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Frontiers in Medicine 2023Lung squamous cell carcinoma (LUSC) is a devastating and difficult-to-treat type of lung cancer, and the prognosis of LUSC is the worst. The functional roles of focal...
BACKGROUND
Lung squamous cell carcinoma (LUSC) is a devastating and difficult-to-treat type of lung cancer, and the prognosis of LUSC is the worst. The functional roles of focal adhesion-related genes were explored in LUSC based on data from The Cancer Genome Atlas (TCGA).
METHODS
RNA sequencing data and clinical characteristics of LUSC patients in TCGA-LUSC were obtained from the TCGA database. Through systematic analysis, we screened the prognostic genes and determined the focal adhesion-related pathways closely associated with LUSC.
RESULTS
We identified 444 prognostic genes and focal adhesion-related pathways intimately associated with LUSC. According to the focal adhesion-related genes, TCGA-LUSC patients were well divided into two groups: the low-risk group (G1) and the high-risk group (G2). A differential expression analysis identified 44 differentially expressed genes (DEGs) upregulated in the low-risk G1 group and 379 DEGs upregulated in the high-risk G2 group. The upregulated DEGs in the G1 group were primarily related to tyrosine metabolism, steroid hormone biosynthesis, retinol metabolism, platinum drug resistance, pentose and glucuronate interconversions, and metabolism of xenobiotics by cytochrome P450, while the downregulated DEGs in the G1 group were primarily related to ECM-receptor interaction, focal adhesion, proteoglycans in cancer, small cell lung cancer, cytokine-cytokine receptor interaction, and TGF-beta signaling pathway. The immune activity of the G1 group was lower than that of the G2 group, and the half-maximal inhibitory concentration (IC50) of five chemotherapy drugs (i.e., gemcitabine, methotrexate, vinorelbine, paclitaxel, and cisplatin) was significantly different between the G1 and G2 groups. Furthermore, a 10-gene prognostic model was constructed to predict the prognosis for LUSC patients: , , , , , , , , , and .
CONCLUSION
The status of focal adhesion-related genes has a close relationship with tumor classification and immunity in LUSC patients. A novel focal adhesion-related signature had good prognostic and predictive performance for LUSC. Our findings may provide new insight into the diagnosis and treatment of LUSC.
PubMed: 38259849
DOI: 10.3389/fmed.2023.1284490 -
Cancers Jan 2024Identification of the optimal treatment strategy is challenging in elderly with localized non-small cell lung cancer (NSCLC). Concurrent chemotherapy with low-dose...
Identification of the optimal treatment strategy is challenging in elderly with localized non-small cell lung cancer (NSCLC). Concurrent chemotherapy with low-dose cisplatin represents an option for elderly. Outcomes (1) in elderly (≥70 years, = 158) vs. younger patients ( = 188) and (2), independently of age, in definitive radiochemotherapy, with low-dose cisplatin ( = 125) vs. cisplatin/vinorelbine ( = 76) were studied. Elderly included more males, had a lower Karnofsky index, more comorbidities, and lower stages. Low-dose cisplatin patients (vs. cisplatin/vinorelbine) had higher age, more comorbidities, and lower stages. We observed reduced dermatitis and dysphagia and increased anemia and thrombocytopenia in elderly vs. younger patients, without increased ≥grade 3 toxicities. Low-dose cisplatin was less toxic than cisplatin/vinorelbine. Survival outcomes were lower in elderly vs. younger and comparable between low-dose cisplatin and cisplatin/vinorelbine. In elderly, gender, Karnofsky index, stage, and multimodal treatment (including additional surgery/systemic therapy) were identified as prognostic factors. In conclusion, we found evidence for an acceptable toxicity profile and the need for improvement of outcomes in elderly with localized NSCLC. Multimodal strategies (including additional surgery/systemic treatment) showed favorable outcomes and should be reasonably considered in elderly who are deemed fit enough. Low-dose cisplatin should be discussed on an individual basis due to favorable toxicity and outcomes.
PubMed: 38254817
DOI: 10.3390/cancers16020327 -
International Journal of Molecular... Dec 2023Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of...
Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of rapamycin/sirolimus (mTOR) and microtubules are prominent druggable targets for HCC. In this study, we demonstrated that co-targeting mTOR using mTOR inhibitors (everolimus and sirolimus) along with the microtubule inhibitor vinorelbine yielded results superior to those of the monotherapies in HCC PDX models. Our research showed that the vinorelbine arrests cells at the mitotic phase, induces apoptosis, and normalizes tumor blood vessels but upregulates survivin and activates the mTOR/p70S6K/4EBP1 pathway. The addition of the everolimus significantly improved the tumor response to the vinorelbine, leading to improved overall survival (OS) in most tested orthotopic HCC PDX models. The mechanistic investigation revealed that this marked antitumor effect was accompanied by the downregulations of mTOR targets (p-p70S6K, p-4EBP1, and p-S6K); several key cell-cycle regulators; and the antiapoptotic protein survivin. These effects did not compromise the normalization of the blood vessels observed in response to the vinorelbine in the vinorelbine-sensitive PDX models or to the everolimus in the everolimus-sensitive PDX models. The combination of the everolimus and vinorelbine (everolimus/vinorelbine) also promoted apoptosis with minimal toxicity. Given the cost-effectiveness and established effectiveness of everolimus, and especially sirolimus, this strategy warrants further investigation in early-phase clinical trials.
