Recent patents on anti-cancer drug discovery最新文献

Introduction: This study aims to develop a predictive signature based on lactylation to complement existing staging systems and improve prognostic accuracy in clinical settings.

Methods: A database of lactylation-associated genes was obtained from The Cancer Genome Atlas (TCGA). Cox and LASSO regression analyses were used to identify a risk signature. Differential expression and enrichment analyses were performed to explore functional differences between these groups, and the influence of lactylation-associated genes on the tumor immune microenvironment and chemotherapy sensitivity was evaluated. After screening for lactylationassociated genes highly expressed and prognostically relevant in BC, in vitro assays were conducted to examine the role of these genes in tumor proliferation and metastasis.

Results: We identified six lactylation-associated genes, including SH3GL1, XRCC4, PCMT1, DECR1, ALDH1A1, and RPL14. XRCC4 was highly expressed and identified as a significant factor affecting patients' overall survival in BC. Patients in the high-risk groups exhibited poorer prognoses compared to those in the low-risk groups. Tumor mutation burden, chemotherapeutic sensitivity, and immune infiltration differed significantly between the two groups.

Discussion: Our results propose XRCC4 as a potential therapeutic target in BC. Although the current evidence is constrained, we are actively expanding the sample size and will develop dedicated validation cohorts to corroborate the lactylation-related findings.

Conclusion: Our findings highlight the potential of lactylation-associated genes, particularly XRCC4, in BC progression and clinical treatment strategies. The development of an XRCC4 inhibitor may be eligible for patent protection and could potentially serve as a novel therapeutic option for BC.

Introduction: The hypoxic microenvironment is a hallmark of solid tumors, driving metastasis through Hypoxia-Inducible Factor-1α (HIF-1α)-mediated Epithelial-Mesenchymal Transition (EMT). Histone deacetylases (HDACs) critically enhance HIF-1α signaling by deacetylation, making them a potential therapeutic target for metastasis inhibition.

Methods: We conducted a systematic review of literature from PubMed, Web of Science, and Embase databases; patent data from WIPO PATENTSCOPE, USPTO, and CNIPA (January 2015 to July 2024); and clinical trial data from ClinicalTrials.gov and the Synapse database. Search terms included MeSH keywords: "Histone Deacetylase Inhibitors," "hypoxia," "Epithelial- Mesenchymal Transition," and "Neoplasm Metastasis."

Results: Recent patents demonstrate improved HDAC inhibitor delivery systems and isoformselective compounds, particularly targeting HDAC1/3/6. Clinical data show that HDAC inhibitors reverse EMT markers, such as E-cadherin, in solid tumors, though efficacy varies by cancer type. Mechanistically, HDAC4/6 stabilize HIF-1α through direct deacetylation and Hsp90-P300 regulation, driving hypoxia-induced EMT across multiple cancers. Combination therapies with immunotherapy show promising synergistic effects.

Discussion: HDACs regulate hypoxia-induced EMT through HIF-1α stabilization, with isoform- selective inhibitors showing improved tumor specificity. While effective at reversing EMT markers, responses vary by cancer type, necessitating biomarker-guided approaches. Combination therapies show promise but require monitoring for potential risks of EMT induction.

Conclusion: HDAC inhibition represents a viable strategy against hypoxia-driven metastasis. Future work should optimize selective inhibitors, develop predictive biomarkers, and explore natural compound derivatives to enhance efficacy and reduce toxicity.

Skull base chordoma is a rare, slow-growing primary tumor. Due to its proximity to the brainstem, blood vessels, and nerves, complete surgical resection is challenging. Therefore, postoperative radiotherapy is required to achieve full disease eradication. Compared to photon therapy, proton therapy offers physical dosimetric advantages, ensuring an adequate target dose while minimizing damage to surrounding tissues. Long-term follow-up has confirmed that proton therapy provides survival benefits and enhanced safety in treating skull base chordoma. Consequently, it is considered the standard radiotherapy approach for this condition. However, due to the low incidence of skull base chordoma and the high cost of proton therapy, only a limited number of prospective studies have evaluated its use in this disorder. To date, there is no consensus on proton therapy dosage, fractionation, or target delineation. In this review, we assess the latest advancements and challenges associated with proton therapy for chordomas located at the skull base, aiming to provide a comprehensive understanding of radiotherapy strategies for this disease.

Objective: Oxaliplatin (OXA) is commonly used in combination therapy for patients with advanced hepatocellular carcinoma. While the emergence of acquired resistance dramatically reduces its efficacy. It was previously found that the sensitivity of drug-resistant hepatocellular carcinoma cells to OXA could be enhanced by a synthesized ethyl derivative (patented) of epigallocatechin-3-gallate, and also initially found that the reversal mechanism might be related to the miR-338-3p/HIF-1α/ TWIST pathway. In this study, the function of the miR-338- 3p/HIF-1α / TWIST pathway was investigated in OXA-resistant hepatocellular carcinoma cells, particularly its involvement in reversing chemoresistance mediated by EMT.

