-
BMC Cancer Apr 2024This study aimed to systematically analyze the effect of a serine/threonine kinase (STK11) mutation (STK11) on therapeutic efficacy and prognosis in patients with... (Meta-Analysis)
Meta-Analysis
Effect of the STK11 mutation on therapeutic efficacy and prognosis in patients with non-small cell lung cancer: a comprehensive study based on meta-analyses and bioinformatics analyses.
BACKGROUND
This study aimed to systematically analyze the effect of a serine/threonine kinase (STK11) mutation (STK11) on therapeutic efficacy and prognosis in patients with non-small cell lung cancer (NSCLC).
METHODS
Candidate articles were identified through a search of relevant literature published on or before April 1, 2023, in PubMed, Embase, Cochrane Library, CNKI and Wanfang databases. The extracted and analyzed data included the hazard ratios (HRs) of PFS and OS, the objective response rate (ORR) of immune checkpoint inhibitors (ICIs), and the positive rates of PD-L1 expression. The HR of PFS and OS and the merged ratios were calculated using a meta-analysis. The correlation between STK11 and clinical characteristics was further analyzed in NSCLC datasets from public databases.
RESULTS
Fourteen retrospective studies including 4317 patients with NSCLC of whom 605 had STK11 were included. The meta-analysis revealed that the ORR of ICIs in patients with STK11 was 10.1% (95%CI 0.9-25.2), and the positive rate of PD-L1 expression was 41.1% (95%CI 25.3-57.0). STK11 was associated with poor PFS (HR = 1.49, 95%CI 1.28-1.74) and poor OS (HR = 1.44, 95%CI 1.24-1.67). In the bioinformatics analysis, PFS and OS in patients with STK11 alterations were worse than those in patients without alterations (p < 0.001, p = 0.002). Nutlin-3a, 5-fluorouracil, and vinorelbine may have better sensitivity in patients with STK11 than in those with STK11.
CONCLUSIONS
Patients with STK11-mutant NSCLC had low PD-L1 expression and ORR to ICIs, and their PFS and OS were worse than patients with STK11 after comprehensive treatment. In the future, more reasonable systematic treatments should be explored for this subgroup of patients with STK11-mutant NSCLC.
Topics: Humans; AMP-Activated Protein Kinase Kinases; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; Prognosis; Protein Serine-Threonine Kinases; Retrospective Studies
PubMed: 38632512
DOI: 10.1186/s12885-024-12130-y -
Current Pharmaceutical Biotechnology Apr 2024Breast cancer remains a leading cause of cancer-related deaths among women, primarily attributed to the formidable challenge of multidrug resistance, often driven by the...
BACKGROUND
Breast cancer remains a leading cause of cancer-related deaths among women, primarily attributed to the formidable challenge of multidrug resistance, often driven by the overexpression of the ABCB1 gene.
OBJECTIVE
This study aimed to assess the synergistic effects of siRNA, doxorubicin, and vinorelbine on ABCB1 gene expression and cell viability in doxorubicin-resistant MCF-7/ADR breast cancer cells, with siRNA targeting ABCB1 to reduce its expression and doxorubicin/ vinorelbine to eradicate cancer cells.
METHODS
Our methodology involved culturing MCF-7 and MCF-7/ADR cells in standard cell culture conditions. The synthesized siRNA sequences transfected cells with siRNA at final concentrations of 10, 20, and 30 nM and assessed cell viability using the MTT assay was performed. Real-time PCR was employed to quantify ABCB1 mRNA expression levels.
RESULTS
Results indicated that MCF-7/ADR cells exhibited substantial resistance to vinorelbine and doxorubicin compared to MCF-7 cells, displaying resistance at 12.50 μM and 25.00 μM for vinorelbine and 6.25 μM and 25.00 μM for doxorubicin. Remarkably, siRNA treatment effectively reversed drug resistance in MCF-7/ADR cells across all concentrations of vinorelbine and doxorubicin tested. When combined, siRNA, doxorubicin, and vinorelbine yielded a significantly greater reduction in cell viability compared to individual drug treatments, particularly at a 20 μM siRNA concentration. This combination therapy also significantly suppressed ABCB1 gene expression by a factor of 41.48 in MCF-7 cells relative to MCF-7/ADR cells.