Topics: Humans; Everolimus; Carcinoma, Hepatocellular; Vinorelbine; Survivin; Ribosomal Protein S6 Kinases, 70-kDa; Liver Neoplasms; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 38203186
DOI: 10.3390/ijms25010017 -
Biomedicines Dec 2023Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most common type. In addition, NSCLC has a...
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most common type. In addition, NSCLC has a high mortality rate and an overall adverse patient outcome. Although significant improvements have been made in therapeutic options, effectiveness is still limited in late stages, so the need for a better understanding of the genomics events underlying the current therapies is crucial to aid future drug development. Vinorelbine (VRB) is an anti-mitotic chemotherapy drug (third-generation vinca alkaloid) used to treat several malignancies, including NSCLC. However, despite its widespread clinical use, very little is known about VRB-associated genomic alterations in different subtypes of NSCLC. This article is an in vitro investigation of the cytotoxic effects of VRB on three different types of NSCLC cell lines, A549, Calu-6, and H1792, with a closer focus on post-treatment genetic alterations. Based on the obtained results, VRB cytotoxicity produces modifications on a cellular level, altering biological processes such as apoptosis, autophagy, cellular motility, cellular adhesion, and cell cycle, but also at a genomic level, dysregulating the expression of some coding genes, such as , and long non-coding RNAs (lncRNAs), including , , , , , , , and , that are implicated in the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, although extensive validation is required, these results pave the way towards a better understanding of the cellular and genomic alterations underlying the cytotoxicity of VRB.
PubMed: 38137519
DOI: 10.3390/biomedicines11123298 -
Veterinary Sciences Nov 2023Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven...
Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven antineoplastic activity and a low toxicity profile in dogs. Treatment-naïve, client-owned dogs with a cyto/histological diagnosis of advanced pulmonary carcinoma, selected from a laboratory database and previously subjected to imaging, were enrolled in the study. Vinorelbine (15 mg/m) was administered weekly for 4 weeks and then fortnightly until progressive disease was documented. Staging work-up was repeated by means of diagnostic imaging after the fourth VRL (i.e., 28 days) and monthly thereafter; response to treatment was evaluated according to the RECIST. Toxicity was graded following the VCOGC group. Ten dogs met the inclusion criteria. Partial response was documented in eight dogs. Median time to progression was 88 days (range: 7-112) and median survival time for all dogs was 100 days (range 7-635). The most common side effect was neutropenia. The main limitations of the study were the absence of histological diagnosis in eight cases and the limited number of treated dogs. VRL is well tolerated with an adequate toxicity profile and may be useful in the management of advanced lung tumours if used as a first-line treatment strategy.
PubMed: 38133215
DOI: 10.3390/vetsci10120664 -
International Journal of Oncology Feb 2024Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study,...
Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5‑FU) were chosen to study the dose‑response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual‑directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5‑FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF‑κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid‑derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low‑ and high‑dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5‑FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.
Topics: Mice; Animals; Humans; Female; Vinorelbine; Breast Neoplasms; Fluorouracil; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Administration, Metronomic
PubMed: 38063236
DOI: 10.3892/ijo.2023.5601 -
Therapeutic Advances in Medical Oncology 2023Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire...
BACKGROUND
Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have platinum-refractory disease.
OBJECTIVES
To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC.
DESIGN AND METHODS
Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either or (, four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and treatment studies were undertaken.
RESULTS
Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary mutations, two -mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the fusion, known to upregulate drug efflux MDR1.
CONCLUSION
The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.
PubMed: 38028140
DOI: 10.1177/17588359231208674 -
Surgery Open Science Dec 2023The purpose of this study was to compare the efficacy and safety of utidelone plus capecitabine for advanced first-line versus second-line or above therapy in metastatic...
BACKGROUND
The purpose of this study was to compare the efficacy and safety of utidelone plus capecitabine for advanced first-line versus second-line or above therapy in metastatic breast cancer patients who had previously received anthracycline and taxane. At the same time, we compared the efficacy of utidelone plus capecitabine and vinorelbine plus cisplatin in advanced first-line treatment of metastatic breast cancer.
PATIENTS AND METHODS
A retrospective cohort of 11 patients with metastatic breast cancer previously treated with anthracycline and taxane (including neoadjuvant and adjuvant therapies) for advanced first-line with utidelone plus capecitabine, 32 patients treated with second-line or above, and 60 patients with vinorelbine plus cisplatin between October 2011 and August 2022 was collected. The first and second groups were treated with utidelone plus capecitabine, and the third group was treated with vinorelbine plus cisplatin. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), objective response rate (ORR), and treatment safety.
