Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-based Cohorts (LEANORA)
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PROVIDER: PRJNA1159914 | ENA |
REPOSITORIES: ENA
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Project description:Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-based Cohorts (LEANORA)
| PRJNA1159915 | ENA
Project description:Ongoing studies suggest that letrozole (LTZ), a drug used in the treatment of breast cancer, can potentially be repurposed as a novel therapeutic for Glioblastoma (GBM). In a phase 0/1 trial in recurrent GBM patients we observed that LTZ permeates into the GBM tissue and triggers dose-dependent changes in the expression of genes regulating cell cycle (e.g. CDKN2A/N2B, CDK4). Based on these observations, we hypothesized that a combination of cyclin dependent kinase (CDK) 4/6 inhibitors with LTZ may result in synergistic anti-GBM activity. Therefore, we assessed the anti-tumor effects of LTZ in combination with ribociclib, a third-generation CDK4/6 inhibitor and the brain pharmacokinetics of ribociclib. Using cell viability and neurosphere growth assay against a panel of patient-derived GBM lines both compounds were found to be cytotoxic when used as single agents and were strongly synergistic when used in combination. We then assessed the DNA damaging effects (ɣH2AX induction), cell cycle arrest and the induction of apoptosis (Annexin V-FITC/PI) of both compounds as single agents and when used in combination. LTZ potentiated ribociclib-induced DNA damage and cell cycle arrest leading to apoptosis. Systemic and brain pharmacokinetics analysis of ribociclib in Sprague-Dawley (SD) rats by serial blood and brain extracellular fluid (ECF) sampling showed that ribociclib penetrates the blood-brain barrier with a partitioning coefficient (Kpu, u, brain) of about 10%. Overall, our studies suggest that a combination of ribociclib with LTZ is likely to be strongly synergistic against GBM at concentrations of the drugs that can be achieved in the brain
2025-09-05 | GSE301688 | GEO
Project description:We report transcriptional response to ribociclib treatment in resistant and sensitive CAMA-1 cells using RNA sequencing. Acquired ribociclib resistant cells were generated by treating CAMA-1 cells over a period of 5 month. Cells were then treated with ribociclib or DMSO control and processed for RNA sequencing.
2020-06-22 | GSE143944 | GEO
Project description:To study mechanisms underlying response to ribociclib.
2022-01-10 | GSE182288 | GEO
Project description:Clinical Pharmacogenomics study. Renal Cell Carcinoma subjects were treated with CCI-779 and peripheral blood mononuclear cells were profiled over time of treatment. Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomics responses in patients with advanced renal cancer. Clin Pharm Therapeutics Dec 2004 Keywords: other
2004-12-01 | GSE1982 | GEO
Project description:Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3, *6, and *7). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve did not significantly differ between PMs (39,230 h*ng/mL) and IM/NMs (43,546 h*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.
| S-EPMC11442496 | biostudies-literature
Project description:Transcriptional profiling of ribociclib-treated sensitive and ribociclib resistant CAMA-1 cells
| PRJNA602306 | ENA
Project description:The green algal Botryococcus braunii (Chlorophyte) is known for accumulating high levels of hydrocarbons that are a useful alternative to fossil fuels. B. braunii is categorized into three groups based on types of their accumulated hydrocarbons: alkadiene/triene in race A, botryococcenes in race B, and lycopadiene in race L. Transcriptomic studies in race A and race B have discovered tremendous information related to the genes encoding proteins involved in hydrocarbon biosynthesis. However, transcriptome of race L has not been reported. In this study, we report a transcriptome of race L B. braunii AC768 through the de novo assembly using Hiseq platform. Our analyses indicate that photosynthesis and protein biosynthesis are the most abundantly transcribed in actively growing race L B. braunii. We show that the transcriptome of race L shares similar amounts (~20%) of mutual best-hits with that of race A or race B. Sequence homologous analyses indicate that enzymes involved in squalene and phytoene biosynthesis are well separated into geranyl-diphosphate synthase, farnesyl-diphosphate synthase, geranylgeranyl-diphosphate synthase, phytoene synthase, and squalene synthase. Both B. braunii specific enzymes botryococcene synthase SSL3 and lycopaoctaene synthase LOS are found to form distinctive subgroups in the group of squalene synthase. One of the ESTs in AC768 transcriptome that falls into the subgroup with LOS and shares >88% identity with that of LOS. Together, our results show that SSL and LOS are unique to race B and race L B. braunii subspecies, respectively. We propose that phytoene synthase in race L shares higher homolog to squalene synthase than phytoene synthase in other algae.
2019-11-21 | GSE96585 | GEO
Project description:Purpose: DDL and LMS are two common subtypes of soft tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting CDK4/6 in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus, have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients.Methods: This was a single arm, open label, multi-center phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression free rate (PFR) at 16 weeks. Secondary endpoints included progression free (PFS) and overall survival, safety and biomarker analyses. Results: In the DDL cohort, 33.3% (95% CI 15.6%-55.3%) of patients were progression free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%) and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor.Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects.
2023-11-09 | GSE247026 | GEO
Project description:Pharmacogenomics of Rheumatoid Arthritis Therapy
| PRJNA294477 | ENA