Current cancer drug targets最新文献

Dysregulation of signaling pathways facilitated by the RB1 tumor suppressor gene or the MYC family of oncogenes is often observed in various malignancies. Identifying drug targets for such cancers is challenging, as RB1 mutations are typically loss-of-function alterations, while MYCN is difficult to target pharmacologically due to its intrinsically disordered structure. Recent studies, including our own investigations in retinoblastoma, have emphasized the potential of targeting aurora kinases (AURKs), specifically aurora kinase A (AURKA) and aurora kinase B (AURKB), as favourable therapeutic strategies for cancers driven by dysregulation of pRB and/or MYCN. In this review, we discuss the rationale for targeting AURKs as a treatment strategy and their functional roles. In addition, we review the status of AURKA-specific inhibitors in clinical evaluation and their associated adverse effects. Finally, we cite the emerging therapeutic strategy of proteolysis targeting chimeras (PROTACs) as an innovative means to selectively degrade AURKs, offering a novel approach to targeted cancer therapy.

Liver cancer currently stands as the leading cause of cancer-related mortality worldwide, with Hepatocellular Carcinoma (HCC) accounting for approximately 90% of all cases, making it the most prevalent and clinically significant form of primary liver cancer. First-line treatments typically include sorafenib, lenvatinib, or immunotherapies such as immune checkpoint inhibitors. However, drug resistance and treatment-associated toxicities have significantly limited the overall effectiveness of these therapeutic approaches, contributing to persistently high mortality rates despite medical advances. Unfortunately, alternative interventions such as transarterial chemoembolization and ablation are often not feasible due to the advanced stage at which the disease is usually diagnosed, thereby restricting the applicability of localized or surgical approaches with curative potential. Recent literature has increasingly highlighted the urgent need to develop innovative therapeutic strategies that focus on targeting alternative signaling pathways and exploring novel drug candidates capable of overcoming well-established resistance mechanisms. In this context, our study presents a comprehensive analysis of key kinase targets associated with HCC that have been under clinical investigation over the past decade, emphasizing molecular mechanisms involved in tumor progression, angiogenesis, metabolic dysregulation, and immune evasion. Our findings indicate promising advances, particularly in the development of next-generation multikinase inhibitors and in combining targeted therapies with immunotherapy, which have already demonstrated the potential to significantly improve clinical responses, extend survival outcomes, and reduce adverse effects. These findings underscore the importance of adopting personalized, tumor biology-based strategies and highlight a clear perspective that kinase-targeted therapies represent a promising direction for the future of HCC treatment.

Tumor cells preferentially engage in aerobic glycolysis (the Warburg effect) despite normoxic conditions, manifesting in pathological glucose avidity and excessive lactate accu-mulation relative to adjacent normal tissues. Beyond serving as a glycolytic endpoint, lactate acts as a versatile oncometabolite. It epigenetically reinforces multidrug resistance by remod-eling the extracellular microenvironment and driving transcriptional reprogramming via intra-cellular lactylation. Mechanistic studies reveal that lactate-mediated chemoresistance arises from stabilization of DNA repair machineries and metabolic adaptation pathways. This review synthesizes current understanding of lactate/lactylation-mediated therapeutic resistance mech-anisms across solid tumors, while proposing actionable targets within lactate metabolic cir-cuitry. Pharmacological disruption of lactate homeostasis coupled with lactylation modulation may reverse tumor adaptive resilience and resensitize refractory cancers to conventional ther-apeutics.

Introduction: Breast cancer is one of the most prevalent malignancies in women globally, characterized by diverse histological and molecular subtypes, each with varying clinical outcomes. Understanding these subtypes and their associated risk factors is critical for accurate diagnosis, prognosis, and treatment planning.

Methodology: The study scrutinized 187 breast cancer (BC) patients from Hail region of Saudi Arabia, focusing on ABO blood group distribution, histological type, cancer subtype, metastases size, age distribution, body mass index (BMI), gestational diabetes mellitus (GDM) status, and biochemical markers, including plasma calcium, magnesium, and HBA1C levels.

Results: Blood group distribution showed O+ (50.27%) as the most common blood type, followed by A+ (14.97%) and B+ (11.2%). Histologically, Invasive Ductal Carcinoma (IDC) accounts for 64.1% (120) cases, while Triple Negative Breast Cancer (TNBC) con-stitutes 17.1% (32) cases. The most common metastatic sites are the lungs (25.1%) and ax-illary lymph nodes (17.6%). HER2-positive breast cancer, seen in 9.1% of cases, can lead to multi-organ metastases in some cases. Age distribution indicated most patients were 46-55 years old (50 cases), while BMI data exhibited the highest frequency in the obese cate-gory (~90 cases), with 12 having GDM and 177 not having GDM. Calcium levels across age groups slightly fell below the typical adult range (2.1-2.6 mmol/L) with an average of around 2.06 mmol/L. Magnesium levels were elevated in patients less than 35 years of age (7.02 mmol/L) and were low in other groups. HbA1C levels in all age groups ranged from 6.44 to 6.67 mg/dL, aligning with prediabetic or diabetic thresholds. Plasma calcium and magnesium levels were elevated in the weight category, showing slight deviations from the normal range. Underweight patients displayed the lowest HbA1C levels with all weight cat-egories exceeding 6.5 mg/dL, indicating diabetes.

