OncoTargets and therapy最新文献

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors, making it difficult to treat with targeted therapies. The Epidermal Growth Factor Receptor (EGFR) is overexpressed in TNBC and is crucial in promoting tumor growth and survival. Despite chemotherapeutics like 5-fluorouracil (5-FU), resistance remains a clinical challenge, underscoring the need for novel therapeutic strategies.

Methods: High-throughput virtual screening (HTVS) was employed to identify inhibitors targeting the inactive conformation of EGFR. The top-ranked compounds underwent molecular dynamics (MD) simulations and binding free energy calculations using Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA). MDA-MB-231, Hs578T, and 5-FU resistant- MDA-MB-231/5-FU^R cells were utilized to assess the anti-proliferative, EGFR, and apoptosis.

Results: HTVS identified EG31 showing strong binding affinities towards EGFR. MD simulations confirmed the stable binding of EG31 to EGFR, as indicated by consistent Root Mean Square Deviation and hydrogen bond patterns throughout the simulation. MMPBSA calculations revealed highly favorable binding free energies. EG31 inhibited MDA-MB-231 and Hs578T proliferations with GI₅₀ values of 498.90 nM and 740.73 nM, respectively. The compound decreased EGFR-positive populations and favored early and late-phase apoptosis in these cells. Furthermore, EG31 retained the anti-proliferative efficacy in the MDA-MB-231/5-FU^R cells, while 5-FU lost its effectiveness by 6-fold.

Conclusion: This study identified EG31 targeting the inactive conformation of EGFR, offering a promising therapeutic approach to overcome 5-FU resistance in TNBC. Further research could enhance treatment efficacy and provide a new avenue for managing this challenging cancer subtype.

With the enhancement of public living standards and health awareness, demands for high-quality treatment with hematological malignancies are increasing, correspondingly. However, since significant adverse events have been found associated with chemotherapy, radiotherapy and other traditional anticancer measures, and a considerable number of patients still experience relapse or drug resistance, developing new treatment strategies has become the focus in the field of hematological malignancies. The measles virus vaccine strain, as an oncolytic virus, has been paid special attention to, due to its dual advantages of selectively invading and killing tumor cells and activating anti-tumor immunity. Currently, multiple studies have shown the effectiveness of unmodified measles virus vaccine strains in treating hematological malignancies. However, due to the systemic invasiveness and complexity of hematological malignancies, the concept of genetically engineered measles virus vaccine strain has garnered significant attention. In this article, we reviewed the progress on measles virus vaccine strains in the treatment of hematological malignancies, especially on the application of genetic engineering technology. Meanwhile, we also explored the challenges encountered in current treatments and discussed future design direction for modifying measles virus vaccine strains.

[This corrects the article DOI: 10.2147/OTT.S503674.].

Lung cancer is the leading cause of global cancer mortality, accounting for an estimated 2 million diagnoses and 1.8 million deaths annually. Treatment choices for non-small cell lung cancer include surgery, radiation therapy, chemotherapy, immunotherapy, or molecularly targeted therapy. Antibody-drug conjugates (ADCs), often likened to "biological missiles", are rapidly evolving as a targeted therapeutic approach. Trophoblast cell surface antigen 2 (Trop 2) is a 36-kDa cell surface glycoprotein, which is expressed in various cancers. This fuels oncogenic signaling pathways, driving tumor advancement, invasion, and spread. Its limited expression in healthy human tissues underscores its potential as a target for cancer treatment. Datopotamab Deruxtecan (Dato-Dxd) is an investigational ADC that targets Trop-2. This review discusses the current treatment landscape involving therapy with Dato-Dxd for advanced NSCLC. Dato-DXd was first used in metastatic solid tumors in the Phase I TROPION-PanTumor 01 trial, which showed promising antitumor activity in the previously pretreated NSCLC cohort and a manageable safety outline. In TROPION-Lung01, Dato-DXD was studied in metastatic NSCLC patients who were previously treated and showed an objective response rate of 26.4% (Dato-DXd). Other trials, including TROPION PanTumor 02, ICARUS - Lung 01, and TROPION Lung 05, showed comparable results. Dato-DXd used along with pembrolizumab, with or without systemic chemotherapy, in TROPION Lung 02 with promising efficacy results. The most common any-grade treatment-emergent adverse events were stomatitis, nausea, and hair loss, mostly grade 1-2. There are several clinical trials in the pipeline using Dato-DXd in the front-line metastatic setting and resectable NSCLC patients. Dato-DXd is currently pending approval from the US Food and Drug Administration (FDA). If approved, datopotamab deruxtecan will be the first TROP2-directed antibody-drug conjugate for non-small cell lung cancer.