RESULTS
By 03/31/2023, median PFS reached 11.70 months (95 % CI 0.093-0.141) in utidelone plus capecitabine group in the advanced first-line therapy, compared to 5.60 months (95 % CI 0.025-0.079) in the second-line or above therapy [HR 0.42, (95 % CI 0.226-0.787), P = 0.0077]. In utidelone plus capecitabine, the median OS was not reached in the advanced first-line therapy, with a mean overall survival of 23.16 months (95 % CI 0.198-0.265); whereas the median OS in the second-line or above therapy was 19.50 months (95 % CI 0.083-0.307), with a mean overall survival of 16.89 months (95 % CI 0.136-0.202) [HR 0.26, (95 % CI 0.098-0.678), P = 0.0495]. The ORR for advanced first-line therapy was 27.27 % (95%CI 0.060, 0.610) compared with 15.63 % (95%CI 0.053, 0.328) for second-line or above. In advanced first-line therapy, utidelone plus capecitabine was superior to vinorelbine plus cisplatin with a median PFS of 6.12 months (95 % CI 0.051-0.072) [HR 0.49, (95 % CI 0.286-0.839), P = 0.0291]. Compared with utidelone plus capecitabine, the median OS in vinorelbine plus cisplatin advanced first-line therapy group was 35.37 months (95 % CI 0.258-0.449), and the mean overall survival was 40.79 months (95 % CI 0.315-0.501) [HR 0.54, (95 % CI 0.188-1.568), P = 0.2587]. The ORR for vinorelbine plus cisplatin was 18.33 % (95 % CI 0.095, 0.304). The most common adverse events in our study were neurological toxicity, hand-foot syndrome, hematological toxicity, gastrointestinal toxicity, and hepatic and renal function abnormalities. There were no deaths due to adverse effects during the utidelone plus capecitabine treatment period.
CONCLUSIONS
In MBC, advanced first-line therapy with utidelone plus capecitabine resulted in more favorable PFS, OS, and ORR than second-line or above therapy. In advanced first-line therapy, utidelone plus capecitabine had superior PFS, and ORR compared with vinorelbine plus cisplatin. This study concludes that utidelone plus capecitabine is a more valuable chemotherapy option in advanced first-line MBC.
PubMed: 38026829
DOI: 10.1016/j.sopen.2023.10.008 -
Frontiers in Veterinary Science 2023Canine mesothelioma is a rare malignant tumor that mostly affects body cavities, such as the pericardial and pleural cavities. Chemotherapy plays a crucial role in the...
INTRODUCTION
Canine mesothelioma is a rare malignant tumor that mostly affects body cavities, such as the pericardial and pleural cavities. Chemotherapy plays a crucial role in the treatment of canine mesotheliomas. We aimed to compare the antitumor effects of single-agent and combination chemotherapeutic agents on patient-derived primary cultures of canine pericardial mesothelioma established in this study. We planned to generate xenograft models for future studies.
MATERIAL AND METHODS
Effusion samples were collected from three dogs with histologically diagnosed pericardial mesothelioma and used for primary culture. Cultured cells were characterized by immunostaining for pan-cytokeratin AE1/AE3, vimentin, Wilms' tumor suppressor gene 1 (WT1), and cytokeratin 5 (CK5). To assess the tumorigenic properties of cells in the effusion and generate a xenograft model, the cell suspension was injected into a severe combined immunodeficient (SCID) mouse either subcutaneously (SC) or intraperitoneally (IP). Lastly, chemosensitivity of established primary cultures against four drugs, doxorubicin, vinorelbine, carboplatin, and gemcitabine, by single-agent treatment as well as combination treatment of carboplatin at a fixed concentration, either 10 or 100 μM, and gemcitabine at different concentrations ranging from 0-1000 μM was assessed by cell viability assay.
RESULTS
Primary cultures were successfully generated and characterized by dual positivity for AE1/AE3 and vimentin and positive staining for WT-1 and CK5, confirming the mesothelial origin of the cells. In the xenograft models, SC mouse developed a subcutaneous mass, whereas IP mouse developed multiple intraperitoneal nodules. The masses were histopathologically consistent with mesotheliomas. The chemosensitivity assay revealed that carboplatin had the highest anti-tumor effects among the four tested single-agent treatments. Furthermore, carboplatin at 100 μM combined with gemcitabine at clinically relevant doses demonstrated the augmented anti-tumor effects compared to single-agent treatment.
DISCUSSION AND CONCLUSION
Primary cultures and xenograft models generated in this study could be useful tools for and studies of canine mesothelioma. Carboplatin is a highly effective chemotherapeutic agent against canine mesothelioma when used as a sole agent and in combination with gemcitabine.
PubMed: 38026668
DOI: 10.3389/fvets.2023.1267359 -
Blood Research Dec 2023
PubMed: 37964656
DOI: 10.5045/br.2023.2023182