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Molecular Oncology Oct 2023Chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA-binding protein Hu...
Chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA-binding protein Hu antigen R (HuR) could be a potential therapeutic target to enhance the chemotherapy efficacy. HuR is known to mainly stabilize its target mRNAs, and/or promote the translation of encoded proteins, which are implicated in multiple cancer hallmarks, including chemoresistance. In this study, a docetaxel-resistant cell subline (231-TR) was established from the human TNBC cell line MDA-MB-231. Both the parental and resistant cell lines exhibited similar sensitivity to the small molecule functional inhibitor of HuR, KH-3. Docetaxel and KH-3 combination therapy synergistically inhibited cell proliferation in TNBC cells and tumor growth in three animal models. KH-3 downregulated the expression levels of HuR targets (e.g., β-Catenin and BCL2) in a time- and dose-dependent manner. Moreover, KH-3 restored docetaxel's effects on activating Caspase-3 and cleaving PARP in 231-TR cells, induced apoptotic cell death, and caused S-phase cell cycle arrest. Together, our findings suggest that HuR is a critical mediator of docetaxel resistance and provide a rationale for combining HuR inhibitors and chemotherapeutic agents to enhance chemotherapy efficacy.
Topics: Animals; Humans; Apoptosis; Cell Line, Tumor; Cell Proliferation; Docetaxel; RNA-Binding Proteins; Triple Negative Breast Neoplasms
PubMed: 37357618
DOI: 10.1002/1878-0261.13478 -
Radiology and Oncology Sep 2023The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune...
Efficacy and safety of nintedanib and docetaxel in patients with previously treated lung non-squamous non-small cell lung cancer: a multicenter retrospective real-world analysis.
BACKGROUND
The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune checkpoint inhibitors (ICI) and/or chemotherapy (ChT). Therapy after failing ICI +/- ChT remains an open question, and docetaxel plus nintedanib represent a valid second line option.
PATIENTS AND METHODS
A multicenter retrospective trial of real-life treatment patterns and outcomes of patients with advanced lung adenocarcinoma treated with docetaxel plus nintedanib after the failure of ICI and/or ChT was performed. Patients from 2 Slovenian and 1 Croatian oncological center treated between June 2014 and August 2022 were enrolled. We assessed objective response (ORR), disease control rate (DCR), median progression free survival (PFS), median overall survival (OS), and safety profile of treatment.
RESULTS
There were 96 patients included in the analysis, with ORR of 18.8%, DCR of 57.3%, median PFS of 3.0 months (95% CI: 3.0-5.0 months), and a median OS of 8.0 months (95% CI: 7.0-10.0 months). The majority of patients (n = 47,49%) received docetaxel plus nintedanib as third-line therapy. The ORR for this subset of patients was 19.1%, with a DCR of 57.4%. The highest response rate was observed in patients who received second-line docetaxel plus nintedanib after first-line combination of ChT-ICI therapy (n = 24), with an ORR of 29.2% and DCR of 66.7% and median PFS of 4.0 months (95% CI: 3.0-8.0 months). Fifty-three patients (55.2%) experienced adverse events (AEs), most frequently gastrointestinal; diarrhea (n = 29, 30.2%), and increased liver enzyme levels (n = 17, 17.7%).
CONCLUSIONS
The combination of docetaxel and nintedanib can be considered an effective therapy option with an acceptable toxicity profile for patients with advanced NSCLC after the failure of ICI +/- ChT.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Retrospective Studies; Lung Neoplasms; Lung
PubMed: 37665737
DOI: 10.2478/raon-2023-0040 -
Cancer Immunology, Immunotherapy : CII Aug 2023There is strong evidence that chemotherapy can induce tumor necrosis which can be exploited for the targeted delivery of immuno-oncology agents into the tumor...
