OncoTargets and therapy最新文献

Background: Insufficient ablation is a significant factor contributing to the recurrence of non-small cell lung cancer (NSCLC), and it is of great significance to explore the protein expression profile of lung cancer cells after insufficient ablation.

Methods: We establish an insufficient microwave ablation model of lung cancer xenograft in mice, identify differentially expressed proteins (DEPs) and involved signaling pathways through proteomic sequencing, and confirm proteins expression via immunohistochemistry (IHC). Utilizing The Cancer Genome Atlas (TCGA) dataset, we investigate proteins associated with human lung cancer prognosis.

Results: Proteomic sequencing results reveal that 99 proteins exhibited differential expression levels. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that the DEPs are significantly enriched in metabolic processes. Several DEPs are identified and subsequently confirmed through immunohistochemistry (IHC). Among these proteins, CTP synthase 1 (CTPS1) and Thymidylate synthetase (TYMS), both of which play roles in nucleotide metabolism, are found to be significantly associated with the survival outcomes of patients with lung cancer.

Conclusion: Insufficient ablation can cause alterations in nucleotide metabolism, potentially leading to recurrence and metastasis.

As hematological tumor patients are surviving long-term, the long-term toxicities of therapeutic regimens have become increasingly evident. The coexistence of two hematological tumors in the same patient is extremely rare and typically shows an aggressive clinical course and unsatisfactory prognosis. In the present case, we describe the case of a 64-year-old man who was admitted to the hospital because of fatigue. Biochemical showed an elevated monoclonal immunoglobulin M (IgM) at 37g/L. Next Generation Sequencing (NGS) analysis revealed MYD88^L265p mutation, CXCR4 wild type. In August 2020, he was diagnosed with Waldenström macroglobulinemia (WM) and underwent six cycles of chemotherapy with bendamustine, zanubrutinib, and rituximab. However, he was admitted to the hospital in December 2022 following six-month history of Leukocytosis. Bone marrow (BM) flow cytometry (FCM) showed increased MO1 monocytes. Molecular studies were positive for TET2 mutations. He was finally diagnosed with WM and chronic myelomonocytic leukemia (CMML). Then he accepted hematopoietic stem cell transplantation (HSCT). Unfortunately, after 6 months, the patient died as a consequence of severe pulmonary infection.

Background: The efficacy of Fms-like tyrosine kinase 3 (FLT3) inhibitors has been well established against acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations. However, comparative data on the available inhibitors are limited, and drug resistance remains a major concern.

Methods: This study examined the inhibitory effects of gilteritinib, quizartinib and midostaurin on Ba/F3 cells with FLT3-ITD mutations, or point mutations in the tyrosine kinase domain (TKD-PM) or juxtamembrane domain (JMD-PM), both in vitro and in vivo. Quizartinib and midostaurin were selected as comparators due to their clinical relevance in the AML setting and differing mechanisms of action.

Results: Gilteritinib showed similar or superior growth inhibition against the majority of FLT3-TKD-PM or FLT3-JMD-PM cells compared to FLT3-ITD-mutant cells. In contrast, the inhibitory effects of quizartinib were reduced on cells with most types of FLT3-TKD-PM, and the inhibitory effects of midostaurin were attenuated on cells with FLT3-TKD-PM N676K. Gilteritinib also effectively suppressed FLT3 autophosphorylation and phosphorylation of signal transducer and activator of transcription 5 (STAT5), AKT and extracellular signal-regulated kinase (ERK) in FLT3-TKD-PM cells, while quizartinib showed a reduced inhibitory effect on FLT3 autophosphorylation and phosphorylation of downstream signaling molecules in FLT3-TKD-PM cells. In mice xenografted with Ba/F3 cells expressing FLT3-ITD mutations or FLT3-TKD-PM, gilteritinib showed a potent antitumor effect, whereas the antitumor effect of quizartinib was significantly diminished in the FLT3-TKD-PM xenograft model.

Conclusion: These findings highlight the potent efficacy of gilteritinib against a wide range of FLT3 mutations, including TKD-PM and JMD-PM, as well as those associated with resistance to quizartinib or midostaurin. This comparative analysis underscores the need for tailored therapeutic strategies in AML treatment, emphasizing the clinical significance of gilteritinib in overcoming drug resistance.

Aim: Breast cancer remains a prevalent and challenging health issue for women globally. In the pursuit of more effective and less harmful therapies, researchers have focused on natural compounds, especially phenolic compounds found in various plants and fruits.

Purpose: This study aims to explore the potency of coumarin compounds from Citrus aurantiifolia (Christm.) Swingle peel as alternative treatment for breast cancer through in vitro and in silico studies.

Methods: Three coumarins were isolated from C. aurantiifolia peel through multiple steps of column chromatograph. Their cytotoxic activities against the MCF-7 breast cancer cell line were evaluated using the MTT assay. Additionally, in silico studies, including molecular docking and molecular dynamics simulations, were conducted to evaluate the interactions of the most potent compound with estrogen receptor alpha (ERα).

