Project description:Early chemotherapy for advanced/metastatic non-castration resistant prostate cancer (PCa) may improve overall patient survival. We studied the safety, tolerability and early efficacy of up-front docetaxel chemotherapy and androgen deprivation therapy (ADT) versus ADT alone for patients with newly-diagnosed advanced/metastatic PCa. As proof of concept, we undertook in vivo gene expression profiling by next generation RNA sequencing (RNA-Seq).
Project description:Early chemotherapy for advanced/metastatic non-castration resistant prostate cancer (PCa) may improve overall patient survival. We studied the safety, tolerability and early efficacy of up-front docetaxel chemotherapy and androgen deprivation therapy (ADT) versus ADT alone for patients with newly-diagnosed advanced/metastatic PCa. As proof of concept, we undertook in vivo gene expression profiling by next generation RNA sequencing (RNA-Seq). Tumour biposies from 6 patients were taken before and after treatment with combined ADT and docetaxcel for 6 weeks
Project description:Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit due to emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure.
Project description:Comparison of the new generation taxane cabazitaxel with docetaxel in prostate cancer cells Cabazitaxel impacts distint molecular pathways as compared to docetaxel, which could underlie its efficacy after docetaxel treatment has failed in castration resistant prostate cancer patients 12 samples were analysed. A genome-wide expression array was performed on a GeneChip Human Gene 2.0ST Array (Affymetrix, 902112) with C4-2 cells, treated for 16h with 1nM cabazitaxel, docetaxel or vehicle (EtOH), in duplicates. The expression data were RMA normalized, and filtered to remove low-expressing genes. Differential gene expression with corresponding p-values (student’s ttest) was determined of drug-treated over control.
Project description:Docetaxel-based chemotherapy is the standard first-line therapy in metastatic castration-resistant prostate cancer. However, most patients eventually develop resistance to this treatment. The aim of the study was to identify key molecular genes and networks associated with docetaxel resistance in 2 models of docetaxel-resistant castration-resistant prostate cancer cell lines.
Project description:Comparison of the new generation taxane cabazitaxel with docetaxel in prostate cancer cells Cabazitaxel impacts distint molecular pathways as compared to docetaxel, which could underlie its efficacy after docetaxel treatment has failed in castration resistant prostate cancer patients
Project description:Comparison of the new generation taxane cabazitaxel with docetaxel in prostate cancer cells Cabazitaxel impacts distint molecular pathways as compared to docetaxel, which could underlie its efficacy after docetaxel treatment has failed in castration resistant prostate cancer patients
Project description:Comparison of the new generation taxane cabazitaxel with docetaxel in prostate cancer cells Cabazitaxel impacts distint molecular pathways as compared to docetaxel, which could underlie its efficacy after docetaxel treatment has failed in castration resistant prostate cancer patients 12 samples were analysed. A genome-wide expression array was performed on a GeneChip Human Gene 2.0ST Array (Affymetrix, 902112) with LNCaP cells infected with a control plasmid (MSCV-LMP), treated for 16h with 1nM cabazitaxel, docetaxel or vehicle (EtOH), in duplicates. The expression data were RMA normalized, and filtered to remove low-expressing genes. Differential gene expression with corresponding p-values (student’s ttest) was determined of drug-treated over control.
Project description:Purpose: To determine whether docetaxel therapy of advanced prostate cancer can be improved by using docetaxel in combination with Aneustat (OMN54), a multivalent botanical drug candidate undergoing a Phase-I Clinical Trial, and to identify the molecular action of this drug combination. Experimental Design: Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, either alone or in combination. Culture growth (at 48 hours) and xenograft size (at 3 weeks) were determined and animal health monitored. Xenografts were gene expression profiled using gene expression microarrays. Androgen receptor (AR) expression and AKT phosphorylation were examined. Results: Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner in vitro, reducing AR expression and AKT phosphorylation. Aneustat was not as effective as docetaxel in inhibiting LTL-313H xenograft growth. When combined, Aneustat and docetaxel markedly and synergistically enhanced anti-tumor activity without inducing major host toxicity, even leading to complete growth inhibition and tumor shrinkage not obtained with the single drugs. AR expression and AKT signalling in the xenografts were inhibited by docetaxel+Aneustat, but not by the single agents. Expression microarray analysis indicated that docetaxel+Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the drugs on their own. Conclusion: Our findings, obtained with a clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.