Methods: The cell viability, migration, invasion, and epithelial-mesenchymal transition markers of SMMC-7721 and SMMC-7721/OXA cells were measured using the MTT assay, wound healing assay, transwell assay, western blot, and qRT-PCR. The effects of miR-338-3p overexpression were evaluated by transfecting cells with miR-338-3p mimic or negative control mimic.

Results and discussion: The SMMC-7721/OXA cells exhibited an epithelial-mesenchymal transition phenotype, characterized by increased migration and invasion, reduced E-cadherin, and elevated vimentin expression. The miR-338-3p expression was dramatically downregulated in SMMC-7721/OXA cells. Overexpression of miR-338-3p enhanced OXA sensitivity, with the IC50 value of OXA decreasing from 51.23 μM to 19.26 μM, reversed the epithelialmesenchymal transition phenotype, and reduced the expression of hypoxia-inducible factor-1α and twist family bHLH transcription factor 1, key regulators of epithelial-mesenchymal transition. The results indicated that the miR-338-3p regulates epithelial-mesenchymal transition and chemoresistance in OXA-resistant hepatocellular carcinoma cells by targeting hypoxiainducible factor-1α and subsequently down-regulating twist family bHLH transcription factor 1.

Conclusion: This study implies that the resistance of SMMC-7721/OXA cells to OXA is likely related to the acquisition of the EMT phenotype. The up-regulating miR-338-3p could be a new treatment method for over-coming OXA resistance in hepatocellular carcinoma.

Introduction: Muscle-invasive bladder cancer (MIBC) is characterized by high malignancy and poor prognosis. Advances in single-cell RNA sequencing (scRNA-seq) have provided new insights into the molecular heterogeneity and progression of MIBC.

Methods: A single-cell atlas of bladder cancer (BCa) was constructed, and MIBC-related epithelial subclusters (Epi_MIBC) were identified. Key transcription factors and dysregulated cell death pathways were characterized. A prognostic model based on MIBC-related cell death genes (MIBC.CDGs) was developed using machine learning algorithms and validated across multiple cohorts. The functional role and druggability of TOMM7, a core gene, were evaluated through in vitro experiments and molecular docking analysis.

Results: The MIBC-related cell death score (MIBC.CDS) was shown to effectively stratify patient prognosis and predict immunotherapy response. Multiple cell death pathways were found to be activated in MIBC. Knockdown of TOMM7 suppressed proliferation, invasion, and migration in T24 cells, while modulating apoptosis, autophagy, mitophagy, cuproptosis, and ferroptosis. Molecular docking analysis identified sorafenib as a potential TOMM7-targeted therapeutic agent.

Discussion: The findings highlighted the critical role of cell death dysregulation in MIBC progression and underscored TOMM7 as a novel oncogenic regulator. The integration of multiomics data and machine learning enhanced our understanding of tumor biology and provided a foundation for developing personalized treatment strategies.

Conclusion: TOMM7 was found to drive MIBC progression by regulating multiple cell death pathways. The MIBC.CDS may serve as a promising tool for prognostic evaluation and therapeutic stratification. Sorafenib was identified as a potential candidate for TOMM7-targeted therapy in MIBC.

Introduction: This study aimed to investigate the role of ZNF146 in osteosarcoma progression and its potential as a therapeutic target and prognostic biomarker, focusing on its interaction with the HMGB1-NF-κB signaling pathway.

Methods: ZNF146 expression was analyzed in osteosarcoma tissues versus normal tissues using RNA-seq data from the TARGET database and validated in a cohort of 36 patients via RTqPCR, Western blot, and IHC. Functional assays (Transwell, wound healing, colony formation, CCK-8) and molecular analyses (dual-luciferase reporter, ChIP, Western blot) were conducted in MG63 and U2OS cells with ZNF146 modulation. An MG63 xenograft mouse model was used for in vivo validation.

Results: ZNF146 was significantly upregulated in osteosarcoma tissues, correlating with poor patient prognosis (p =0.0307). Functionally, ZNF146 overexpression promoted cell proliferation, migration, and invasion, while its knockdown suppressed these effects. Mechanistically, ZNF146 directly binds to the HMGB1 promoter, thereby enhancing HMGB1 expression and activating the NF-κB pathway, which leads to increased cyclin D1 and MMP9 levels. In vivo, ZNF146 knockdown resulted in reduced tumor growth and Ki-67/PCNA expression.

Discussion: These findings establish ZNF146 as a key oncogenic driver in osteosarcoma via HMGB1-NF-κB signaling. The results align with studies implicating ZNF proteins in tumor progression but highlight a novel mechanism. Limitations include unexplored effects on the tumor microenvironment and the need for validation in larger clinical cohorts.

Conclusion: ZNF146 promotes osteosarcoma progression through HMGB1-mediated NF-κB activation, suggesting its potential as both a prognostic biomarker and a therapeutic target. Inhibition of ZNF146 or HMGB1 may offer novel strategies for osteosarcoma treatment.