There is strong evidence that chemotherapy can induce tumor necrosis which can be exploited for the targeted delivery of immuno-oncology agents into the tumor microenvironment (TME). We hypothesized that docetaxel, a chemotherapeutic agent that induces necrosis, in combination with the bifunctional molecule NHS-IL-12 (M9241), which delivers recombinant IL-12 through specific targeting of necrotic regions in the tumor, would provide a significant antitumor benefit in the poorly inflamed murine tumor model, EMT6 (breast), and in the moderately immune-infiltrated tumor model, MC38 (colorectal). Docetaxel, as monotherapy or in combination with NHS-IL-12, promoted tumor necrosis, leading to the improved accumulation and retention of NHS-IL-12 in the TME. Significant antitumor activity and prolonged survival were observed in cohorts receiving docetaxel and NHS-IL-12 combination therapy in both the MC38 and EMT6 murine models. The therapeutic effects were associated with increased tumor infiltrating lymphocytes and were dependent on CD8 T cells. Transcriptomics of the TME of mice receiving the combination therapy revealed the upregulation of genes involving crosstalk between innate and adaptive immunity factors, as well as the downregulation of signatures of myeloid cells. In addition, docetaxel and NHS-IL-12 combination therapy effectively controlled tumor growth of PD-L1 wild-type and PD-L1 knockout MC38 in vivo, implying this combination could be applied in immune checkpoint refractory tumors, and/or tumors regardless of PD-L1 status. The data presented herein provide the rationale for the design of clinical studies employing this combination or similar combinations of agents.
Topics: Mice; Animals; Docetaxel; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Neoplasms; Interleukin-12; Necrosis; Tumor Microenvironment; Cell Line, Tumor; Immunotherapy
PubMed: 37166485
DOI: 10.1007/s00262-023-03459-7 -
Cancers Aug 2023Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in... (Review)
Review
Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer.
PubMed: 37568784
DOI: 10.3390/cancers15153969 -
JAMA Network Open Nov 2023Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment paradigm.
OBJECTIVE
To assess for these patients whether adding docetaxel to standard of care (SOC) treatment is associated with decreased prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM).
DATA SOURCES
PubMed search from 2000 to 2022.
STUDY SELECTION
Five prospective randomized clinical trials (RCTs) performed in the US, France, and the United Kingdom evaluating SOC treatment with radiotherapy and androgen deprivation therapy (ADT) or with radical prostatectomy vs SOC plus docetaxel.
DATA EXTRACTION AND SYNTHESIS
Individual data were included from patients with nonmetastatic prostate cancer, a PSA level of less than 4 ng/mL, and a Gleason score of 8 to 10. Patients initiated treatment between February 21, 2006, and December 31, 2015 (median follow-up, 7.1 [IQR, 5.4-9.9] years). Data were analyzed on December 16, 2022.
MAIN OUTCOMES AND MEASURES
Hazard ratio (HR) of ACM and subdistribution HR (sHR) of PCSM adjusted for performance status (1 vs 0 or good health), Gleason score (9 or 10 vs 8), tumor category (T3-T4 vs T1-T2 or TX), and duration of ADT (2 years vs 4-6 months).
RESULTS
From a cohort of 2184 patients, 145 patients (6.6%) in 4 RCTs were eligible (median age, 63 [IQR, 46-67] years). Thirty-one patients died, and of these deaths, 22 were due to prostate cancer. Performance status was 0 for 139 patients (95.9%) and 1 for 6 patients (4.1%). A reduced but nonsignificant risk of ACM (HR, 0.51 [95% CI, 0.24-1.09]) and PCSM (sHR, 0.42 [95% CI, 0.17-1.02]) was associated with patients randomized to SOC plus docetaxel compared with SOC. The risk reduction in ACM (HR, 0.46 [95% CI, 0.21-1.02]) was more pronounced among patients with a performance status of 0 and was significant for PCSM (sHR, 0.30 [95% CI, 0.11-0.86]).
CONCLUSIONS AND RELEVANCE
Adding docetaxel to SOC treatment for patients who are in otherwise good health with a PSA level of less than 4 ng/mL and a Gleason score of 8 to 10 was associated with a significant reduction in PCSM and therefore has the potential to improve prognosis.
