OncoTargets and therapy最新文献

Background: Induction chemotherapy (IC) is the standard treatment protocol for locally advanced nasopharyngeal carcinoma (LANPC), though concerns persist regarding high rates of recurrence and metastasis. This retrospective study aims to evaluate the efficacy, potential benefits, and safety of combining PD-1 inhibitors with IC, followed by nimotuzumab and intensity-modulated radiation therapy (IMRT).

Methodology: We analyzed data from 103 patients diagnosed with non-keratinizing LANPC (according to WHO criteria) at clinical stages III-IVA. These patients, treated from May 2020 to November 2023, received four cycles of IC combined with PD-1 inhibitors, followed by nimotuzumab and IMRT. Efficacy assessments were conducted according to RECIST v1.1 guidelines, with the primary endpoint being a clinical complete response (CCR), defined as the absence of detectable tumors or mucosal bulges upon nasoendoscopy.

Results: Among the evaluable patients, the CCR rate reached 66% (95% CI, 56-75%), while the objective response rate (ORR) was 97% (95% CI, 92-99%) and the disease control rate (DCR) reached 99% (95% CI, 95-100%). During the median follow-up of 16.1 months, neither the median progression-free survival (PFS) nor median overall survival (OS) was reached. Notably, patients with T4-stage disease exhibited lower CCR rates, highlighting stage-specific variations in treatment responses. The treatment regimen was well-tolerated, with no significant adverse safety events reported.

Conclusion: The combination of PD-1 inhibitors with IC, followed by nimotuzumab and IMRT, shows promising efficacy and safety in the treatment of LANPC.

Background: Base of tongue squamous cell carcinoma (BOTSCC) is a prevalent and aggressive form of oral cancer, often associated with poor patient outcomes. The tumor microenvironment (TME) of HPV-positive BOTSCC is critical in influencing cancer progression and treatment response.

Objective: This study aims to analyze the TME of HPV-positive BOTSCC by examining the expression of key genes involved in various biological processes.

Methods: We utilized the RT2 Profiler PCR Array to quantify the expression of 168 genes related to inflammation, immunity, oncogenesis, tumor suppression, apoptosis, and angiogenesis. Enrichment analysis of cancer hallmarks was performed on all upregulated genes. Additionally, we investigated the correlation between the expression levels of the ten most highly upregulated genes and survival prognosis in HPV-associated BOTSCC patients.

Results: Our analysis revealed dysregulation of 42 genes associated with tumor-immune interactions, with 20 genes upregulated and 22 downregulated. Furthermore, we identified 64 genes linked to cancer development, with 33 upregulated and 31 downregulated. High-risk HPV (hr-HPV) genotypes were found in 81% of patients, predominantly HPV-35 and HPV-16.

Conclusion: This study highlights the complexity of the HPV-positive BOTSCC TME, underscoring the need for further research into molecular pathways and immune interactions to identify new therapeutic targets for improved cancer treatment.

Cancer persists as a ubiquitous global challenge despite the remarkable advances. It is caused by uncontrolled cell growth and metastasis. The Transforming Growth Factor-beta (TGF-β) signaling pathway is considered a primary regulator of various normal physiological processes in the human body. Recently, factors determining the nature of TGF-β response have received attention, specifically its signaling pathway which can be an attractive therapeutic target for various cancer treatments. The TGF-β receptor is activated by its ligands and undergoes transduction of signals via canonical (SMAD dependent) or non-canonical (SMAD independent) signaling pathways regulating several cellular functions. Furthermore, the cross talk of the TGF-β signaling pathway cross with other signaling pathways has shown the controlled regulation of cellular functions. This review highlights the cross talk between various major signaling pathways and TGF-β. These signaling pathways include Wnt, NF-κB, PI3K/Akt, and Hedgehog (Hh). TGF-β signaling pathway has a dual role at different stages. It can suppress tumor formation at early stages and promote progression at advanced stages. This complex behaviour of TGF-β has made it a promising target for therapeutic interventions. Moreover, many strategies have been designed to control TGF-β signaling pathways at different levels, inhibiting tumor-promoting while enhancing tumor-suppressive effects, each with unique molecular mechanisms and clinical implications. This review also discusses various therapeutic inhibitors including ligand traps, small molecule inhibitors (SMIs), monoclonal antibodies (mAbs), and antisense oligonucleotides which target specific components of TGF-β signaling pathway to inhibit TGF-β signaling and are studied in both preclinical and clinical trials for different types of cancer. The review also highlights the prospect of TGF-β signaling in normal physiology and in the case of dysregulation, TGF-β inhibitors, and different therapeutic effects in cancer therapy along with the perspective of combinational therapies to treat cancer.