Background: The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), contributes to prostate cancer (PCa) metastasis, however, the role of CAF heterogeneity remains incompletely characterized. The study aims to identify and functionally characterize a metastasis-competent CAF subpopulation in PCa and evaluate its potential as a biomarker for predicting metastatic progression.

Methods: We integrated single-cell RNA sequencing data from 1,214 CAFs across 14 PCa specimens. Metastasis-derived CAFs were functionally validated in vitro. Stromal marker expression was assessed by multiplex immunofluorescence in 78 PCa tissues samples.

Results: A 20-gene signature stratified CAFs into three subsets, with the MFAP5-expressing subset (CAFa) enriched in metastatic patients. Co-expression of MFAP5 and THY1 specifically identified CAFa with 96.2% specificity. MFAP5 secretion was associated with AKT phosphorylation, Slug upregulation, and epithelial-mesenchymal transition (EMT). Stromal MFAP5⁷THY1⁷ colocalization predicted postoperative metastasis risk independently of Gleason score (multivariate HR = 5.69, p < 0.001).

Discussion: Our findings establish stromal MFAP5⁷THY1⁷ co-localization as a potential prognostic biomarker that could complement Gleason scoring. Further validation in multi-center cohorts is required to confirm its clinical independence.

Conclusion: We identified a metastasis-competent CAF subpopulation defined by MFAP5⁷THY1⁷ co-expression, where THY1 serves as a spatial anchor for MFAP5 detection and MFAP5 secretion is functionally linked to AKT/EMT pathway activation.

Introduction: CAR-T technology represents a state-of-the-art approach in cancer treatment. This study constructs a multi-dimensional framework for analyzing the technological trajectory to comprehensively clarify the evolution trend of CAR-T technology in cancer treatment.

Methods: Based on relevant patent data, three methodologies were applied: MPA (to identify dominant technological pathways), Word2Vec (to convert textual content into semantic vectors), and PCA-Kmeans (for dimensionality reduction and clustering). These methods facilitated the construction of one comprehensive technological trajectory and three supplementary trajectories.

Results: The comprehensive technological trajectory exhibits a linear evolutionary trend. In its early stages, the focus was primarily on optimizing the CAR signal transduction domain. Recently, patent technologies have predominantly focused on T-cell modification and expansion, as well as the identification of multiple target antigens. Future research is expected to emphasize the co-expression of antigen targets with immune checkpoint inhibitors. Additionally, the supplementary technology trajectories suggest that refining the CAR-T regulatory mechanism, coexpressing GPX4 to enhance cellular anti-apoptotic capabilities, and expanding investigations into NKG2D targets may represent critical strategies for addressing the high costs and limited long-term persistence associated with CAR-T technology.

Discussion: Systematic guidance is provided for formulating CAR-T technology patent strategies, and limitations in the current multi-dimensional analysis framework-such as data sources, indication analysis, and modeling methods-are highlighted, necessitating further optimization through integration with clinical data and advanced algorithms.

Conclusion: A systematic technical synthesis is provided for both academic investigations and enterprise R&D, revealing the intrinsic patterns and potential advancements in the technological evolution of the field.

Introduction: Preliminary investigations into the feasibility of Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase (CAD)-targeted therapies have been conducted in a limited range of cancer types in pre-clinical studies. A comprehensive exploration of the diagnostic and prognostic capabilities of CAD, along with an understanding of its underlying biological mechanisms, is needed.

Methods: A range of bioinformatics tools was employed to produce an extensive pan-cancer analysis of CAD expression. Experimental validation of the role of CAD in enzalutamide resistance in prostate cells was conducted. The molecular classification and drug patents of CAD were reviewed using the Worldwide Espacenet ®.

Results: Our study revealed that CAD was upregulated in tumor tissues in most cancer types. The expression of CAD was significantly different in clinical stages, pathological grades, and clinical prognosis. The highest frequency of CAD mutation was shown, but CAD mutations did not affect the clinical outcome of cancer patients. Comprehensive data across different cancer types illustrate the relationship between the expression of CAD and tumor mutation burden (TMB), microsatellite instability (MSI), and homologous recombination deficiency (HRD). Immune infiltration algorithms showed a positive link between CAD level and the prevalence of tumor-associated fibroblasts, MDSC, mast cells, and CD4+T cells. CAD level was positively linked to the immune checkpoint, suggesting a potential synergistic effect between CAD and immunotherapy. The GSEA analysis revealed that CAD expression is significantly associated with angiogenesis and epithelial-mesenchymal transition (EMT) pathways. Finally, we demonstrated that knockdown of CAD inhibits the growth of prostate cancer (PCa) cells and resistance to enzalutamide.

Conclusion: This study revealed the diagnostic and prognostic potential of CAD. Notably, CAD exhibits essential functions in PCa cell proliferation and enzalutamide resistance.