Anti-Cancer Drugs最新文献

Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.

Tumor heterogeneity represents a significant challenge in cancer treatment. Current therapeutic strategies frequently rely on single biopsy assessments that may not fully capture tumor complexity. In this study, we developed prostate patient-derived organoids (PDOs) from a mantle cell lymphoma (MCL) case with prostatic metastasis. Monotherapy experiments revealed that the prostate organoids were sensitive to gemcitabine but resistant to rituximab and oxaliplatin. In combination therapy experiments, the half maximal inhibitory concentration value of gemcitabine increased, indicating that the combination regimen may attenuate its efficacy. In addition, the expression of prostate cancer markers prostate-specific membrane antigen and ETS-related gene was detected in the organoids. The research findings indicate that the PDO model not only dynamically monitors changes in drug sensitivity caused by heterogeneity but also serves as a powerful tool for predicting drug responses and optimizing precision treatment strategies. This is particularly applicable to clinical decision-making for highly heterogeneous tumors like MCL.

In metastatic castration-resistant prostate cancer (mCRPC), several treatments are available, including androgen-receptor pathway inhibitors (ARPis) and chemotherapy (CT). There is a lack of real-world prospective data on treatment sequences and survival. The aim of the study was to evaluate overall survival (OS) in real-world conditions for patients treated for mCRPC. The OPALE study is a French prospective observational multicentre study. We included between 2018 and 2023, 212 patients undergoing first or second-line treatment for mCRPC. The primary outcome was the median OS, defined as the time between mCRPC diagnosis and death from any cause. The key secondary endpoints included OS according to therapeutic sequences, progression-free survival, response, and toxicities. Survival analysis was estimated using the Kaplan-Meier method and compared using the log-rank test. Associations between treatments and survival were assessed using Cox models. The 212 patients received first-line treatment (L1), 130 second-line (L2), 85 third-line (L3), and 51 fourth-line (L4). Most patients received ARPis in L1 (85.8%) and then chemotherapy in L2 (56.2%) and L3 (55.3%). The mean duration of follow-up was 31.8 months. Median OS was 46.4 months [95% confidence interval (CI): 35.9-53.8]. Our data did not significantly demonstrate the superiority of one therapeutic sequence over the others. Limitations are the observational design and the lack of statistical power. The OPALE study provided valuable data on the real-life management of mCRPC, contributing to a better understanding of current practice. We did not identify any optimal regimen, reflecting the evolution of knowledge and recent recommendations.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with central nervous system gliomas, most frequently optic pathway gliomas; however, oligodendrogliomas in the setting of NF1 are exceedingly rare, with no prior documented cases and no established treatment strategies to date. A 53-year-old female with NF1-associated oligodendroglioma experienced multiple recurrences following surgery, radiotherapy, chemotherapy, and targeted therapy. Upon further disease progression, she was treated with a novel combination of thiotepa, bevacizumab, teniposide, and the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor tunlametinib. After one treatment cycle, the patient achieved a marked reduction in tumor volume, consistent with a complete response (CR). She subsequently completed eight additional cycles of the regimen and has maintained CR. The treatment was well-tolerated, with manageable grade 3 myelosuppression controlled by supportive care. As of June 2025, the patient has achieved a CR with a progression-free survival of 9 months before experiencing disease recurrence. This rare case of NF1-associated oligodendroglioma was managed with thiotepa, bevacizumab, teniposide, and tunlametinib, highlighting the potential of MEK inhibition in NF1-related gliomas.

Dual HER2 blockade with trastuzumab and pertuzumab in combination with chemotherapy has improved pathological complete response (pCR) rates in HER2-positive breast cancer in randomized trials. However, real-world pilot data on locoregional and symptomatic outcomes in patients receiving this regimen before surgery are limited. This was a prospective pilot study including 20 patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab, pertuzumab, and chemotherapy. Patients were assessed clinically and radiologically at baseline and following completion of neoadjuvant therapy. Primary endpoints were locoregional response (tumor shrinkage, nodal downstaging, and operability) and symptomatic improvement (pain, heaviness, and nipple/skin changes). All patients subsequently underwent definitive surgery. Median age was 46 years (range 32-65). Most patients presented with locally advanced disease, and 70% had palpable axillary nodes. Following neoadjuvant therapy, the overall clinical response rate was 85%, with 25% achieving complete clinical response and 60% partial response. Median tumor reduction was approximately 50%. Nodal downstaging was seen in 60%, with complete nodal response in 30%. Symptomatic improvement was reported in 80% for pain, 70% for heaviness, and 60% for skin/nipple changes. All patients proceeded to surgery, and pCR was achieved in 25%. The regimen was well tolerated, with no major cardiac events or treatment-related mortality. Neoadjuvant dual HER2 blockade with chemotherapy is feasible in HER2-positive breast cancer, achieving high clinical response rates, meaningful symptomatic improvement, and acceptable safety in this pilot study. These findings provide early single-center, prospective pilot evidence supporting dual HER2-targeted neoadjuvant therapy, with implications for operability and patient-centered outcomes. Larger multicentre studies are needed to validate these results.