CONCLUSION
these findings suggest that combining siRNA, doxorubicin, and vinorelbine holds promise as a therapeutic strategy to overcome ABCB1-mediated multidrug resistance in breast cancer. Further investigations and clinical trials are warranted to evaluate its clinical efficacy rigorously.
PubMed: 38616741
DOI: 10.2174/0113892010284774240328144105 -
Discover Oncology Apr 2024Long non-coding RNAs (LncRNAs) regulating the immune microenvironment of cancer is a hot spot. But little is known about the influence of the immune-related lncRNA...
BACKGROUND
Long non-coding RNAs (LncRNAs) regulating the immune microenvironment of cancer is a hot spot. But little is known about the influence of the immune-related lncRNA (IRlncRs) on the chemotherapeutic responses and prognosis of cervical cancer (CC) patients. The purpose of the study was to identify an immune-related lncRNAs (IRlncRs)-based model for the prospective prediction of clinical outcomes in CC patients.
METHODS
CC patients' relevant data was acquired from The Cancer Genome Atlas (TCGA). Correlation analysis and Cox regression analyses were applied. A risk score formula was formulated. Prognostic factors were combined into a nomogram, while sensitivity for chemotherapy drugs was analyzed using the OncoPredict algorithm.
RESULTS
Eight optimal IRlncRs(ATP2A1-AS1, LINC01943, AL158166.1, LINC00963, AC009065.8, LIPE-AS1, AC105277.1, AC098613.1.) were incorporated in the IRlncRs model. The overall survival (OS) of the high-risk group of the model was inferior to those in the low-risk group. Further analysis demonstrated this eight-IRlncRs model as a useful prognostic marker. The Nomogram had a concordance index of survival prediction of 0.763(95% CI 0.746-0.780) and more robust predictive accuracy. Furthermore, patients in the low-risk group were found to be more sensitive to chemotherapy, including Paclitaxel, Rapamycin, Epirubicin, Vincristine, Docetaxel and Vinorelbine.
CONCLUSIONS
An eight-IRlncRs-based prediction model was identified that has the potential to be an important tool to predict chemotherapeutic responses and prognosis for CC patients.
PubMed: 38615287
DOI: 10.1007/s12672-024-00979-1 -
Animal Models and Experimental Medicine Apr 2024Breast cancer is the most common cancer in women, and in advanced stages, it often metastasizes to the brain. However, research on the biological mechanisms of breast...
BACKGROUND
Breast cancer is the most common cancer in women, and in advanced stages, it often metastasizes to the brain. However, research on the biological mechanisms of breast cancer brain metastasis and potential therapeutic targets are limited.
METHODS
Differential gene expression analysis (DEGs) for the datasets GSE43837 and GSE125989 from the GEO database was performed using online analysis tools such as GEO2R and Sangerbox. Further investigation related to SULF1 was conducted using online databases such as Kaplan-Meier Plotter and cBioPortal. Thus, expression levels, variations, associations with HER2, biological processes, and pathways involving SULF1 could be analyzed using UALCAN, cBioPortal, GEPIA2, and LinkedOmics databases. Moreover, the sensitivity of SULF1 to existing drugs was explored using drug databases such as RNAactDrug and CADSP.
RESULTS
High expression of SULF1 was associated with poor prognosis in advanced breast cancer brain metastasis and was positively correlated with the expression of HER2. In the metastatic breast cancer population, SULF1 ranked top among the 16 DEGs with the highest mutation rate, reaching 11%, primarily due to amplification. KEGG and GSEA analyses revealed that the genes co-expressed with SULF1 were positively enriched in the 'ECM-receptor interaction' gene set and negatively enriched in the 'Ribosome' gene set. Currently, docetaxel and vinorelbine can act as treatment options if the expression of SULF1 is high.
CONCLUSIONS
This study, through bioinformatics analysis, unveiled SULF1 as a potential target for treating breast cancer brain metastasis (BM).
PubMed: 38590118
DOI: 10.1002/ame2.12406 -
Case Reports in Oncology 2024Capecitabine has rarely been associated with neurotoxicity. Cerebellar ataxia, multifocal leukoencephalopathy, and sensorimotor peripheral neuropathy have been reported...
