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Heliyon Apr 2023Phenotypic plasticity (PP) is a major promoter of tumor metastasis and drug resistance. Nevertheless, the molecular features and clinical significance of phenotypic...
BACKGROUND
Phenotypic plasticity (PP) is a major promoter of tumor metastasis and drug resistance. Nevertheless, the molecular features and clinical significance of phenotypic plasticity in lung squamous cell carcinomas (LSCC) remained largely unexplored.
METHODS
Phenotypic plasticity-related genes (PPRG) and clinical information of LSCC were downloaded from the cancer genome atlas (TCGA). The expression profiles of PPRG were compared between patients with and without lymph node metastasis. The prognostic signature was constructed, and survival analysis was performed based on phenotypic plasticity. Immunotherapy responses, chemotherapeutic drugs and targeted drug responses were investigated. In addition, the results were verified in an external cohort.
RESULTS
Patients with and without lymph node metastasis exhibited significantly different genomic characteristics of phenotypic plasticity. Enrichment analysis showed that PP was strongly associated with cell responses and cell contraction. Survival analysis demonstrated that PPRG could serve as independent prognostic factor for overall survival. The phenotypic plasticity-related signature successfully divided patients into high- and low-PP score groups. Patients with low-PP scores were more sensitive to PD-L1, Cisplatin, Gefitinib, Obatoclax. Mesylate, Paclitaxel, Sorafenib and Vinorelbine (all p < 0.05). While, patients with low-PP scores were more sensitive to Axitinib and Camptothecin (all p < 0.05). Consistent with the results from TCGA, the external cohort validated the above findings.
CONCLUSIONS
Our study revealed that phenotypic plasticity may be involved in the lymph node metastasis in LSCC through regulating cell responses and cell contraction. Evaluation of phenotypic plasticity will assist clinicians in making treatment strategies.
PubMed: 37025908
DOI: 10.1016/j.heliyon.2023.e14614 -
Biomedicine & Pharmacotherapy =... Jun 2023Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary...
Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary to find drugs that could improve immune function and synergistically enhance the anti-tumor effect of vinorelbine. Thymosin is reported to inhibit tumor growth as an immunomodulator. Herein, to study the synergistic anti-cancer and attenuation effects of thymosin on vinorelbine, human lung cancer A549 cells that were labeled with CM-DiI were transplanted into zebrafish to establish the lung cancer xenotransplanted model. After treatment of vinorelbine and different concentrations of thymosin, the fluorescence intensity of CM-DiI-labeled A549 cells and the number of apoptotic muscle cells in the tumor-bearing zebrafish were detected. Besides, effects of thymosin on vinorelbine-reduced macrophages and T cells were identified in the transgenic zebrafish (Tg:zlyz-EGFP and Tg:rag2-DsRed). Then, the qRT-PCR was used to determine the alterations of the immune-related factors at the transcription level. Thymosin showed a marked synergistic anti-cancer effect with vinorelbine for the xenograft human lung cancer A549 cells, and the synergistic effect enhanced in a dose-dependent manner. Moreover, thymosin alleviated vinorelbine-induced muscle cell apoptosis, macrophage reduction, and T cell suppression. Compared with the vinorelbine group, co-administration with thymosin raised the mRNA levels of TNF-α, TNF-β, INF-γ, and GM-CSF. Thus, thymosin possesses synergistic anti-cancer effect on vinorelbine, and has protective effect on vinorelbine-induced immunosuppression. Thymosin, as an adjuvant immunomodulatory therapy, has great potential in enhancing the clinical application of vinorelbine.
Topics: Animals; Humans; Vinorelbine; Zebrafish; Thymosin; Cell Line, Tumor; Lung Neoplasms
PubMed: 37018994
DOI: 10.1016/j.biopha.2023.114633 -
Cancer Medicine May 2023Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.
AIMS
The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.
MATERIALS & METHODS
Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies.
RESULTS
One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02).
DISCUSSION
Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS.
CONCLUSION
These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.
Topics: Humans; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Vinorelbine; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Cyclophosphamide; Chronic Disease
PubMed: 37016270
DOI: 10.1002/cam4.5749 -
Cell Reports Apr 2023Patient-derived organoids (PDOs) are widely heralded as a drug-screening platform to develop new anti-cancer therapies. Here, we use a drug-repurposing library to screen...
