Anti-Cancer Drugs最新文献

Eugenol plays a significant role in various cancers and can influence the sensitivity of cancer cells to chemotherapy. This study aimed to investigate the mechanism by which eugenol regulates glycolysis through the tripartite motif containing 59 (TRIM59)/extracellular signal-regulated kinase (ERK) pathway in osimertinib-resistant non-small cell lung cancer (NSCLC). Drug-resistant lung cancer cell lines were established using osimertinib and treated with eugenol at different concentrations for 24 h. After treatment with eugenol, siTRIM59, TRIM59 overexpression, and the ERK inhibitor, either alone or in combination, the cell counting kit-8 was used to assess cell viability in drug-resistant cell lines. Flow cytometry, colony formation assay, and transwell assays were employed to evaluate the effects of eugenol on cell apoptosis, clonogenic ability, migration, and invasion, respectively. Relevant kits were used to measure the glycolytic activity of the cells. Eugenol inhibited the proliferation, invasion, and migration of drug-resistant cells, promoted apoptosis, and reduced glucose consumption, lactate release, and glycolytic activity in drug-resistant cells. TRIM59 expression was higher in drug-resistant cancer cells, while eugenol treatment inhibited the expression of TRIM59 and ERK phosphorylation. Silencing of TRIM59 enhanced the effect of eugenol on drug-resistant cell lines. Overexpression of TRIM59 reversed the effects of eugenol on drug-resistant cell lines, whereas ERK inhibition reversed the effects of TRIM59 and enhanced the therapeutic effects of eugenol on cancer cells. Moreover, eugenol inhibited the tumor growth, TRIM59 expression, and ERK phosphorylation in osimertinib-treated mice. Eugenol can effectively overcome osimertinib resistance in NSCLC by regulating glycolysis through the TRIM59/ERK signaling pathway. Eugenol could serve as a promising adjunctive therapy to improve chemotherapy efficacy and overcome drug resistance in NSCLC.

Immune checkpoint inhibitors (ICIs) are a standard treatment for advanced non-small-cell lung cancer (NSCLC), but limited data exist regarding their use in patients with HIV-positive. This study evaluated the efficacy and safety of ICI-based therapy in this population. In this single-center, comparative study, 18 patients with treatment-naive advanced NSCLC with HIV (experimental group) and 40 HIV-negative controls (control group) received 4-6 cycles of tislelizumab plus platinum-based chemotherapy, followed by tislelizumab maintenance until disease progression or unacceptable toxicity. A higher incidence of tuberculosis was observed in the experimental group compared with the control group (33.3 vs. 20.0%). The objective response rate was 77.8% [95% confidence interval (CI): 56.5-99.1] in the experimental group and 77.5% (95% CI: 64-91) in the control group ( P  = 0.981). The 6-month progression-free survival rate was 83.3% (95% CI: 64.3-99.9) for the experimental group and 82.5% (95% CI: 70.2-94.8) for the control group ( P  = 0.227). The 6-month overall survival rate was 88.9% (95% CI: 72.8-99.9) in the experimental group and 97.5% (95% CI: 92.4-99.9) in the control group ( P  = 0.192). The incidences of grade 3 or higher adverse events were 38.9 and 32.5% in the experimental and control groups, respectively. One patient in the experimental group died due to a serious opportunistic infection. Immunotherapy combined with chemotherapy showed comparable efficacy and safety in patients with advanced NSCLC irrespective of HIV status. Patients with HIV-positive had a higher tendency for opportunistic infections, including tuberculosis.