INTRODUCTION
Capecitabine has rarely been associated with neurotoxicity. Cerebellar ataxia, multifocal leukoencephalopathy, and sensorimotor peripheral neuropathy have been reported in the literature. A case of 6th nerve palsy associated with capecitabine has also been described. This article reports the first case of capecitabine-related 4th nerve palsy.
CASE PRESENTATION
A 72-year-old Caucasian woman was referred by the Oncology Department because she had been complaining of binocular diplopia for 6 months. The symptoms started 1 month after the introduction of capecitabine. A diagnosis of right 4th nerve palsy was made using the Parks three-step test and the Hess test. Neuroimaging analysis was negative. A slow but progressive deterioration of function was confirmed during a year of follow-up. On suspicion of a chemotherapy-related palsy, capecitabine was discontinued and switched to vinorelbine. Subsequent improvement of the clinical picture was confirmed within 2 months.
CONCLUSION
The recognition of chemotherapy-related neurotoxicity is of paramount importance in the management of oncology patients. Once secondary invasion of the brain or the orbit by the tumor itself is ruled out, it must be suspected to prevent further deterioration.
PubMed: 38567168
DOI: 10.1159/000535349 -
Journal of Chemotherapy (Florence,... Apr 2024This study aimed to compare the efficacy of pyrotinib, trastuzumab combined with chemotherapy with different lines therapy in human epidermal growth factor receptor 2-...
This study aimed to compare the efficacy of pyrotinib, trastuzumab combined with chemotherapy with different lines therapy in human epidermal growth factor receptor 2- (HER2-) positive advanced breast cancer (ABC) and analyze the factors affecting the prognosis. A total of 84 patients with median age of 49 year-old. The mPFS of patients receiving first-line pyrotinib plus trastuzumab and chemotherapy was the longest (11 months) compared with second- and third line patients ( = 0.106). The objective response rate (ORR) and disease control rate (DCR) of the total population were 33.3% and 82.1% respectively. Subgroup analysis suggested that using pyrotinib plus trastuzumab and Albumin-bound paclitaxel was not inferior to combine with Vinorelbine in regards of PFS. Histological grade (OR: 0.233[0.069 ∼ 0.781], = 0.018) and tumor location (OR: 0.286[0.087 ∼ 0.942], = 0.040) were independent factors influencing the ORR. Multivariate cox analysis showed that Ki-67 was independently associated with increased risk of progression (HR: 1.843[1.044-3.254], = 0.035). The most common adverse events were diarrhea (17.9%) and neutropenia (11.9%). In the first-, second- and third-line treatment, pyrotinib plus trastuzumab and chemotherapy is effective and safe. Pyrotinib and trastuzumab combined with Albumin-bound paclitaxel may be a potential ideal treatment plan for HER2-positive advanced breast cancer.
PubMed: 38557437
DOI: 10.1080/1120009X.2024.2335714 -
Discovery Medicine Mar 2024The clinical outcomes of chemotherapy (CT) for the treatment of metastatic triple-negative (TN) and hormone receptor-positive (HR+)/human epidermal growth factor...
BACKGROUND
The clinical outcomes of chemotherapy (CT) for the treatment of metastatic triple-negative (TN) and hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) have proven to be disappointing. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, a tumor-promoting signaling cascade frequently mutated in breast cancer (BC), has been implicated in chemoresistance. In this study, our objective is to investigate the efficacy and safety of combining everolimus with chemotherapy in mBC patients exhibiting mutations in the PI3K/AKT/mTOR pathway.
METHODS
We conducted a retrospective analysis to characterize the efficacy, safety, and their association with clinical and molecular characteristics of metastatic lesions in 14 patients with HER2- mBC. These patients harbored at least one altered member of the PI3K/AKT/mTOR signaling pathway and were treated with a combination of a chemotherapy agent and the mTOR inhibitor everolimus (CT+EVE).