Topics: Male; Humans; Middle Aged; Docetaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Prostate; Prostatectomy; Randomized Controlled Trials as Topic
PubMed: 37910103
DOI: 10.1001/jamanetworkopen.2023.40787 -
Scientific Reports Aug 2023Corneal keratoconus (KC) is a dilated (ectatic) corneal disease characterized by a central thinning of the cornea, which causes protrusion into a conical shape that...
Corneal keratoconus (KC) is a dilated (ectatic) corneal disease characterized by a central thinning of the cornea, which causes protrusion into a conical shape that seriously affects vision. However, due to the complex etiology of keratoconus, its entire mechanism remains unclear and there is no mechanism-directed treatment method. Ferroptosis is a novel programmed cell death mechanism related to lipid peroxidation, stress, and amino acid metabolism, which plays a crucial role in various diseases. This study aimed to explore the relationship between keratoconus and ferroptosis, to provide new insights into the mechanism of keratoconus development, and potential treatment options based on further elucidation of this mechanism. The corresponding mRNA microarray expression matrix data of KC patients were obtained from GEO database (GSE204791). Weighted co-expression network analysis (WGCNA) and support vector machine recursive feature elimination (SVM-RFE) were selected to screen hub genes, which were overlapped with ferroptosis genes (FRGs) from FerrDb. GO and GSEA were performed to analyze differential pathways, ssGSEA was used to determine immune status, and then, feasible drugs were predicted by gene-drug network. Additionally, we predicted the miRNA and IncRNA of hub genes to identify the underlying mechanism of disease so as to predict treatment for the disease. The epithelial transcriptome from keratoconus tissue mRNA microarray data (GSE204791) was extracted for the main analysis, including eight epithelial cells and eight epithelial control cells. The differential genes that were overlapped by WGCAN, SVM-RFE and FRGs were mainly related to oxidative stress, immune regulation, cellular inflammation, and metal ion transport. Through further analysis, aldo-keto reductase family 1 member C3 (AKR1C3) was selected, and negatively correlated with mature CD56 natural killer (NK) cells and macrophages. Then, gene-drug interaction network analysis and miRNA prediction were performed through the website. It was concluded that four immune-related drugs (INDOMETHACIN, DAUNORUBICIN, DOXORUBICIN, DOCETAXEL) and a miRNA (has-miR-184) were screened to predict potential drugs and targets for disease treatment. To our knowledge, this was the first report of KC being associated with ferroptosis and prompted search for differential genes to predict drug targets of gene immunotherapy. Our findings provided insight and a solid basis for the analysis and treatment of KC.
Topics: Humans; Keratoconus; Ferroptosis; MicroRNAs; Cornea; Apoptosis
PubMed: 37626095
DOI: 10.1038/s41598-023-41194-2 -
Cell & Bioscience Nov 2023Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients...
BACKGROUND
Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge.
METHODS
We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models. In addition, We assessed the impact of RRM2 knockdown, ANXA1 over-expression, and PI3K/AKT pathway inhibition on the sensitivity of prostate cancer cells to docetaxel. Furthermore, we assessed the sensitivity of prostate cancer cells to the combination treatment of COH29 and docetaxel.
RESULTS
Our results demonstrated a positive association between RRM2 expression and docetaxel resistance in prostate cancer cell lines and tumor xenograft models. Knockdown of RRM2 increased the sensitivity of prostate cancer cells to docetaxel, suggesting its role in mediating resistance. Furthermore, we observed that RRM2 stabilizes the expression of ANXA1, which in turn activates the PI3K/AKT pathway and contributes to docetaxel resistance. Importantly, we found that the combination treatment of COH29 and docetaxel resulted in a synergistic effect, further augmenting the sensitivity of prostate cancer cells to docetaxel.
CONCLUSION
Our findings suggest that RRM2 regulates docetaxel resistance in prostate cancer by stabilizing ANXA1-mediated activation of the PI3K/AKT pathway. Targeting RRM2 or ANXA1 may offer a promising therapeutic strategy to overcome docetaxel resistance in prostate cancer.
PubMed: 37968699
DOI: 10.1186/s13578-023-01157-6 -
Journal of Experimental & Clinical... Nov 2023Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone. Therefore, we separately compared the immunomodulatory effects of EC and D in the setting of a randomized clinical trial.