Multiple myeloma, a hematologic malignancy characterized by the uncontrolled proliferation of plasma cells, presents a significant therapeutic challenge, particularly due to the development of resistance to bortezomib, a cornerstone in its treatment. The prostaglandin E receptor 4 (PTGER4 or EP4), a component of the prostaglandin E2 signaling pathway, has emerged as a potential modulator of drug resistance. However, its precise mechanistic role in multiple myeloma remains inadequately understood. This study aims to elucidate the role of EP4 in bortezomib resistance, specifically focusing on its interaction with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. We employed a comprehensive approach that integrates bioinformatics analysis of multiple myeloma-related genes from public databases with advanced molecular biology techniques. Our investigation examined EP4 expression in both bortezomib-resistant and bortezomib-sensitive multiple myeloma cell lines. The impacts of EP4 overexpression on various cellular processes, including proliferation, apoptosis, endoplasmic reticulum (ER) stress, and bortezomib sensitivity, were examined. Both in vitro and in vivo experiments were conducted to delineate the role of EP4 in modulating the PI3K/AKT pathway and its downstream effects on drug resistance. Our findings revealed a significant decrease in EP4 expression in multiple myeloma tissues, with important implications for patient survival and prognosis. Overexpression of EP4 in bortezomib-resistant cell lines enhanced their sensitivity to the drug, inhibited cell growth, and induced apoptosis. These effects were accompanied by decreased phosphorylation of PI3K and AKT, along with increased expression of glucose-regulated protein 78 000, an indicator of ER stress. Notably, these effects were partially reversed when combined with treatment using an AKT agonist. EP4 plays a significant role in modulating bortezomib resistance in multiple myeloma through its effects on the PI3K/AKT pathway and ER stress. These findings underscore the therapeutic potential of targeting EP4 to enhance bortezomib efficacy and improve clinical outcomes for patients with multiple myeloma.

The standard treatment for advanced ovarian cancer follows a comprehensive 'surgery-chemotherapy-maintenance therapy' mode, typically involving initial cytoreductive surgery aiming for R0 resection, six cycles of platinum-based chemotherapy, followed by maintenance therapy for those who have responded well to the treatment. However, frailty and high incidence of comorbidities in elderly patients often compromise surgical outcomes, necessitate chemotherapy dose reductions, and limit maintenance therapy continuation, resulting in a poor prognosis. Poly (Adenosine diphosphate (ADP)-ribose) polymerase inhibitors (PARPi) have revolutionized the management strategy of homologous recombination deficiency (HRD)-positive patients as a groundbreaking advancement in first-line maintenance therapy. Fluzoparib, the domestically developed PARPi in China, has demonstrated significant efficacy in BRCA-mutated ovarian cancer. In the field of supportive care, megestrol acetate (MA) is recommended as the first-line preferred therapeutic agent for cancer-related anorexia by major guidelines, though its role in first-line ovarian cancer therapy remains unexplored, and evidence for its combination with PARPi is lacking. This article reported a case of an 89-year-old female patient with high-grade serous ovarian carcinoma. Due to intolerance to surgery and chemotherapy, an innovative first-line primary treatment regimen combining fluzoparib with MA was initiated based on BRCA2 mutation and HRD-positive status. Imaging assessments revealed significant tumor reduction without disease progression or grade ≥3 adverse events observed throughout follow-up. This case highlights the potential of combining PARPi and hormone therapy as a 'chemotherapy-free' precision treatment model for elderly and HRD-positive ovarian cancer patients, offering a promising strategy to balance efficacy and tolerability in a population traditionally underserved by conventional regimens.

This study compared the efficacy and safety of S-1 + oxaliplatin (SOX) plus sintilimab, albumin-bound paclitaxel + oxaliplatin (P-SOX), and docetaxel + oxaliplatin + 5-fluorouracil (DOF) as neoadjuvant regimens for advanced gastric cancer. We retrospectively analyzed 289 patients who received neoadjuvant and adjuvant chemotherapy followed by standard D2 radical gastrectomy (SOX + sintilimab, n  = 81; P-SOX, n  = 128; DOF, n  = 80). Patients were randomly divided 7 : 3 into training and validation sets. Short-term efficacy, long-term outcomes, and adverse events were evaluated, and predictors of progression-free survival (PFS) were explored. The objective response rate of SOX + sintilimab was 91.36% by tumor regression grade (TRG) and 70.37% by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), numerically higher than P-SOX (88.38 and 59.20%) and DOF (86.25 and 57.50%) without significance (TRG, P  = 0.587; RECIST 1.1, P  = 0.178). Median overall survival (OS) was 32 months [95% confidence interval (CI): 30.00-not reached] with SOX + sintilimab, superior to P-SOX (28 months; 95% CI: 26.00-31.00) and DOF (26 months; 95% CI: 23.00- 32.00) ( P  = 0.007). Median PFS was 30 months (95% CI: 27.00-33.00) for SOX + sintilimab, 25 months (95% CI: 22.00-26.00) for P-SOX, and 22.5 months (95% CI: 19.00-26.00) for DOF ( P  = 0.096). Common adverse events included grade 1-2 gastrointestinal reactions, peripheral neurotoxicity, and alopecia, with good tolerability. SOX plus sintilimab achieved the most favorable OS with comparable safety.

