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Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation.

ABSTRACT: Prostate cancer is the fifth leading cause of male cancer death worldwide. Although docetaxel chemotherapy has been used for more than fifteen years to treat metastatic castration resistant prostate cancer, the high inter-individual variability of treatment efficacy and toxicity is still not well understood. Since prostate cancer has a high heritability, inherited biomarkers of the genomic signature may be appropriate tools to guide treatment. In this review, we provide an extensive overview and discuss the current state of the art of pharmacogenomic biomarkers modulating docetaxel treatment of prostate cancer. This includes (1) research studies with a focus on germline genomic biomarkers, (2) clinical trials including a range of genetic signatures, and (3) their implementation in treatment guidelines. Based on this work, we suggest that one of the most promising approaches to improve clinical predictive capacity of pharmacogenomic biomarkers in docetaxel treatment of prostate cancer is the use of compound, multigene pharmacogenomic panels defined by specific clinical outcome measures. In conclusion, we discuss the challenges of integrating prostate cancer pharmacogenomic biomarkers into the clinic and the strategies that can be employed to allow a more comprehensive, evidence-based approach to facilitate their clinical integration. Expanding the integration of pharmacogenetic markers in prostate cancer treatment procedures will enhance precision medicine and ultimately improve patient outcomes.

SUBMITTER: Varnai R

PROVIDER: S-EPMC6723793 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation.

Varnai Reka R Koskinen Leena M LM Mäntylä Laura E LE Szabo Istvan I FitzGerald Liesel M LM Sipeky Csilla C

Genes 20190808 8

Prostate cancer is the fifth leading cause of male cancer death worldwide. Although docetaxel chemotherapy has been used for more than fifteen years to treat metastatic castration resistant prostate cancer, the high inter-individual variability of treatment efficacy and toxicity is still not well understood. Since prostate cancer has a high heritability, inherited biomarkers of the genomic signature may be appropriate tools to guide treatment. In this review, we provide an extensive overview and ...[more]

PMID: 31398933

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Project description:ObjectivesTo assess cabazitaxel versus docetaxel re-challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy.Patients and methodsThe CANTATA trial was a prospective, two-arm, open-label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0-2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression-free survival (PFS) as defined by either date of pain progression, date of a cancer-related skeletal-related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012-003835-40.ResultsBetween 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54-76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported.ConclusionDue to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Project description:Docetaxel treatment is a standard chemotherapy strategy for castration-resistant prostate cancer (CRPC), and patients with CRPC eventually develop resistance to treatment. However, little is understood regarding the underlying mechanism of resistance. The present study aimed to identify the underlying crucial genes and regulatory networks associated with docetaxel resistance in prostate cancer using bioinformatics analyses. For this purpose, one expression profile dataset (GSE33455), which included two docetaxel-sensitive and two docetaxel-resistant cell lines, was downloaded from the Gene Expression Omnibus database, and analyses of differential gene expression and function enrichment were performed. A protein-protein interaction (PPI) network was constructed, and the associated hub genes were investigated using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape software. A total of 756 differentially expression genes (DEGs) were identified, including 509 downregulated and 247 upregulated genes. Enrichment analysis revealed that the DEGs were associated with the interferon-γ-mediated signaling pathway, protein binding, bicellular tight junctions and cancer pathways. Two modules were screened from the PPI network, and the corresponding genes were identified to be largely enriched in the interferon-γ-mediated signaling pathway and the negative regulators of the DExD/H-Box helicase 58/interferon induced with helicase C domain 1 signaling pathway, and enriched in cell-cell adhesion and the Rap1 signaling pathway. Among the ten hub genes, epidermal growth factor receptor, spleen tyrosine kinase (SYK), intracellular adhesion molecule 1 (ICAM1), interleukin (IL)6, CXC motif chemokine ligand 8 (CXCL8), cyclin dependent kinase 1 and CD44 molecule (CD44) were significantly differentially expressed in prostate cancer tissues compared with healthy tissues based on The Cancer Genome Atlas data. The Gene Expression Profiling Interactive Analysis database revealed that ICAM1 was positively associated with IL6 and CXCL8, and epidermal growth factor receptor was positively associated with CD44 and SYK. Additionally, ten hub genes, which were identified to be associated with the drug resistance of docetaxel in prostatic carcinoma in the present study, were predominantly associated with tumor progression and metastasis. Reverse transcription-quantitative PCR analysis performed on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines demonstrated that certain hub genes, including CDK1, 2'-5'-oligoadenylate synthetase 3, CXCL8 and CDH1, were highly expressed in the docetaxel-resistant cell lines, which confirmed the bioinformatics results. In conclusion, the present study identified a number of important genes that are associated with the molecular mechanism of docetaxel resistance by integrated bioinformatical analysis, and these genes and regulatory networks may assist with identifying potential gene therapy targets for CRPC. Further functional analyses are required to validate the current findings.

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Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation.

Publications

Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation.

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