MedComm – Oncology最新文献

The coronavirus disease 2019 (COVID-19) pandemic brought about unprecedented challenges to global healthcare systems. Among the most vulnerable populations are cancer patients, who face dilemmas due to their compromised immune systems and the intricate interplay with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This comprehensive review delves into the multifaceted relationship between COVID-19 and cancer. Through an analysis of existing literature and clinical data, this review unravels the structural intricacies of the virus and examines its profound implications for cancer patients, thereby bridging the knowledge gap between virology and oncology. The review commences with an introduction regarding the COVID-19 pandemic and cancer. It then transitions into a detailed examination of the SARS-CoV-2 virus and its variants such as Alpha (PANGO lineage B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529 lineage). Subsequently, an insightful analysis of the impact of COVID-19 on major cancer types (viz., Lung, Colon, Brain, and gastrointestinal cancer) is elaborated. Finally, the therapeutic avenues, oncological care, and management are discussed. The nexus between COVID-19 and cancer adds a layer of complexity to patient care, emphasizing the importance of tailored approaches for those grappling with both conditions. Amid the landscape defined by the evolving viral strains, this review navigates through the multifaceted implications of COVID-19 on cancer patients and underscores the significance of integrating virology and oncology.

Colon cancer is the third most frequently diagnosed cancer worldwide. Considerable progress has been made in the therapeutic strategies and the accuracy of predicting the patients' prognosis. In the past decade, immunotherapy, represented by programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) signaling inhibitors have made remarkable advances in many solid tumors, but limited effect in colon cancer. In particular, colon cancer demonstrates a remarkably poor response to immunotherapy compared with other cancers, with a notable exception of tumors harboring high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR).¹ MSI-H or dMMR tumors are characterized by high mutational/neo-antigen burden, and an inflammatory tumor microenvironment with abundant tumor-infiltrating lymphocytes (TILs).² Although better efficacy could be achieved in a small group of patients with MSI-H or dMMR tumors, a proportion of other patients could benefit from immunotherapy. Thus, more appropriate biomarkers are needed to be discovered to predict the patients' prognosis and immunotherapeutic efficacy.

Different T-cell subsets in the tumor immune microenvironment (TIME) are closely related to the antitumor response and the prognosis of tumor patients. Tumor-specific CD8⁺ T cells are the core cellular components that exert antitumor effects in TIME, by recognizing specific receptors on the tumor surface and secreting cytokines or via the Fas/FsaL pathway. Multiple T-cell subsets are characterized by respective differentiation markers. Currently, with the deepening research of T-cell subsets, the detection of relevant immune indicators and the formulation of therapeutic schedules have attracted increasing clinical attention. By monitoring the expression of T-cell differentiation markers in patients with colon cancer, the benefit of patients receiving immunotherapy can be further evaluated, thus providing a theoretical basis for judging the clinical prognosis and designing more feasible treatment plans.

In this research, we systematically analyzed the prognostic values of multiple markers for different T-cell subsets³ using the Cancer Genome Atlas (TCGA) data set. Among all markers for different T cell subsets, we found that CD95 expression was correlated with better overall survival (OS) and progression-free survival (PFS), while BCL2 and CD122 were only correlated with PFS (Figure 1A,B). Therefore, CD95 was speculated to be associated with prognosis in colon cancer and was selected for further investigation and validation. The analysis of single-cell RNA-sequencing data set confirmed that CD95 was highly expressed in immune cells, especially in various T-cell subtypes (Figure S1A–C). CD95 is a member of the tumor necrosis factor receptor (TNF-R) superfamily and treated as characteristic marker of memeroy cells. It could also be used as the

Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages in cancer therapy. As opposed to noncovalent inhibitory drugs, covalent inhibitors reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming to selectively recognize and bind to protein targets and addressing some of the challenges faced by noncovalent drugs. Most successful targeted covalent inhibitors depend primarily on binding-site cysteine residues, but this has limitations for certain protein targets that lack targetable cysteine residues. Recently, the rational design of covalent inhibitors or covalent probes targeting other nucleophilic residues, such as lysine, tyrosine, serine, has turned out to be another promising strategy for cancer therapy. Thus, the development of novel strategies to extend the scope of covalent binding and improve the binding properties is required. This review gives a summary of the development of covalent inhibitors targeting noncysteine from different aspects, including target identification, structure–activity relationships, drug discovery strategies, and binding properties, in the hope of providing a scientific reference for future covalent drug discovery as a means of expanding research in cancer therapy.

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.