Results: Chemical investigation of C. aurantiifolia peel led to the isolation of three compounds: 5-geranyloxy-7-methoxycoumarin (1), 5-geranyloxypsoralen (2), and 8-geranyloxypsoralen (3). Cytotoxic assays revealed that compound 2 exhibited the highest cytotoxic potency against MCF-7 breast cancer cell line with an IC₅₀ of 138.51 ± 14.44 µg/mL, followed by compounds 1 and 3 with IC₅₀ values of 204.69 ± 22.91 and 478.15 ± 34.85 µg/mL, respectively. Molecular docking studies against estrogen receptor alpha (ERα) showed that 5-geranyloxypsoralen (2) had a lower docking score (-10.63 kcal/mol) compared to estradiol (-9.99 kcal/mol). Molecular dynamics simulation revealed the binding stability ERα-Compound 2 complex as evidence from the root mean square deviation (RMSD) of 2.964 ± 0.460 Å. Furthermore, pharmacokinetic predictions suggested that 5-geranyloxypsoralen may possess favourable pharmacokinetic properties, highlighting its potential as a therapeutic agent.

Conclusion: The study highlights the potential of coumarin compounds from C. aurantiifolia peel as an alternative treatment for breast cancer, particularly 5-geranyloxypsoralen could be a promising therapeutic agent in breast cancer treatment, warranting further investigation.

Purpose: Early relapsed breast cancer, characterized by recurrence within two years post-surgery, often results from drug resistance and rapid progression. The clinicopathological, prognostic and molecular features of these patients still await exploration.

Methods: In this study, 43 patients with early relapsed breast cancer were included as well as 42 advanced breast cancer patients who experienced a recurrence after two years since surgery as the control group. Clinicopathological factors and prognosis were compared among the two groups, and tumor tissue from 27 available early relapsed patients was subjected to genetic sequencing.

Results: Compared with the control group, early relapsed group exhibited more aggressive malignant biological characteristics, shorter median overall survival (27.8 vs 49.8 months, P=0.005) and lower objective response rate for the first line treatment (42.90% vs 86.8%, P<0.001). Genetic sequencing of 27 early relapsed breast cancer demonstrated with TP53 (52%), PIK3CA (22%), and MLL3 (19%) as the top three frequently mutated genes, suggesting potential therapeutic targets for personalized treatment strategies.

Conclusion: Early relapsed breast cancer patients demonstrated poor prognosis and treatment response, indicating a reagent need of effective treatment combination for disease control. Genetic sequencing may identify potential therapeutic targets, providing new therapeutic opportunities for such patients. These findings underline the urgent need for personalized therapeutic strategies informed by genetic profiling to improve outcomes for early-relapsed breast cancer patients.

Objective: This study aims to integrate bulk and single-cell RNA sequencing data to construct a risk score model based on HOXC9-related immune genes (HRIGs) and evaluate its prognostic value in hepatocellular carcinoma (HCC).

Materials and methods: RNA sequencing data and clinical information of HCC were obtained from TCGA and GEO databases. HRIGs were identified and a risk score model was constructed using LASSO-Cox regression analysis. The association between the risk score and tumor microenvironment was analyzed using CIBERSORT and ESTIMATE algorithms. Single-cell RNA sequencing (scRNA-seq) data were used to assess cell type distribution. Cell experiments were conducted to verify the effects of HOXC9 knockdown on HCC cell proliferation and invasion.

Results: HOXC9 is highly expressed in HCC and associated with poor prognosis (p=0.031). The risk score model based on four HRIGs (EGLN3, IMPDH1, LPCAT1, and MARCKSL1) showed good prognostic discrimination in both TCGA and GEO cohorts, with significantly lower overall survival in the high-risk group (p<0.0001). The high-risk group exhibited higher immune scores and increased immune cell infiltration, as well as elevated immune checkpoint expression. scRNA-seq revealed increased hepatocytes and fibroblasts but decreased T/NK cells in HCC tissues. HOXC9 knockdown significantly inhibited HCC cell proliferation and invasion.

Conclusion: HOXC9 is overexpressed in HCC and correlates with poor prognosis. The HRIG-based risk score model effectively evaluates the prognosis and immune response in HCC patients, providing new insights for risk assessment and immunotherapy prediction.

Cancer remains the foremost cause of mortality on a global scale. Immunotherapy has yielded remarkable outcomes in the fight against cancer and is regarded as one of the most crucial and promising therapeutic modalities. PCSK9, a critical target for plasma lipids control, has been extensively and deeply studied in multiple diseases. Currently, the functions of PCSK9 in cancer, particularly its immunomodulatory role, have been progressively revealed. PCSK9 is capable of modulating a variety of immune response throughout tumor progression by orchestrating lipid metabolism. Moreover, PCSK9 governs the cell fate of diverse immune cells, such as inflammatory factor signals, MHC signals, and TCR signals. This review comprehensively summarizes the current state of knowledge regarding the role and underlying mechanisms of PCSK9 in tumorigenesis, progression, immune escape, and drug resistance.