Background: Multiple Myeloma (MM) is the second most common hematologic malignancy, which exhibits strong resistance to bortezomib, the first-line treatment. Circular RNAs (circRNAs) are increasingly considered as important drivers of drug resistance across various cancers, but their roles in multiple myeloma are not well understood.

Aim: To investigate and identify potential circRNA targets and their roles in the mechanisms of bortezomib resistance.

Methods: Bortezomib-resistant MM patient-specific circRNAs were screened using Arraystar circRNA microarrays. The MM circRNA dataset from the GEO database was analyzed with GEO2R to identify candidate circRNAs associated with MM progression and drug resistance. CircRNA-forming and loop-forming sites, along with their structures, were identified via Sanger sequencing. The identified circRNA was validated by qRT-PCR in MM patients with and without bortezomib resistance. Bioinformatic analysis through CircInteractome was conducted to predict potential miRNA and RBP binding for the core circRNAs. Metascape was employed to perform RBP pathway analysis to identify specific biological processes in circRNAs.

Results: The hsa_circ_0058191 was found to be overexpressed in bortezomib-resistant MM patient samples, suggesting its pivotal role in drug resistance mechanisms. The interaction of hsa_circ_0058191 with miR-660 and AGO2 as determined through bioinformatic predictions, indicated that it regulates RNA modification and mRNA regulation pathways. These molecular interactions expand our understanding of the mechanisms of drug resistance in multiple myeloma.

Conclusion: This study identified the role of hsa_circ_0058191 in the development of drug resistance in MM, which provides a theoretical foundation for designing potential therapeutic strategies to prevent drug resistance.

Background and objective: Cystic lung cancer (CLC) presents diagnostic and treatment challenges due to its complex imaging features and unclear molecular mechanisms. Although surgery and standard chemotherapy are frequently used, there is limited information on targeted therapy and other precision treatments. It is crucial to comprehensively understand the molecular mechanisms and explore precision treatments based on targeted therapy.

Methods: Topic keywords including "CLC", "cystic lung cancer", "cavitary lung cancer", "Lung cancer associated with cystic airspaces", and "lung cancer" with ("sac cavity" OR "cystic degeneration" OR "thin-walled cavity" OR "adenocystic carcinoma" OR "cystic airspaces" OR "pulmonary cysts" OR "adenoid cystic carcinoma") searched in the relevant databases, such as PubMed, Google Scholar, and CNKI (China National Knowledge Infrastructure). Then, we reviewed and analyzed the molecular mechanism and its precision therapeutics of CLC.

Key content and findings: Various subtypes of CLC can be identified through histopathological examination, such as cystic adenocarcinoma, and squamous cell carcinoma. However, we still have much to learn about the molecular mechanisms behind CLC. Gene mutation, the abnormal tumor microenvironment, and immune dysfunction are the main mechanisms, along with potential factors like epigenetic modifications and gene susceptibility related to COPD. Recent advancements in treatment include targeted therapies, such as targeted inhibitors for EGFR, ALK, ROS1, BRAF, and MET. Surgical treatment, standardized chemotherapy, immunotherapy, and combination therapy remain important. Future research should focus on genomic and molecular profiling, and the development of precision medicine based on insights into the heterogeneity of CLC. Additionally, investigating resistance mechanisms and developing predictive biomarkers are important for future CLC research.

