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VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide.

ABSTRACT: BACKGROUND: No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone. METHODS: Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (-2578A/C, -634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy-Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan-Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant. RESULTS: Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the -2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the -634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the -634CC genotype had a median PFS of 2.2 months whereas patients with the genotype -634CG/GG had a median PFS of 6.25 months (P=0.0042). CONCLUSION: The -634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule.

SUBMITTER: Orlandi P

PROVIDER: S-EPMC3749570 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundAlthough recent progress has been made in treating castration resistant prostate cancer, the interplay of signaling pathways which enable castration resistant growth is incompletely understood. A data driven, multivariate approach, was used in this study to predict prostate cancer cell survival based on the phosphorylation levels of key proteins in PC3, LNCaP, and MDA-PCa-2b cell lines in response to EGF, IGF1, IL6, TNF?, dihydrotestosterone, and docetaxel treatment.MethodsThe prostate cancer cell lines were treated with ligands or inhibitors, cell lyates were collected, and the amount of phosphoprotein quantified using 384 well ELISA assays. In separate experiments, relative cell viability was determined using an MTT assay. Normalized data was imported into Matlab where regression analysis was performed.ResultsBased on a linear model developed using partial least squares regression, p-Erk1/2 was found to correlate with castration resistant survival along with p-RPS6, and this model was determined to have a leave-one-out cross validated R2 value of 0.61. The effect of androgen on the phosphoproteome was examined, and increases in PI3K related phosphoproteins (p-Akt, p-RPS6, and p-GSK3) were observed which accounted for the majority of the significant increase in androgen-mediated cell survival. Simultaneous inhibition of the PI3K pathway and treatment with androgen resulted in a non-significant increase in survival. Given the strong effect of PI3K related signaling in enabling castration resistant survival, the specific effect of mTor versus complete inhibition was examined using targeted inhibitors. It was determine that mTor inhibition accounts for 52% of the effect of complete PI3K inhibition on cell survival. The differences in signaling between the cell lines were explored it was observed that MDA-PCa-2b exhibited far less activation of p-Erk in response to varying treatments, explaining one of the reasons for the lack of castration resistance.ConclusionIn this work, regression analysis to the phosphoproteome was used to illustrate the sources of castration resistance between the cell lines including reduced p-Erk signaling in MDA-PCa-2b and variations in p-JNK across the cell lines, as well as studying the signaling pathways which androgen acts through, and determining the response to treatment with targeted inhibitors.

Project description:The standard treatment for metastatic prostate cancer, androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP prostate cancer xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR-targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide-resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was dipeptidyl peptidase 4 (DPP4), which encodes a membrane-anchored protein that cleaves dipeptides from multiple growth factors, resulting in their increased degradation. DPP4 mRNA and protein were also decreased in clinical CRPC cases, and inhibition of DPP4 with sitagliptin enhanced the growth of prostate cancer xenografts following castration. Significantly, DPP4 inhibitors are frequently used to treat type 2 diabetes as they increase insulin secretion. Together, these results implicate DPP4 as an AR-regulated tumor suppressor gene whose loss enhances growth factor activity and suggest that treatment with DPP4 inhibitors may accelerate emergence of resistance to ADT.Significance: These findings identify DPP4 as an AR-stimulated tumor suppressor gene that is downregulated during progression to castration-resistant prostate cancer, warning that treatment with DPP4 inhibitors, commonly used to treat type 2 diabetes, may accelerate prostate cancer progression following androgen deprivation therapy. Cancer Res; 78(22); 6354-62. ©2018 AACR.

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VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide.

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