Background: Multiple studies have suggested that lncRNAs and pyroptosis play important roles in ovarian cancer (OC). However, the function of pyroptosis-related lncRNAs (PRLs) in OC is not fully understood.

Methods: Clinical information and RNA-seq data of OC patients (n = 379) were collected from TCGA database. Pearson correlation analysis and univariate Cox analysis were performed to identify prognostic PRLs, respectively. LASSO-COX regression was utilized to construct a prognostic PRLs signature. Kaplan-Meier (K-M) curve analyses and receiver operating characteristics (ROC) were used to evaluate the prognostic prediction of the signature. The association between risk score and tumor microenvironment infiltration, immunotherapy response and chemotherapy sensitivity were also analyzed. In addition, the function of TYMSOS on OC and pyroptosis was experimentally confirmed in cell lines.

Results: Firstly, 32 prognostic PRLs were identified, and a novel prognostic PRLs signature was constructed and validated. Surprisingly, the prognostic PRLs signature could solidly predict the clinical outcome of patients with OC and patients with high-risk score shown a short overall survival. GSEA results suggested that the RPLs were mainly enriched in the inflammatory response pathway, p53 pathway, TGF-β signaling and TNFα signaling. Besides, our results demonstrated that the risk score was significantly associated with patients with immune infiltration, immunotherapy response and the sensitivity of veliparib and metformin. Furthermore, the oncogene effect of TYMSOS on OC by inhibiting pyroptosis was verified by experiments.

Conclusion: This study found that the prognostic PRLs signature may serve as an efficient biomarker in predicting the prognosis, tumor microenvironment infiltration, and sensitivity of chemotherapeutic agents. TYMSOS is a potential biomarker in OC, and it might promote tumor progression by inhibiting pyroptosis.

Background: Nowadays, immune checkpoint blockade (ICB) therapy has become a milestone in immunotherapy for hepatocellular carcinoma (HCC). However, its clinical effectiveness remains low. Soluble (s) immune checkpoints (ICs), functional components of membrane ICs, are novel physiological immunomodulators. We investigated the prognostic value of sICs in patients of hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and provided clinical clues for potential new targets for future immunotherapy.

Methods: A total of 256 participants were included in this study. We compared the plasma levels of 14 sICs in healthy controls (HC), chronic hepatitis B (CHB), hepatitis B-related liver cirrhosis (HBV-LC), and HBV-HCC groups. COX and random survival forest (RSF) were used to select variables and construct a model to predict overall survival of patients with HBV-HCC. We evaluated the predictive efficacy and analyzed the correlations between sICs, clinical parameters, and membrane ICs.

Results: The levels of 14 sICs in HBV-HCC were elevated compared to that in HC. The areas under the receiver operating characteristic values of 1-, 2-, and 3-year survival predicted by the RSF model were 0.96, 0.85, and 0.81 in the training set, and 0.91, 0.80, and 0.71 in the validation set. The model could adapt to different event distributions and clinical staging systems. Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR), soluble programmed cell death-ligand 1 (sPD-L1) and soluble T cell immunoglobulin and mucin domain-containing protein 3 (sTIM-3) were closely associated with the prognosis of patients. Soluble PD-L1 was negatively correlated with HGB and positively correlated with AST and NLR (P < 0.05). Soluble TIM-3 was negatively correlated with ALB and CD8+ T cells and positively correlated with HBV-DNA, AST, LDH and mTIM-3 expression in CD8+ T cells (P<0.05).

Conclusion: We constructed a predictive model based on sICs to predict different survival times in HBV-HCC patients. The risk stratification effectively identified potentially critical patients. Soluble GITR, sPD-L1 and sTIM-3 were important immunological indicators which could dynamically monitor patients' immune status.