Conclusion: The key molecular mechanisms of CLC involve gene mutations and TME immune dysfunction. CLC still requires standard comprehensive treatment based on lung cancer staging, and targeted therapy has shown significant advantages and development prospects.

Breast cancer is one of the most common malignant tumours in women worldwide. A primary route for breast cancer cells to disseminate is through regional lymphatic vessels and nodes. Cancer cell-induced lymphangiogenesis plays a crucial role in lymphatic metastasis and is associated with poor survival of breast cancer. Advances in molecular biology have led to the identification of biomarkers associated with lymphangiogenesis and lymphatic metastasis, including lymphatic vessel endothelial cell (LVEC) markers and tumour microenvironment markers, such as vascular endothelial growth factor receptor 3 (VEGFR3), podoplanin (PDPN), and lymphatic endothelial hyaluronan receptor-1 (LYVE1). LVEC molecular markers play a profound role in both the formation of new lymphatic vessels and the invasive expansion of primary tumour. Abnormal expression of LVEC markers may contribute to lymphatic vessel disease and/or metastasis of cancer cells through the lymphatic system. These molecular markers may present a potential for targeted therapies and precision diagnostics for managing lymphatic metastasis in breast cancer. This review aims to provide a comprehensive summary of the current understanding of the molecular and cellular machinery underlying lymphatic metastasis in breast cancer, with a particular focus on the lymphangiogenic markers and their role in the lymphatic dissemination.

Objective: The study investigated microRNA-152-3p-mediated autophagy and sensitivity of paclitaxel-resistant ovarian cancer cells.

Methods: The miR-152-3p mimics and miR-152-3p inhibitor were transfected in A2780 cells and A2780T cells, and the scrambled sequences were transfected as a negative control group, the transfection efficiency was detected by qPCR technology. MTT was used to detect the proliferation and IC50 value of the cells after transfection. The expression of target proteins in A2780 cells and A2780T cells were detected by qPCR; The expression of phosphatase and tensin homolog (PTEN) and ATG4D after transfection were analyzed by Western blot. The knockdown efficiency of PTEN was detected by reverse qRT-PCR, MTT and Western blot.

Results: The expression level of miR-152-3p in A2780T cells was 52-fold higher than that in A2780 cells according to the results of qPCR. Downregulation of miR-152-3p reversed PTX-induced autophagy, inhibited cell proliferation and apoptosis, and reduced drug resistance in A2780T cells. Moreover, PTEN appeared to be a potential target of miR-152-3p, and low expression levels of miR-152-3p increased PTX sensitivity by downregulating PTEN in vitro.

Conclusion: PTEN may be a novel therapeutic target gene for patients with PTX-resistant ovarian cancer. These findings provide a potential translational framework for developing novel therapeutic strategies to overcome paclitaxel resistance in ovarian cancer.

Background: Cancer remains a major global health challenge, with early detection and prompt treatment being crucial for reducing mortality rates. The SPINK4 has been linked to the development of several tumors, and there is growing evidence of its involvement. However, its specific functions and effects in different cancer types remain unclear.

Methods: The association between SPINK4 expression levels and tumor progression was investigated and confirmed using the TCGA dataset. Kaplan-Meier curves were utilized to examine the correlation between SPINK4 expression with survival outcomes in pan-cancer patients. The Pearson method was employed to investigate the association of SPINK4 expression with the tumor microenvironment, stemness score, immunoinfiltrating subtype, and chemotherapy sensitivity in human different cancer types. Wound healing and Transwell assays were performed to confirm the roles of the model gene in colon adenocarcinoma cells.