RESULTS
The majority of patients belonged to the triple-negative (TN) subtype (9/14, 64.3%), having already undergone 2 lines of chemotherapy (CT) in the metastatic setting (11, 78.6%). These patients carried altered phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha () and were administered a vinorelbine-containing regimen (10, 71.4%). The objective response rate (ORR) was 42.9%, with a disease control rate of 92.9%. The median progression-free survival (PFS) and overall survival (OS) were 5.9 (95% confidence interval (CI): 4.9-13.6) months and 14.3 (95% CI: 8.5-not reached (NR)) months, respectively. Patients with fewer prior treatment lines tended to exhibit longer PFS. OS, PFS, and ORR were comparable between hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) patients, but numerical improvements were noted in patients with a single PI3K pathway alteration compared to those with more than one alteration. Genomic alterations that surfaced upon progression on CT+EVE included cyclin dependent kinase 4 () and epidermal growth factor receptor () amplification, as well as neurofibromin 1 () mutation, suggesting potential mechanisms of acquired resistance. An analysis of adverse events indicated manageable toxicities.
CONCLUSIONS
The findings of this study suggest both activity and safety for the combination of chemotherapy and the mTOR inhibitor everolimus (CT+EVE) in patients with HER2- mBC who have alterations in the PI3K pathway, particularly those who have received fewer prior chemotherapy. However, it is crucial to note that large-scale, randomized control studies are warranted to more comprehensively characterize the efficacy and safety of this combination therapy.
Topics: Humans; Female; Everolimus; Breast Neoplasms; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Retrospective Studies; Receptor, ErbB-2; Antineoplastic Combined Chemotherapy Protocols; TOR Serine-Threonine Kinases
PubMed: 38531793
DOI: 10.24976/Discov.Med.202436182.49 -
PeerJ 2024Peroxisome proliferator-activated receptors (PPARs) exert multiple functions in the initiation and progression of stomach adenocarcinomas (STAD). This study analyzed the...
BACKGROUND
Peroxisome proliferator-activated receptors (PPARs) exert multiple functions in the initiation and progression of stomach adenocarcinomas (STAD). This study analyzed the relationship between PPARs and the immune status, molecular mutations, and drug therapy in STAD.
METHODS
The expression profiles of three PPAR genes (PPARA, PPARD and PPARG) were downloaded from The Cancer Genome Atlas (TCGA) dataset to analyze their expression patterns across pan-cancer. The associations between PPARs and clinicopathologic features, prognosis, tumor microenvironment, genome mutation and drug sensitivity were also explored. Co-expression between two PPAR genes was calculated using Pearson analysis. Regulatory pathways of PPARs were scored using gene set variation analysis (GSVA) package. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to analyze the expression and function of the PPAR genes in STAD cell lines (AGS and SGC7901 cells).
RESULTS
PPARA, PPARD and PPARG were more abnormally expressed in STAD samples and cell lines when compared to most of 32 type cancers in TCGA. In STAD, the expression of PPARD was higher in Grade 3+4 and male patients, while that of PPARG was higher in patient with Grade 3+4 and age > 60. Patients in high-PPARA expression group tended to have longer survival time. Co-expression analysis revealed 6 genes significantly correlated with the three PPAR genes in STAD. Single-sample GSEA (ssGSEA) showed that the three PPAR genes were enriched in 23 pathways, including MITOTIC_SPINDLE, MYC_TARGETS_V1, E2F_TARGETS and were closely correlated with immune cells, including NK_cells_resting, T_cells_CD4_memory_resting, and macrophages_M0. Immune checkpoint genes (CD274, SIGLEC15) were abnormally expressed between high-PPAR expression and low-PPAR expression groups. TTN, MUC16, FAT2 and ANK3 genes had a high mutation frequency in both high-PPARA/PPARG and low-PPARA/PPARG expression group. Fourteen and two PPARA/PPARD drugs were identified to be able to effectively treat patients in high-PPARA/PPARG and low-PPARA/PPARG expression groups, respectively. We also found that the chemotherapy drug Vinorelbine was positively correlated with the three PPAR genes, showing the potential of Vinorelbine to serve as a treatment drug for STAD. Furthermore, cell experiments demonstrated that PPARG had higher expression in AGS and SGC7901 cells, and that inhibiting PPARG suppressed the viability, migration and invasion of AGS and SGC7901 cells.
CONCLUSIONS
The current results confirmed that the three PPAR genes (PPARA, PPARD and PPARG) affected STAD development through mediating immune microenvironment and genome mutation.