Conclusion: The results highlight IDC as a predominant BC type, with O+ as the most common blood group among patients. TNBC remains a treatment challenge due to a lack of hormone receptors. Metastases mainly affect the lungs and lymph nodes. Elevated BMI, calcium, and magnesium levels correlate with increased HbA1C, suggesting a diabetic link. Emphasizing personalized treatment, obesity management, and electrolyte monitoring., the present research advocates a holistic approach for improved BC outcomes and suggests fu-ture exploration of metabolic influences.

Background: Molecular subtyping guides bladder cancer (BCa) care but typically requires RNA profiling. This study aimed to develop pathology-based subtypes of BCa using pathology deep learning features derived from routinely obtained hematoxylin and eosin (H&E)-stained whole-slide images (WSIs).

Methods: We developed a pathology-based subtype of BCa based on deep learning features extracted from H&E-stained WSIs. A modified Net50 model was trained to distinguish between tumor and normal regions and extract patch-level deep features. These features were aggregated at the WSI level, followed by weighted gene co-expression network analysis (WGCNA), Cox regression, and unsupervised K-means clustering to define pathology-based subtypes. External validation was performed using WSIs from four independent centers and transcriptomic data from IMvigor210 and GSE32894 cohorts. Interpretability used Grad-CAM on tumor patches.

Results: The Resnet50 model achieved high and consistent performance in distinguishing tumor and normal patches. The analysis identified four BCa subtypes, with distinct clinical outcomes. Clusters 2/3 were predominantly luminal-like (cluster 3 was enriched for FGFR3 and had the lowest TMB), whereas clusters 0/1 exhibited mixed luminal/basal features with higher immune/stromal scores; regulon and pathway profiles diverged (e.g., EGFR/FOXM1/STAT3 in cluster 1 vs. FGFR3/FOXA1/PPARG in cluster 3). Grad-CAM highlighted distinct nuclear morphologies supporting interpretability.

Conclusion: We present a pathology-based subtype of BCa that is portable, prognostically informative, and mechanistically concordant with RNA-defined biology. The approach offers a cost-effective and accessible alternative to traditional molecular profiling methods, with potential applications in personalized treatment and improved patient stratification.

Introduction: Adrenocortical Carcinoma (ACC) is regarded as an aggressive endocrine malignant tumor. The understanding of ACC tumorigenesis is still incomplete. This study aims to identify candidate tumor mutation burden (TMB)-related prognostic genes and explored the potential molecular mechanism of ACC based on comprehensive bioinformatic methods.

Methods: Single-nucleotide variations and transcriptome data were downloaded from the TCGA database. TMB scores were calculated using single-nucleotide variation data, and then, the correlation of TMB with tumor immune microenvironment, clinicopathologic characteristics, and PD-L1 expression level was explored. Differentially Expressed Genes (DEGs), ranging from high and low TMB scores, were identified. Weighted Gene Co-expression Network Analysis (WGCNA), Protein-Protein Interaction (PPI) networks, and Kaplan-Meier survival analysis were used to screen candidate TMB-related prognostic genes. Preliminary experimental verification of ASPM and KIF11 in ACC tumorigenesis was conducted.

Results: Patients with high TMB had worse OS, DSS, PFS, advanced pathological stage, lower PD-L1 expression level, lower stromal score, lower immune score, and higher tumor purity score. Seven ninety-seven DEGs in all between the high and low TMB groups were identified, including 203 downregulated DEGs and 594 upregulated DEGs. Functional enrichment analysis suggested that these DEGs might participate in cell division and cell cycle regulation. Furthermore, WGCNA analysis identified the turquoise module as the most significantly associated module with TMB. After screening with the PPI network and validating using survival analysis, a total of eight candidate TMB-related prognostic genes for ACC patients were finally identified, including ASPM, BIRC5, BUB1, CDC20, CDCA5, CEP55, KIF11, and TPX2. Preliminary experimental verification revealed that ASPM and KIF11 could promote the proliferation of ACC cells and the tumor growth of mice.

Discussion: ASPM and KIF11, identified as key TMB-related prognostic genes, promoted proliferation and inhibited apoptosis of ACC cells. This functional role revealed their significant potential as novel therapeutic targets for ACC.

Conclusion: A total of eight candidate TMB-related prognostic genes (including ASPM, BIRC5, BUB1, CDC20, CDCA5, CEP55, KIF11, and TPX2) for ACC patients were identified. Preliminary experimental verification revealed that ASPM and KIF11 could promote the proliferation of ACC cells and ACC tumor growth in vivo.