Introduction: Nicotinamide plays a critical role in the prevention and treatment of tumors, and its metabolism is closely associated with tumor progression. The aim of this study was to understand the prognostic and immunological significance of nicotinamide metabolism-related genes in pan-cancer.

Methods: We downloaded The Cancer Genome Atlas and Genotype Tissue Expression pan-cancer datasets for NMNAT1 from the UCSC database. We analyzed the differential expression, prognosis, genetic alterations, DNA methylation, immune infiltration, and co-expression with RNA modification-related genes and immune checkpoint-related genes. Genes with expression patterns similar to NMNAT1 were identified using the GEPIA library. The GSCA database was used to investigate the correlation between gene expression and drug sensitivity, as assessed by GDSC and CTRP. The CancerSEA database was employed to examine the association of NMNAT1 expression at the single-cell level across different tumors and its relation to 14 functional states. Immunohistochemistry was performed to assess the clinical significance of NMNAT1 expression.

Results: NMNAT1 exhibited differential expression across 25 tumor types, including colorectal cancer (CRC), and its expression was significantly associated with the prognosis of 11 tumors. Furthermore, NMNAT1 expression correlated significantly with clinicopathological features. NMNAT1 was strongly associated with immune cells, RNA modification-related genes, and immune checkpoint-related genes in most tumors, affecting immune responses. The expression of NMNAT1 also correlated with sensitivity and resistance to several drugs. Single-cell analysis revealed that NMNAT1 is involved in the progression of retinoblastoma, uveal melanoma, and CRC. Immunohistochemical analysis confirmed that NMNAT1 expression is an independent prognostic factor in patients with CRC.

Conclusion: NMNAT1 is a crucial prognostic and immune marker gene for nicotinamide metabolism, particularly in CRC. It has potential as a clinical biomarker and a therapeutic target for cancer treatment.

Purpose: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. In the FLAURA trial, osimertinib demonstrated longer progression-free survival (PFS) and overall survival (OS) compared to gefitinib or erlotinib. In the trial, dose reductions occurred in 5% of patients, primarily due to QT prolongation. However, various adverse events can also lead to dose reductions in clinical practice, and the efficacy of osimertinib after dose reduction remains unclear. The present study was conducted to evaluate the clinical impact of osimertinib dose reduction.

Patients and methods: This monocentric retrospective study was conducted at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. Ninety patients with EGFR mutation-positive non-squamous non-small-cell lung cancer receiving osimertinib as their first-line therapy between August 2018 and December 2021 were included.

Results: Of the cohort, 23 patients had an osimertinib dose reduction during their clinical course. The dose reduction group tended to have a lower median body weight and a higher proportion of elderly patients aged 80 years or older. The median PFS was 21.2 months (95% confidence interval [CI]: 8.22-34.18) in the dose reduction group and 18.6 (95% CI: 13.04-24.23) months in the regular-dose group. The median OS was 29.6 months (95% CI: 17.44-41.70) in the osimertinib dose-reduction group and 37.7 (95% CI: 27.10-48.23) months in the regular-dose group. Dose reduction did not significantly impact the time-dependent hazard ratio (HR) for PFS (HR 1.22 [95% CI: 0.55-1.89]) or OS (HR: 1.24 [95% CI: 0.64-2.42]). The adverse events leading to dose reduction were mainly rash, anorexia, and paronychia, and no fatal adverse events were observed after dose reduction.

Conclusion: The present study suggests that dose reduction may not compromise the efficacy of osimertinib. However, the clinical impact of dose reduction is not fully understood. Physicians should carefully weigh its benefits and risks before implementation.

Introduction: Osteosarcoma, a prevalent bone malignancy in children and adolescents, is currently treated through surgical resection and chemotherapy. Advancements in cancer research are targeting immune checkpoint molecules, such as indoleamine 2,3-dioxygenase, to advance the development of immunotherapy. However, the scarcity of research on IDO in osteosarcoma results in an absence of comprehensive data, highlighting the conflicting findings surrounding IDO's role in various cancers. Our study aims to explore IDO expression in primary tumors and metastatic lesions among osteosarcoma patients, investigating its association with clinicopathological characteristics and assessing its impact on survival outcomes.

Methods: 150 patients diagnosed with osteosarcoma were selected between 2009 and 2019 from the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. FFPE tissue samples of primary tumors and metastatic lesions were retrieved to conduct immunohistochemical analysis. Moreover, the clinicopathological data of these patients were gathered from the hospital information system.

Results: Out of 150 patients, primary tumors were accessible for 134 individuals, while metastatic lesions were available for 49 patients. IDO expression was identified in 9 (6.71%) primary tumors and 2 (4.08%) metastatic lesions among osteosarcoma patients. Furthermore, 3 patients exhibited high expression (27.3%), while 8 displayed low IDO expression (72.7%).

Conclusion: Our comprehensive study findings indicate that most osteosarcoma patients do not exhibit expression of IDO. This absence of expression aligns with the characteristic "cold" tumor microenvironment observed in osteosarcoma. Further investigations are imperative to provide deeper insights into the intricacies of this immunomodulatory factor in the context of osteosarcoma.