Lenvatinib, a multiple-receptor tyrosine kinase inhibitor, has gained recent approval for its use as a first-line treatment of hepatocellular carcinoma (HCC). While lenvatinib demonstrates notable therapeutic efficacy, the drug resistance undermines its sustained tumor control potential. The restricted clinical utility of lenvatinib underscores the imperative necessity to elucidate the mechanisms underpinning drug resistance. We established lenvatinib-resistant cell lines and investigated the changes in their biological characteristics. Next-generation sequencing was performed to identify genes associated with lenvatinib resistance. Western blots were utilized to confirm the involvement of these genes. Using lentiviral technology, we generated cell lines with lowered nuclear receptor coactivator 5 (NCOA5), a pivotal drug resistance-related gene, to explore the underlying resistance mechanism. Moreover, we developed a subcutaneous HCC xenograft tumor model to explore strategies for reversing drug resistance. Our study showed that HCC cells acquire resistance to lenvatinib through the activation of NCOA5, thereby stimulating the NCOA5-Protein Kinase B-mammalian target of rapamycin (AKT-mTOR) axis. Furthermore, the clinical evaluation of HCC specimens established a correlation between the activation of the NCOA5 pathway and the response to lenvatinib treatment. Everolimus, an mTOR inhibitor, in combination with lenvatinib and everolimus, exerted significant synergistic effects against HCC in vivo and in vitro . HCC cells develop resistance to lenvatinib by activating the NCOA5-AKT-mTOR pathway. The combination therapy of lenvatinib with everolimus is a promising strategy to overcome acquired resistance, thereby enhancing the clinical efficacy of lenvatinib.

Osimertinib is an effective strategy for nonsmall-cell lung cancer (NSCLC). However, the acquired resistance neutralizes the efficacy of osimertinib. Herein, we investigated the potential biomarkers of osimertinib-resistant lung cancer. GSE200894 was used to analyze the differentially expressed genes in osimertinib-resistant lung cancer. Sixty-two paired surgical specimens were collected from NSCLC patients with stage I-IV. Gene expression was detected using reverse transcription (RT)-qPCR, western blot, and immunohistochemistry. V-set domain containing T cell activation inhibitor 1 (VTCN1) was overexpressed in osimertinib-resistant lung cancer. High levels of VTCN1 predicted advanced stages and distant metastasis. Moreover, VTCN1 expression was negatively correlated with the purity of CD8+ T cells in lung cancer patients. VTCN1 inhibits the infiltration of effector-memory CD8+ T cells. In addition, overexpressed VTCN1 predicted the exhaustion of CD8+ T cells. VTCN1 inhibits the tumor-killing ability of CD8+ T cells. In summary, VTCN1 is overexpressed in osimertinib-resistant lung cancer patients. High levels of VTCN1 confer to inhibition of CD8+ T cell immunity and immune tolerance in osimertinib-resistant lung cancer patients.

Isocitrate dehydrogenase 1 (IDH1) mutations have gained interest because of their association with malignancies, including cholangiocarcinoma and acute myeloid leukemia. Ivosidenib, an inhibitor of IDH1 mutations, inhibits the formation of the oncometabolite D-2-HG, restoring normal cellular turnover and inhibiting tumorigenesis. In July 2024, a literature search was done using these databases: PubMed, Cochrane Library, and Embase. Studies were to show the safety and efficacy of ivosidenib using 95% confidence intervals (CIs). Preferred Reporting Items for Systematic reviews and Meta-Analyses flow guidelines were followed. Four articles involving 533 patients were included. The objective response rate (ORR) and progression-free survival (PFS) were significantly improved in the control group where risk ratio was 0.79, 95% CI: 0.71-0.89, Z = 4.05, a P value less than 0.001 for PFS, and odds ratio was 0.45, 95% CI: 0.30-0.68, Z value of 3.86, and P = 0.001 for ORR. The safety profile was favorable. Overall survival (OS) did not change significantly within the groups, as indicated by a P value of 0.78, risk ratio of 0.98, 95% CI: 0.83-1.15, and Z = 0.27. Ivosidenib demonstrated a PFS advantage and improved ORR with a favorable safety profile, but no effect on the OS. Evidence is suggestive of its plausibility for clinical usage as an adjunct therapy.