Introduction: The changing landscape of hepatocellular carcinoma detection and treatment is examined in this study, focusing on recent advancements in therapeutic methods across several stages. Early identification of hepatocellular cancer cells continues to pose a serious threat to human health and is of utmost significance. It is crucial to create a useful signature to diagnose hepatocellular carcinoma early.

Methods: Chemotherapy and immunotherapy are high-stage treatment options for hepatocellular cancer. These treatments can be coupled with nanotechnology to increase effectiveness and minimize adverse effects. Furthermore, immunotherapy and chemotherapy might be combined to increase therapeutic efficacy and overcome resistance. Artificial intelligence technologies have the potential to significantly enhance hepatocellular carcinoma diagnosis and management.

Results: Numerous models performed as well as or better than experienced radiologists while indicating the ability to improve radiologists' accuracy, showing encouraging outcomes for applying Artificial Intelligence to hepatocellular carcinoma-related diagnostic tasks.

Discussion: Treatment for hepatocellular carcinoma has changed dramatically, moving from traditional techniques to cutting-edge technologies. Precision in diagnosis, prognosis, and treatment has increased due to innovations like molecular diagnostics, tailored medicines, and nanotechnology. This change improves patient outcomes and presents encouraging avenues for future research and treatment of hepatocellular cancer.

Conclusion: Recent advances in imaging techniques, biomarkers, and personalized medicine approaches have improved diagnostic accuracy and treatment outcomes. The emergence of immunotherapy, targeted therapies, and combination regimens has expanded treatment options, offering new hope for patients with advanced disease.

Introduction: Metastases frequently occur in patients with colorectal cancer, resulting in a higher death rate. The study aimed to evaluate the mechanism by which Ti-mosaponin AIII affects colorectal cancer metastases.

Methods: Different concentrations of Timosaponin AIII were used to treat colorectal cancer cell lines. The CCK8 assay was used to evaluate how Timosaponin AIII affected cell viability. Transwell chamber assays were employed to evaluate the impact of the treatment on the migratory and invasive abilities of colorectal cancer cells. The influence of Timosaponin AIII on apoptosis was detected through flow cytometry, and western blot, PCR, and immunofluorescence staining were utilized to assess its effect on the expression of proteins. The effect of Timosaponin AIII on tumor growth was studied by using xenograft tumor models.

Results: In this study, we observed that, in comparison with the control group, Timosaponin AIII could inhibit the proliferation, migration, and invasive capabilities of colorectal cancer cell lines and promote the process of apoptosis. Timosaponin AIII is capable of enhancing the phosphorylation levels of PI3K, AKT, and mTOR, as well as increasing E - E-cadherin while decreasing N - N-cadherin, Vimentin, Snail, and Slug, thereby inhibiting the epithelial-mesenchymal transition process.

Discussion: The present study has limitations, as the mechanistic investigations were mainly conducted at the cellular level. Future studies should validate the molecular mechanisms through animal models.

Conclusions: Timosaponin AIII restrains the activation of the PI3K-AKT-mTOR signal pathway, thereby regulating the EMT process to suppress metastases of colorectal cancer cell lines. This research provides a critical foundation for the clinical application of Ti-mosaponin AIII in colorectal cancer treatment.

Introduction: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the Philadelphia chromosome. Imatinib is considered the standard therapy for CML due to its targeted action against the BCR::ABL1 tyrosine kinase. However, resistance to imatinib often emerges, particularly in the advanced stages of CML. One factor associated with imatinib resistance is the overexpression of survivin (baculoviral IAP repeat-containing 5, BIRC5). YM155 is an innovative survivin inhibitor that suppresses survivin expression and triggers apoptosis. Combination therapy is a strategy used to enhance the effectiveness of cancer treatment and overcome resistance.

Methods: Our study explored the in vitro anticancer effects of YM155 as monotherapy and as a combination therapy with imatinib on imatinib-sensitive (K-562) and imatinib-resistant (K562-r) BCR::ABL1+ CML cell lines.

Results: Survivin inhibition significantly reduced pro-liferation in both K-562 and K562-r cells. Combination therapy with YM155 and imatinib produced a synergistic effect. In K562-r cells (imatinib IC50 = 6 μM), the combination reduced the IC50 by 6.2-fold. In K-562 cells, the IC50 decreased by 16.3-fold. Both monotherapy and combination therapy markedly increased apoptosis, with combination therapy inducing significantly greater apoptosis. The combination also downregulated survivin and BCR::ABL1 tyrosine kinase expression and significantly reduced BCR::ABL1 mRNA levels.

Conclusion: YM155 enhances imatinib's efficacy against both sensitive and resistant CML cells, overcoming resistance through synergistic inhibition of proliferation, increased apoptosis, and suppression of survivin and BCR::ABL1 expression. These results support further investigation of YM155-Imatinib combination therapy as a potential strategy for resistant CML.