Patient-derived organoids (PDOs) are widely heralded as a drug-screening platform to develop new anti-cancer therapies. Here, we use a drug-repurposing library to screen PDOs of colorectal cancer (CRC) to identify hidden vulnerabilities within therapy-induced phenotypes. Using a microscopy-based screen that accurately scores drug-induced cell killing, we have tested 414 putative anti-cancer drugs for their ability to switch the EGFRi/MEKi-induced cytostatic phenotype toward cytotoxicity. A majority of validated hits (9/37) are microtubule-targeting agents that are commonly used in clinical oncology, such as taxanes and vinca-alkaloids. One of these drugs, vinorelbine, is consistently effective across a panel of >25 different CRC PDOs, independent of RAS mutational status. Unlike vinorelbine alone, its combination with EGFR/MEK inhibition induces apoptosis at all stages of the cell cycle and shows tolerability and effective anti-tumor activity in vivo, setting the basis for a clinical trial to treat patients with metastatic RAS-mutant CRC.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Colorectal Neoplasms; Vinorelbine; Drug Repositioning; Cell Line, Tumor; Colonic Neoplasms; Antineoplastic Agents; Organoids
PubMed: 37000626
DOI: 10.1016/j.celrep.2023.112324 -
EXCLI Journal 2023In metastatic breast cancer (MBC), mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance...
In metastatic breast cancer (MBC), mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, -mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type ) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of -mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, wild-type BC cells. The p110α expression was downregulated or not affected in mutated cell lines, and not significantly upregulated in wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, -mutated BC cells, providing a rationale for further efforts to evaluate this combination .
PubMed: 36998707
DOI: 10.17179/excli2022-5064 -
Oncology Letters Apr 2023Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are...
Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are increasingly used in combination with cytotoxic treatments, such as chemotherapy. Although combined treatments are more effective, not all patients respond to the therapy; therefore, a detailed understanding of the effect of treatment combinations at the tumour level is needed. The present study aimed to explore whether ICIs could affect the cytotoxic effects of chemotherapy on lung adenocarcinoma cell lines with different PD-L1 expression levels (high, HCC-44; low, A-549). Using the resazurin-based assay, the efficacy of seven chemotherapeutic agents (cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel and paclitaxel) was compared in the presence or absence of the individually chosen single doses of four ICIs (nivolumab, pembrolizumab, atezolizumab and durvalumab). The results revealed that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or lung adenocarcinoma cell line used. Durvalumab was the most promising ICI, which potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. By contrast, nivolumab, exhibited depotentiating trends in several combinations. The immunostaining of γH2AX in treated cells confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage; however, this effect was strongly dependent on the chemotherapy agent and cell line used. Our future studies aim to address the specific mechanisms underlying the observed ICI-induced potentiation or depotentiation.
PubMed: 36936028
DOI: 10.3892/ol.2023.13738 -
Medicine Mar 2023The aim of this study was to assess the therapeutic efficacy of a cisplatin and vinorelbine combination as second- or higher-line palliative chemotherapy in patients...
The aim of this study was to assess the therapeutic efficacy of a cisplatin and vinorelbine combination as second- or higher-line palliative chemotherapy in patients with advanced ovarian cancer. We retrospectively reviewed the medical records of patients with advanced ovarian cancer who were treated with cisplatin (60 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1 and 8) every 3 weeks between January 2004 and March 2021. Treatment responses, progression-free survival (PFS), and overall survival (OS) were assessed; laboratory data were reviewed to determine toxicity. Thirty-two patients with advanced ovarian cancer were treated with a combination of vinorelbine and cisplatin. The objective response rate (ORR) was 18.8% and the disease control rate was 75.1%. The median PFS was 4.13 months (95% confidence interval [CI], 2.4-5.8 months). The median OS was 56.9 months (95% CI, 50.5-63.7 months). The ORR (42.9% vs 9.1%; P = .035) was higher in the platinum-sensitive group than in the platinum-resistant group. The median PFS tended to be longer in the platinum-sensitive group (5.3 vs 3.8 months; P = .339) and the median OS was significantly longer in the platinum-sensitive group than in the platinum-resistant group (69.6 vs 24 months; P < .001). All patients developed hematological toxicities, with 56% experiencing grade 3 to 4 neutropenia. Two (6.2%) patients developed febrile neutropenia, but no treatment-related death occurred. This combination therapy may be effective in patients with heavily treated advanced ovarian cancer, particularly in platinum-sensitive patients.
Topics: Humans; Female; Vinorelbine; Cisplatin; Vinblastine; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Platinum; Ovarian Neoplasms; Lung Neoplasms
PubMed: 36930110
DOI: 10.1097/MD.0000000000033271 -
Cancer Research Communications Sep 2022In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates...