Results: The expression of SPINK4 shows heterogeneity across pan-cancer tissues, and is closely associated with poor prognosis, immune cell invasion, tumor cell resistance, and tumor metastasis in a various human cancer. Mutation of SPINK4 hold significant predictive value for poor prognosis of pan-cancer patients. In addition, SPINK4 expression was significantly correlated with the tumor microenvironment (stromal cells and immune cells) and stemness score (DNAss and RNAss) in human pan-cancer tissues, particularly in BLCA and COAD. Single-cell sequencing analysis showed that SPINK4 is mainly expressed in endothelial cells in BLCA and in malignant cells in COAD. Drug resistance analysis showed a significant association between SPINK4 expression and sensitivity to several cancer chemotherapy drugs. Importantly, overexpression of SPINK4 promoted the metastasis of colon cancer cell lines (HCT116 and RKO), whereas SPINK4 knockout markedly inhibited their metastasis.

Conclusion: These findings reveal the crucial role of SPINK4 in the pan-cancer process and may have significant implications for the diagnosis and treatment of cancer in the future.

The KRAS gene is nearly ubiquitously subjected to activating mutation in pancreatic adenocarcinomas (PDAC), occurring at a frequency of over 90% in tumors. Mutant KRAS drives sustained signaling through the MAPK pathway to affect frequently disrupted cancer phenotypes including transcription, proliferation and cell survival. Recent research has shown that PDAC tumor growth and survival required a guanine nucleotide exchange factor for RAS homolog family member A (RhoA) called GEF-H1. The GEF-H1 protein, encoded by the ARHGEF2 gene, is a microtubule-associated GEF for RhoA that promotes invasion-migration of PDAC cells via activation of RhoA. Unexpectedly, independent of its RhoGEF activity, GEF-H1 was found to potentiate MAPK signaling by scaffolding protein phosphatase 2A (PP2A) to the kinase suppressor of Ras 1 (KSR-1). In a feedback-dependent manner, enhanced MAPK activity drives expression of ARHGEF2 via regulation of transcription factors ETS and SP, and the RAS responsive element-binding protein 1 (RREB1). RREB1 a negative regulator of ARHGEF2 expression, is downregulated in PDAC cells, which permits sustained expression of GEF-H1 for PDAC tumor survival and subsequent MAPK pathway activation. Given that MAPK targeted therapies show limited clinical efficacy, highlights the need for novel targets. This review describes the unexpected complexity of GEF-H1 function leading to positive feedback that potentiates RAS-MAPK signaling and suggests inhibition of GEF-H1 as a therapeutic strategy for RAS-driven cancers.

Background: Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion is crucial for autophagy, making YKT6, a key modulator of cell membrane fusion, a potential target for cancer therapy. However, its oncogenic role across different cancers remains unclear. This study was to investigate the prognostic value and potential immunological functions of YKT6, including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).

Methods: Multiple bioinformatics databases, including The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) databases, were used to investigate the correlation of the YKT6 expression pattern with the pathological stage and survival rate across cancers. Furthermore, ImmuCellAI, the UCSC Xena platform, and the ESTIMATE algorithm were subsequently utilized to explore the potential relationship between YKT6 expression, the tumor microenvironment, and tumor immune infiltration. Profiling of YKT6 gene mutation and amplification, methylation, and copy number alteration (CNA) was performed on the basis of the TCGA database. Moreover, q-PCR, TMA staining, and siRNA assays were used to validate the cancer-promoting role of YKT6 in CESCs.

Results: Our results reveal that YKT6 is a potential prognostic and cancer immunity biomarker. Elevated YKT6 expression is correlated with poor overall survival (OS) and disease-free survival (DFS). Distinct gene mutation, methylation, and CNA patterns for YKT6 were found in certain types of cancers. The correlation of YKT6 expression with tumor-infiltrating immune cells was verified by analyzing the StromalScore, ESTIMATEScore, ImmuneScore, and tumor purity. In vitro analysis confirmed that YKT6 was highly expressed in advanced-grade CESCs and that the knockdown of YKT6 inhibited the proliferation of cervical cancer cells.

Conclusion: The SNARE protein YKT6 serves as a biomarker and candidate oncogene with actionable mutations. Moreover, YKT6 has the potential to be a prognostic indicator in CESCs. Targeting YKT6 could enhance autophagy regulation and improve therapeutic strategies for personalized cancer treatment.