This study aims to assess the effects of combined amlexanox and an antimonocyte chemoattractant protein-1 (MCP-1) mAb therapy in a murine Lewis lung carcinoma (LLC) model. A subcutaneous LLC model was established in mice, which were allocated to either a control group or an intervention group receiving combined amlexanox and anti-MCP-1 mAb. Tumor size was monitored regularly. Immunofluorescence staining was performed to detect MCP-1 and Ki67 expression. Western blot analysis was conducted to assess the expression of TANK-binding kinase 1 (TBK1), macrophage polarization markers (iNOS and arginase-1), and apoptosis-related proteins (MCL-1, Bcl-xL, and Bcl-2). Flow cytometry was employed to quantify macrophage phenotype distributions. TBK1 expression was significantly elevated in LLC tumor tissues. MCP-1 was found to colocalize with the M2 macrophage marker CD206. The combination therapy resulted in a significant reduction in Ki67 expression. arginase-1 expression decreased significantly, while iNOS expression indicated an upward trend, though the change was not statistically significant. Levels of the antiapoptotic proteins MCL-1 and Bcl-xL were significantly downregulated ( P  < 0.05), whereas Bcl-2 levels did not differ significantly from those in the control group ( P  > 0.05). Flow cytometric analysis indicated a significant decrease in M2 macrophages (F4/80+CD206+) in the intervention group, with no substantial change observed in the proportion of M1 macrophages (F4/80+CD86+). Combined administration of amlexanox and anti-MCP-1 mAb inhibited tumor cell proliferation, promoted apoptosis, and reduced infiltration of tumor-associated M2 macrophages, thereby contributing to suppression of tumor progression in the LLC murine model.

In this meta-analysis study, the effect of valproate (VPA) and levetiracetam (LEV) on the survival of glioma patients taking temozolomide (TMZ) was investigated. The cumulative hazard ratios (HR) of overall survival (OS) and progression-free survival from published clinical studies were determined using a random effects model to estimate the strength of the association between VPA/LEV and survival in glioma patients. The results showed that VPA (data from 2304 patients from 14 clinical trial studies) and LEV (data from 1610 patients from 11 clinical trial studies) increase OS by 20% [HR = 0.80; 95% confidence interval (CI), 0.69-0.94; P  = 0.01] and 18% (HR = 0.82; 95% CI, 0.68-0.98; P  = 0.03), respectively. Use of VPA and LEV as anticonvulsant drugs increased the OS of patients with glioma taking TMZ to an almost equal extent. These findings need to be confirmed in larger prospective studies.

The circadian clock governs daily rhythms in numerous physiological processes through precise regulation of gene expression and biochemical functions. Dysregulation of the circadian rhythm has been implicated in carcinogenesis and cancer progression. However, the mechanisms by which the circadian clock influences cancer phenotype and chemotherapy resistance, particularly in cholangiocarcinoma (CCA), remain poorly understood. Using cell lines established from primary CCA and metastatic ascites of two male patients, we manipulated core clock genes ( BMAL1 , PER2 , and NR1D1 ) to evaluate their effects on circadian rhythms. We analyzed alterations in circadian phenotypes at dynamic and single time points and assessed their impact on cancer-related phenotypic changes, including proliferation, apoptosis, cell cycle regulation, migration, invasion, and the expression of epithelial-to-mesenchymal transition (EMT) and cancer stem cell markers. Additionally, we examined the impact of circadian disruption on gemcitabine sensitivity. Genetic deletion of BMAL1 , PER2 , and NR1D1 disrupted circadian rhythm and significantly altered cancer phenotypes. Notably, BMAL1 and NR1D1 impairment exacerbated cell migration, invasion, and EMT activation in CCA cells. BMAL1 loss also induced gemcitabine resistance. In contrast, PER2 repression enhanced chemosensitivity and inhibited metastasis. The modulation of the circadian gene triggered phenotypic changes in CCA cells, indicating a crucial involvement of core-clock components in the pathological mechanisms hastening bile duct cancer malignancy. Our findings advance the understanding of regulating CCA malignancy and may offer a novel target for its treatment.

Leptomeningeal metastasis (LM), a devastating complication of advanced nonsmall cell lung cancer (NSCLC), severely compromises patient survival and quality of life. Currently, standardized diagnostic criteria and treatment protocols for NSCLC-associated LM remain undefined, posing significant clinical challenges. Here, we present a case of a 58-year-old female with advanced epidermal growth factor receptor (EGFR)-mutated (exon 19 deletion) lung adenocarcinoma who developed LM after failing first-line gefitinib therapy. Initial treatment with osimertinib (80 mg/day), a third-generation EGFR-tyrosine kinase inhibitor (TKI), achieved 8 months of disease control before LM progression. Cerebrospinal fluid genomic analysis revealed acquired EGFR mutations (exon19 L747-A750delins and exon18 L718Q). Combination therapy with intrathecal pemetrexed and standard-dose osimertinib temporarily alleviated neurological symptoms. Upon disease recurrence after 6 months, therapeutic intensification through increased intrathecal pemetrexed frequency and high-dose osimertinib (160 mg/day) resulted in sustained neurological improvement and prolonged survival with manageable toxicity. This case demonstrates the potential of optimized intrathecal/systemic TKI combination strategies for EGFR-mutant NSCLC with LM, providing clinical insights for this therapeutic dilemma.