UNLABELLED
In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates how different data sources can contribute to and assist phase I trial designs. Single-drug and drug combination toxicity and pharmacokinetic data were primarily reviewed from several databases. We focused on the MTD, dose-limiting toxicity (DLT), toxicity, and pharmacokinetic profiles. To demonstrate the feasibility and utility of these data sources in improving trial designs, phase I studies reported in ClincalTrials.gov from January 1, 2018 to December 31, 2018 were used as examples. We evaluated whether and how these studies could have been designed differently given toxicity and pharmacokinetic data. None of the existing pharmacokinetic and toxicity databases contain either MTD or DLT. Among 268 candidate trials, four drug combinations were studied in other phase I trials before 2018; 185 combinations had complete or partial information on drug interactions or overlapping toxicity, and 79 combinations did not have available information. Two drug combination trials were selected as case studies. The nivolumab-axitinib trial could have been designed as a dose deescalating study, and the vinorelbine-trastuzumab emtansine trial could have been designed with a lower dose of either drug. Public data sources contain significant knowledge of the drug combination phase I trial design. Some important data (MTD and DLT) are not available in existing databases but in the literature. Some phase I studies could have been designed more efficiently with additional preliminary data.
SIGNIFICANCE
Prior preclinical and clinical knowledge is critical for designing effective and efficient cancer drug combinatory trials. We reported results on the feasibility and utility of different informatics resources for contributing to and assisting phase I trial designs based on our designed classification approach. We also found that public data sources contained significant knowledge for drug combination phase I trial design, but some critical data elements (MTD and DLT) were missing.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Vinorelbine
PubMed: 36922938
DOI: 10.1158/2767-9764.CRC-22-0160 -
Gland Surgery Feb 2023Trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard guideline-recommended neoadjuvant therapy recommended for patients with human epidermal growth...
Neoadjuvant pyrotinib plus trastuzumab and vinorelbine for HER2-positive locally advanced breast cancer patient who was initially resistant to HP therapy: a case report and literature review.
BACKGROUND
Trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard guideline-recommended neoadjuvant therapy recommended for patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer (BC), which has dramatically improved patient prognosis. However, over 10% of patients develop primary drug resistance to HP and did not respond to treatment. There is no standard second-line neoadjuvant therapy approach for these individuals at the present. Pyrotinib and vinorelbine have shown promising efficacy in HER2-positive metastatic breast cancer, but their usage in neoadjuvant therapy has not been reported so far.
CASE DESCRIPTION
Here, we present a case of a 58-year-old female patient with locally advanced HER2-positive BC who was initially resistant to HP neoadjuvant therapy. Following the failure of the treatment, this patient was given pyrotinib plus trastuzumab and vinorelbine as second-line neoadjuvant therapy. The patient tolerated this treatment well, with mild symptoms of diarrhea. After 6 cycles of neoadjuvant therapy, the efficacy was assessed to be partial remission (PR), and a modified radical mastectomy was finally conducted. This patient remained disease-free for 23 months after surgery.
CONCLUSIONS
This is the first report to present a case of neoadjuvant pyrotinib plus trastuzumab and vinorelbine in a patient with HER2-positive locally advanced BC, suggesting that the combination could be a new option for patients who have developed resistance to HP neoadjuvant treatment.
PubMed: 36915810
DOI: 10.21037/gs-22-751 -
Frontiers in Pediatrics 2023In immunocompetent individuals, cytomegalovirus (CMV) infection is usually mild but may cause severe complications such as retinitis, pneumonitis, and encephalitis in...
In immunocompetent individuals, cytomegalovirus (CMV) infection is usually mild but may cause severe complications such as retinitis, pneumonitis, and encephalitis in immunocompromised individuals. So far, cases of CMV retinitis in patients with medulloblastoma undergoing chemotherapy and radiotherapy, have not been reported. We herein report the case of a pediatric patient with high-risk medulloblastoma who experienced an unexpected CMV retinopathy and leukoencephalopathy following high dose thiotepa and proton irradiation. The patient underwent a four-course induction therapy (1st cycle: methotrexate and vinorelbine; 2nd cycle: etoposide and hematopoietic stem cells apheresis; 3rd cycle: cyclophosphamide and vinorelbine; 4th cycle: carboplatin and vinorelbine) and then a consolidation phase consisting in high dose thiotepa followed by autologous HSC transplant and proton cranio-spinal irradiation plus boost to the primary tumor site and pituitary site with concomitant vinorelbine. After two months of maintenance treatment with lomustine and vinorelbine, the patient showed complete blindness and leukoencephalopathy. A diagnosis of CMV retinopathy was made and oral valganciclovir was administered. CMV retinopathy was judged to be possibly related to the use of high dose thiotepa worsened by radiotherapy. This case report suggests that in pediatric patients undergoing immunosuppressive chemo-radiotherapy, CMV reactivation should be carefully monitored to prevent serious complications such as retinopathy and visual loss.
PubMed: 36896395
DOI: 10.3389/fped.2023.1145941