Addition of atezolizumab to carboplatin significantly improves survival of patients with metastatic triple-negative breast cancer: TBCRC 043 phase 2 randomized clinical trial
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PROVIDER: PRJNA1103250 | ENA |
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Project description:Addition of atezolizumab to carboplatin significantly improves survival of patients with metastatic triple-negative breast cancer: TBCRC 043 phase 2 randomized clinical trial
| PRJNA1103252 | ENA
Project description:The Phase 3 1L urothelial carcinoma (IMvigor130) trial revealed more favorable effects on overall survival with atezolizumab combined with gemcitabine and cisplatin (GemCis) than with atezolizumab combined with gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin vs carboplatin as a potential explanation for these clinical observations. GemCis compared with GemCarbo ± atezolizumab induced transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T-cell activation programs. In vitro experiments demonstrated that cisplatin, compared with carboplatin, exerted direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in urothelial carcinoma and highlight the potential importance of specific chemotherapy backbones for immune checkpoint blockade combination therapies.
2023-11-02 | GSE235066 | GEO
Project description:Following the re-exposure to lipopolysaccharide (LPS), macrophages exhibit the immunosuppressive state contribute to low production of proinflammatory cytokines and inability to respond the stimuli, a phenomenon is termed “tolerance”. Histone modification has been found in LPS-induced tolerant macrophages. Carboplatin, an antitumor drug, exerts its general effect on inhibition of DNA replication and transcription as well as epigenetic modification. Therefore, we hypothesized that carboplatin can be used to rescue the tolerance in macrophages. We found that carboplatin increases IL-6 but not TNF-α production in LPS-primed cells. The significant inductions were examined in carboplatin-treated tolerant macrophages evaluated by ELISA and qPCR. GSEA analyses revealed that p53 was the significant hallmark in both primed and tolerant RNA-Seq transcripts under carboplatin exposure while E2F ang G2/M were the upmost in negative hallmarks. HP1-α, heterochromatin protein 1, was significantly reduced in carboplatin-treated tolerant macrophages. The significant lower transcript of H3K9me3 methyltransferase, setdb2, was determined whereas kdm4d, demethylase encoding gene was significantly up-regulated in the presence of carboplatin in tolerant macrophages. Based on our data we suggested that carboplatin mediated upregulation of proinflammatory cytokine and rescue tolerance via the H3K9me3 modification. Carboplatin is potentially be a therapeutic drug for tolerance recovery in sepsis patients.
2021-11-10 | GSE179974 | GEO
Project description:Brucella melitensis 043 Genome sequencing and assembly
| PRJNA182774 | ENA
Project description:Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
2021-07-07 | PXD021726 | Pride
Project description:Sulfitobacter sp. MF3-043 Genome sequencing
| PRJNA1157548 | ENA
Project description:This is a 3 arm Phase 3 study to evaluate the safety and efficacy of the addition of veliparib plus carboplatin versus the addition of carboplatin to standard neoadjuvant chemotherapy versus standard neoadjuvant chemotherapy in subjects with early stage TNBC.
| 2158476 | ecrin-mdr-crc
Project description:SK-OV-3 cells under prolonged carboplatin exposition turn into giant cells. This dataset contains the transcriptome of cultured SK-OV-3 cells with and without carboplatin.
2016-04-30 | E-MTAB-3770 | biostudies-arrayexpress
Project description:ImportanceAgents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with PD-L1-positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined.ObjectiveTo evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC.Design, setting, and participantsThis phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021.InterventionsPatients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up.Main outcome and measuresThe primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers.ResultsAll 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio [HR], 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1-positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype.Conclusions and relevanceIn this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels.Trial registrationClinicalTrials.gov Identifier: NCT03206203.
| S-EPMC10722391 | biostudies-literature