METHODS
Tumor and blood samples of 154 patients from the ABCSG-34 trial were available (76 patients received four cycles of EC followed by four cycles of D; 78 patients get the reverse treatment sequence). Tumor-infiltrating lymphocytes, circulating lymphocytes and 14 soluble immune mediators were determined at baseline and at drug change. Furthermore, six BC cell lines were treated with E, C or D and co-cultured with immune cells.
RESULTS
Initial treatment with four cycles of EC reduced circulating B and T cells by 94% and 45%, respectively. In contrast, no comparable effects on lymphocytes were observed in patients treated with initial four cycles of D. Most immune mediators decreased under EC whereas D-treatment resulted in elevated levels of CXCL10, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR). Accordingly, only the exposure of BC cell lines to D induced similar increases as compared to E. While treatment of BC cells with E was associated with cell shrinkage and apoptosis, D induced cell swelling and accumulation of cells in G2 phase.
CONCLUSION
The deleterious effect of EC on lymphocytes indicates strong immunosuppressive properties of this combination therapy. D, in contrast, has no effect on lymphocytes, but triggers the secretion of stimulatory proteins in vivo and in vitro, indicating a supportive effect on the immune system. Underlying differences in the induced cell death might be causal. These divergent immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel should be considered when planning future combinations with immunotherapies in breast cancer.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Docetaxel; Epirubicin; Fluorouracil; Neoadjuvant Therapy; Treatment Outcome
PubMed: 37957750
DOI: 10.1186/s13046-023-02876-x -
Science Advances Jun 2023Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a...
Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme BCD8 T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.
Topics: Humans; Animals; Mice; Hydrogels; Immunogenic Cell Death; CD8-Positive T-Lymphocytes; Triple Negative Breast Neoplasms; Ceramides; Disease Models, Animal; Immunosuppressive Agents; Unfolded Protein Response; Tumor Microenvironment
PubMed: 37390205
DOI: 10.1126/sciadv.adf2746 -
Cancer Cell International Oct 2023Prostate cancer is currently the second most lethal malignancy in men worldwide due to metastasis and invasion in advanced stages. Studies have revealed that androgen...
BACKGROUND
Prostate cancer is currently the second most lethal malignancy in men worldwide due to metastasis and invasion in advanced stages. Studies have revealed that androgen deprivation therapy can induce stable remission in patients with advanced prostate cancer, although most patients will develop castration-resistant prostate cancer (CRPC) in 1-2 years. Docetaxel and enzalutamide improve survival in patients with CRPC, although only for a short time, eventually patients develop primary or secondary resistance, causing disease progression or biochemical relapse.
METHODS
The gene expression profiles of docetaxel-sensitive or -resistant prostate cancer cell lines, namely GSE33455, GSE36135, GSE78201, GSE104935, and GSE143408, were sequentially analyzed for differentially expressed genes and progress-free interval significance. Subsequently, the overall survival significance and clinic-pathological features were analyzed by the R package. The implications of hub genes mutations, methylation in prostate cancer and the relationship with the tumor immune cell infiltration microenvironment were assessed with the help of cBioPortal, UALCAN and TISIDB web resources. Finally, effects of the hub genes on the progression and drug resistance in prostate cancer were explored using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, cell phenotype, and drug sensitivity.
RESULT
Glutamate decarboxylase 1 (GAD1) was tentatively identified by bioinformatic analysis as an hub gene for the development of drug resistance, including docetaxel and enzalutamide, in prostate cancer. Additionally, GAD1 expression, mutation and methylation were significantly correlated with the clinicopathological features and the tumor immune microenvironment. RT-PCR, immunohistochemistry, cell phenotype and drug sensitivity experiments further demonstrated that GAD1 promoted prostate cancer progression and decreased the therapeutic effect of docetaxel or enzalutamide.
CONCLUSION
This research confirmed that GAD1 was a hub gene in the progression and development of drug resistance in prostate cancer. This helped to explain prostate cancer drug resistance and provides new immune-related therapeutic targets and biomarkers for it.
PubMed: 37904122
DOI: 10.1186/s12935-023-03093-4