Topics: Humans; Male; PPAR gamma; Vinorelbine; PPAR alpha; PPAR delta; Adenocarcinoma; Drug Resistance; Stomach; Tumor Microenvironment
PubMed: 38529307
DOI: 10.7717/peerj.17082 -
Journal of Pharmaceutical Sciences Jul 2024The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading...
The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading Pgp must be developed. Despite similarities in structure, vinca alkaloids (VAs) show disparate Pgp-mediated efflux ratios. ATPase activity and binding affinity studies show at least two binding sites for the VAs: high- and low-affinity sites that stimulate and inhibit the ATPase activity rate, respectively. The affinity for ATP from the ATPase kinetics curve for vinblastine (VBL) at the high-affinity site was 2- and 9-fold higher than vinorelbine (VRL) and vincristine (VCR), respectively. Conversely, VBL had the highest K (ATP) for the low-affinity site. The dissociation constants (Ks) determined by protein fluorescence quenching were in the order VBL < VRL< VCR. The order of the Ks was reversed at higher substrate concentrations. Acrylamide quenching of protein fluorescence indicate that the VAs, either at 10 µM or 150 µM, predominantly maintain Pgp in an open-outward conformation. When 3.2 mM AMPPNP was present, 10 µM of either VBL, VRL, or VCR cause Pgp to shift to an open-outward conformation, while 150 µM of the VAs shifted the conformation of Pgp to an intermediate orientation, between opened inward and open-outward. However, the conformational shift induced by saturating AMPPNP and VCR condition was less than either VBL or VRL in the presence of AMPPNP. At 150 µM, atomic force microscopy (AFM) revealed that the VAs shift Pgp population to a predominantly open-inward conformation. Additionally, STDD NMR studies revealed comparable groups in VBL, VRL, and VCR are in contact with the protein during binding. Our results, when coupled with VAs-microtubule structure-activity relationship studies, could lay the foundation for developing next-generation VAs that are effective as anti-tumor agents. A model that illustrates the intricate process of Pgp-mediated transport of the VAs is presented.
Topics: Vinca Alkaloids; ATP Binding Cassette Transporter, Subfamily B, Member 1; Humans; Vinblastine; Binding Sites; Vincristine; Biological Transport; Adenosine Triphosphatases; Kinetics
PubMed: 38527618
DOI: 10.1016/j.xphs.2024.03.014 -
International Cancer Conference Journal Apr 2024Hepatic arterial infusion chemotherapy (HAIC) for liver metastases (LMs) from breast cancer is not a standard of care, but its effectiveness in patients with extensive...
Anthracycline-based hepatic arterial infusion chemotherapy achieved 17 months of disease regression in a patient with breast cancer liver metastases resistant to multiple systemic chemotherapies.
Hepatic arterial infusion chemotherapy (HAIC) for liver metastases (LMs) from breast cancer is not a standard of care, but its effectiveness in patients with extensive LMs who cannot tolerate systemic therapy has been reported. Herein, we report a case of breast cancer LMs that were controlled by anthracycline-based HAIC. A 46-year-old woman with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer who had multiple LMs and bone metastases underwent seven lines of systemic therapy (paclitaxel/bevacizumab for 38 months; letrozole, nivolumab/fulvestrant, eribulin, gemcitabine/vinorelbine, high-dose toremifene/abemaciclib, and capecitabine for 21 months in total). However, owing to its adverse effects and the continued progression of the LMs, systemic therapy was switched to HAIC (40 mg/body epirubicin on day 1, 4 mg/body mitomycin C on days 1 and 15, and 500 mg/body 5-fluorouracil on days 1, 8, and 15; 28-day courses). In response to HAIC, the LMs remarkably regressed and were controlled for 17 months without severe adverse effects. HAIC was stopped when multiple brain metastases arose, and the patient died 2 months later. This case suggests that HAIC is a reasonable option for patients with extensive LMs, even in the late stage of treatment. HAIC recipients should be carefully selected through multidisciplinary discussions as the survival benefits of HAIC over systemic treatment remain unclear. Our findings identify a potential window for the use of traditional chemotherapeutic agents such as anthracyclines. Novel strategies to improve drug delivery are warranted in the future.
PubMed: 38524659
DOI: 10.1007/s13691-024-00656-8