancer-related death due to a lack of efficient disease control by drugs. With the increasing unmet needs in cancer treatment, developing novel effective cancer drugs is in great demand. Macrocyclic molecules represent a group of drug molecules with a cyclic skeleton which endows them with unique drug properties such as improved bioavailability, enhanced metabolic stability, increased binding affinity, and favorable pharmacokinetics parameters. The Food and Drug Administration (FDA) has approved a bunch of macrocyclic drugs to treat cancer patients. However, the importance of such molecules in cancer drug development remains underestimated. Recent studies support that macrocyclic molecules can also serve as an effective strategy to overcome drug resistance in cancer treatment, but is a lack of review. The purpose of this manuscript was to provide shreds of evidence on the applications of macrocyclic molecules for cancer therapy: (1) act as cancer drugs to target different proteins critical for cancer development; (2) act as cancer drugs to target resistant mutants of oncogenes to overcome drug resistance in targeted therapy. This review will help to attract more interest in developing macrocyclic drugs for cancer therapy and potentially provide more novel strategies to benefit cancer patients and society.

The advancement of diverse technologies has led to a substantial increase in valuable biomedical data, particularly in the field of acute myeloid leukemia (AML). Effective utilization of this wealth of data is crucial for attaining a comprehensive and in-depth understanding of AML, thereby facilitating optimal diagnosis, treatment, and prognosis. Among the various approaches to data acquisition, single-cell sequencing has emerged as an impressive tool. The developments of single-cell sequencing methods have empowered researchers to analyze the genome, transcriptome, proteome, and epigenome data at the single-cell level. It also offers a means to uncover fine information, providing unique prognostic insights and aiding in the identification of therapeutic targets. Furthermore, it enhances our understanding of AML heterogeneity, clonal evolution, and resistance mechanisms, ultimately leading to the development of better treatment strategies. In this review, we present an overview of AML as well as single-cell sequencing technologies, then explore their potential contributions to AML research in different aspects, and provide some information about resources and data processing.

Immunotherapy has revolutionized antitumor therapy. Since the discovery of stimulators of interferon genes (STING), efforts have been made to elucidate their mechanisms and physiological functions and explore the potential of STING as a therapeutic target in immune-related diseases and malignant tumors. In recent years, STING agonists have become a popular research topic. Activation of the cyclic GMP–AMP synthase (cGAS)-STING pathway produces large amounts of type I interferons, which play key roles in activating innate and acquired immune responses. The cGAS-STING pathway influences almost all aspects of tumorigenesis and has great antitumor potential. In addition, the activation of the cGAS-STING pathway is associated with tumor regression, prolonged survival of patients with cancer, and enhanced immunotherapy. Given the positive role of STING in antitumor immunity, the development of STING-targeted drugs is important. In this review, we summarize the activation and potential mechanisms of the cGAS-STING pathway, discuss the association of the cGAS-STING pathway with tumors and autoimmune diseases, and highlight research progress, clinical applications, and combination drug strategies for STING agonists.

Microtubules are pivotal in diverse cellular functions encompassing cell signaling, morphology, intracellular trafficking, and cell mitosis/division. They are validated targets for disease treatment, notably hematological cancers and solid tumors. Microtubule-targeting agents (MTAs) exert their effects by modulating microtubule dynamics, impeding cell proliferation, and promoting cell death. Recent advances in structural biology have unveiled novel perspectives for investigating multiple binding sites and mechanisms of action used by MTAs. In this review, we first provide an overview of the intricate structure and dynamics of microtubules. Then we explore the seven binding sites and the three primary strategies (stabilization, destabilization, and degradation) harnessed by MTAs. Furthermore, we introduce the emerging domain of microtubule-targeting degraders, exemplified by PROteolysis TArgeting Chimeras and small-molecule degraders, which enable precise degradation of specific microtubule-associated proteins implicated in cancer pathogenesis. Additionally, we discuss the promising realm of precision-targeted approaches, including antibody–drug conjugates and the utilization of photopharmacology in MTAs. Lastly, we provide a comprehensive overview of the clinical applications of microtubule-targeting therapies, assessing their efficacy and current challenges. We aim to provide a global picture of MTAs development as well as insights into the microtubule-targeting drug discovery for cancer treatment.

Roux-en-Y (RY) and Billroth II with Braun (BB) reconstruction are two similar methods of reconstruction after distal gastrectomy (DG). Currently, it is unclear which method is superior. This meta-analysis was performed to compare the safety and efficacy of BB and RY reconstruction after DG for gastric cancer. A literature search of Pubmed, Embase, Web of Science, and Cochrane Library was conducted to identify studies comparing BB with RY after DG for gastric cancer until the end of October 2022. Main outcomes assessed were perioperative outcomes, postoperative complications, functional findings, and nutritional status. Meta-analyses were performed using RevMan 5.4 software. Finally, eight studies with a total of 910 patients were considered for the meta-analysis. The meta-analysis results revealed that operation time, anastomosis time, incidence of total complications, and delayed gastric emptying were reduced, and the incidence of bile reflux was increased in patients undergoing BB compared to RY reconstruction. In conclusion, BB has the advantage of reducing operative time, anastomotic time, intraoperative blood loss, overall postoperative complications, and delayed gastric emptying. RY has the advantage of preventing bile reflux and gastritis after surgery.