For patients with advanced EGFR -mutant lung adenocarcinoma, progression-free survival (PFS) is significantly improved by epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) medications. However, a subset of patients still experiences early disease progression. In this study, we aimed to identify potential risk factors associated with shorter PFS through next-generation sequencing (NGS) analysis. This retrospective study included patients with advanced EGFR -mutant lung adenocarcinoma who received first-line EGFR-TKI treatment with upfront NGS. The genetic alterations included two types, mutations and copy number variations. Alterations involving EGFR downstream signaling pathways were classified as ' PIK3CA-AKT/RAS-RAF alterations'. Clinical and histopathological data were also collected and analyzed. We studied a total of 82 advanced lung cancer patients with sensitive EGFR mutations. Multivariable analyses showed associations with a shorter PFS for the following factors: P IK3CA-AKT/RAS-RAF alterations [hazard ratio (HR) 3.197, P  = 0.006], age ≤50 (HR 3.034, P  = 0.010), and PD-L1 ≥50% (HR 2.256, P  = 0.035). Based on the above risk factors, patients were classified into no-risk and ≥1 risk groups. In the no-risk group, third-generation EGFR-TKIs showed a numerically longer PFS compared to first/second-generation EGFR-TKIs (not reached vs. 20.0 months, P  = 0.084). However, in patients with ≥1 risk factor, third-generation EGFR-TKIs showed no PFS advantages (6.6 vs. 6.2 months, P  = 0.831). In conclusion, besides clinicopathological factors, NGS provides additional insights to predict shorter PFS after EGFR-TKI treatment. We identified three risk factors: (1) PIK3CA-AKT/RAS-RAF alterations, (2) age ≤50, and (3) PD-L1 ≥50%. Patients with these factors had poor PFS regardless of EGFR-TKI generation.

Nonsmall cell lung cancer (NSCLC) with SMARCA4 deficiency represents a rare subset of lung tumors characterized by early metastasis, poor response to chemotherapy, and unfavorable prognosis. Established therapy strategies for SMARCA4-deficient NSCLC remain elusive. While immune checkpoint inhibitors have been proposed as a potential solution, their efficacy remains uncertain. Clinical factors such as tumor mutational burden (TMB), microsatellite instability, comutations, and programmed death-ligand 1 (PD-L1) expression may influence the treatment response of SMARCA4-deficient NSCLC. Additionally, PD-L1 expression on circulating tumor cells (CTCs) provides novel insights for monitoring, and its utility in SMARCA4-deficient NSCLC remains unexplored. The present report describes the case of a 71-year-old man diagnosed with SMARCA4-deficient NSCLC who had a history of heavy smoking and chronic cough. Imaging examination revealed metastatic lymph nodes. All serum tumor markers were elevated above the normal range. Histopathological and immunohistochemical analyses of the biopsy specimen from a primary lesion in the right upper lung demonstrated irregularly arranged tumor cells, SMARCA4 deficiency, and positive PD-L1 expression. Further next-generation sequencing confirmed SMARCA4 mutation, high TMB, and microsatellite stability (MSS). The patient received pembrolizumab treatment and experienced a sustained benefit for >40 months, with persistent PD-L1 expression on CTCs observed throughout the treatment. It was revealed that pembrolizumab therapy shows promise for patients with SMARCA4-deficient NSCLC with positive PD-L1 expression, high TMB, and MSS. Dynamic monitoring of PD-L1 status on CTCs may facilitate the assessment of the immunotherapy response, and the sustained positive PD-L1 expression on CTCs may imply continued benefit from immunotherapy for patients with SMARCA4-deficient NSCLC.