Receptors coupled with G proteins (GPCRs) are expressed in large numbers in multiple systems, such as endocrine, cardiovascular, digestive, immune, and reproductive systems. As an important signal transduction mediator, in recent years, the research on GPCRs has become more and more in-depth. Many articles have verified that in the gastrointestinal, reproductive, and urinary systems, GPCRs are contributed to the development and occurrence of cancerous tumors and have been associated with the infiltration of malignant tumors and metastasis. Currently, in clinical practice, GPCRs become the target of action for about 30% of drugs. However, it should be noted that there are still over 100 GPCRs collectively referred to as orphan GPCRs (OGPCRs) due to the lack of corresponding ligands. Despite the lack of known ligands, research in animals and experiments has proved that numerous OGPCRs regulate crucial physiological functions and are intriguing and undeveloped targets for therapeutics. GPR137 is a member of OGPCRS, which promotes carcinogenesis and progression of cancers, and its expression is elevated in various malignant tumor tissues. Additionally, GPR137 has been shown to play a role in promoting tumorigenesis and metastasis in colorectal, gastric, hepatocellular, ovarian and prostate cancers. Knockdown of the GPR137 leads to cell cycle arrest within cancer cells, effectively inhibiting their proliferation and colony-forming ability while promoting apoptosis. This highlights its potential therapeutic significance as a target for numerous cancers.

Osimertinib has become the standard of care in the first-line treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Although previous studies reported that the BRAF V600E mutation is a unique resistance mechanism to osimertinib, the treatment of lung adenocarcinoma patients harboring both EGFR and acquired BRAF-V600E comutations remains unclear. Here, we report a case of a 36-year-old woman diagnosed with stage IV lung adenocarcinoma harboring the EGFR L858R mutation. She received osimertinib for 24 months and experienced progressive disease. Rebiopsy pathology revealed that the lung lesion was still adenocarcinoma, and NGS revealed gains of BRAF V600E and TP53 mutations in addition to the EGFR L858R mutation. This patient subsequently received aumolertinib in combination with dabrafenib and trametinib and achieved a complete response for 8 months. In conclusion, acquired BRAF-V600E mutations may contribute to osimertinib resistance. Aumolertinib plus BRAF inhibitors improves outcomes in patients with EGFR-L858R and acquired BRAF-V600E comutant lung adenocarcinoma in whom osimertinib treatment has failed.

Purpose: The objective of this study was to identify biomarkers associated with immunogenic cell death (ICD) in lung squamous cell carcinoma (LUSC), focusing on subtypes with distinct immunological characteristics and prognosis. Given the heterogeneous nature of LUSC, understanding ICD's role is crucial for developing tailored therapeutic strategies.

Patients and methods: RNA sequencing data from 504 LUSC samples were analyzed using unsupervised clustering to identify ICD-related gene expression patterns. These patterns were linked to immune scores, immune cell infiltration, and clinical outcomes. A separate dataset was used to validate the association between ICD-related subtypes and immunotherapy efficacy.

Results: Unsupervised clustering revealed two distinct ICD-related subtypes with significantly different immune scores, immune cell infiltration levels, and prognosis. A prognostic model was developed based on differentially expressed ICD-related genes, which demonstrated strong predictive power for patient survival and immune response. This model may offer valuable insights for clinical decision-making, particularly for immunotherapy strategies.

Conclusion: This study identified key ICD-related biomarkers and developed a prognostic model that can enhance our understanding of ICD in LUSC, ultimately guiding personalized treatment approaches.

Regorafenib, a multikinase inhibitor, frequently induces severe hand-foot skin reactions (HFSR), often requiring dose reduction or discontinuation. This case report demonstrates the successful management of HFSR in a patient with fibromyxoid sarcoma using topical Chinese medicine "Shouzuping" soaking combined with urea ointment. It suggests the unique advantages of integrated traditional Chinese and Western medicine in managing HFSR. This article further reviews the clinical characteristics, pathogenesis, prevention and treatment strategies of HFSR caused by targeted therapies, with a view to providing valuable clinical insights.