Regulatory genes in the androgen production, uptake and conversion (APUC) pathway in advanced prostate cancer.
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SUBMITTER: McSweeney S
PROVIDER: S-EPMC10259352 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Regulatory genes in the androgen production, uptake and conversion (APUC) pathway in advanced prostate cancer.
McSweeney Sean S Bergom Hannah E HE Prizment Anna A Halabi Susan S Sharifi Nima N Ryan Charles C Hwang Justin J
Endocrine oncology (Bristol, England) 20220101 1
The androgen receptor (AR) signaling pathway regulates the progression of prostate cancer (PC). Metastatic castration-resistant prostate cancer (mCRPC) patients generally receive AR-targeted therapies (ART) or androgen-deprivation therapies (ADT) with the initial response; however, resistance is inevitably observed. Prior studies have shown activity and upregulation of a family of androgen production, uptake, and conversion - APUC genes - based on genomic analyses of patient germlines. Genetic v ...[more]
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Project description:BACKGROUNDProstate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADTs) are a cornerstone of treatment. ADT responsiveness may be associated with germline changes in genes that regulate androgen production, uptake, and conversion (APUC).METHODSWe analyzed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris Precision Oncology Alliance (POA) DNA (592-gene/whole exome) and RNA (whole transcriptome) next-generation sequencing databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival was determined from insurance claims data using Kaplan-Meier estimates.RESULTSSix APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores, suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define 2 subgroups of tumors with differential association with hallmark pathways and cell surface targets.CONCLUSIONSThe APUC-6-high/AR-low tumors represented a subgroup of patients with good clinical outcomes, in contrast with the AR-high or neuroendocrine PCs. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand (rather than AR) driven and require distinct therapeutic strategies.FUNDINGNCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
| S-EPMC11530133 | biostudies-literature
Project description:BackgroundProstate cancer (PC) is the most frequently diagnosed solid tumor in U.S. men. Genome-wide association studies (GWAS) have identified over 40 risk-associated single nucleotide polymorphisms (SNPs), including variants in androgen pathway genes (e.g., KLK3 and AR). Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC.MethodsIn this hypothesis-testing study, we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor (AR). A total of 187 SNPs were genotyped in 1458 cases and 1351 age-matched controls from a population-based study. PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models.ResultsSingle SNP analyses showed evidence (p < 0.05) for associations with 14 SNPs in 9 genes: NKX3.1, HSD17B3, AKR1C3, SULT2A1, CYP17A1, KLK3, JAK2, NCOA4 and STAT3. The most significant result was observed for rs2253502 in HSD17B3 (odds ratio, OR = 0.57, 95% CI: 0.39-0.84). In addition, five SNPs in four genes (CYP17A1, HSD17B4, NCOA4, and SULT2A1) were associated with more aggressive disease (p < 0.01).ConclusionsOur results replicate previously reported associations for SNPs in CYP17A1, HSD17B3, ARK1C3, NKX3.1, NCOA4 and KLK3. In addition, novel associations were observed for SNPs in JAK2, HSD17B4, and SULT2A1. These results will require replication in larger studies.
| S-EPMC3392409 | biostudies-literature
Project description:BACKGROUND:Inherited variability in genes that influence androgen metabolism has been associated with risk of prostate cancer. The objective of this analysis was to evaluate interactions for prostate cancer risk by using classification and regression tree (CART) models (i.e., decision trees), and to evaluate whether these interactive effects add information about prostate cancer risk prediction beyond that of "traditional" risk factors. METHODS:We compared CART models with traditional logistic regression (LR) models for associations of factors with prostate cancer risk using 1,084 prostate cancer cases and 941 controls. All analyses were stratified by race. We used unconditional LR to complement and compare with the race-stratified CART results using the area under curve (AUC) for the receiver operating characteristic curves. RESULTS:The CART modeling of prostate cancer risk showed different interaction profiles by race. For European Americans, interactions among CYP3A43 genotype, history of benign prostate hypertrophy, family history of prostate cancer, and age at consent revealed a distinct hierarchy of gene-environment and gene-gene interactions, whereas for African Americans, interactions among family history of prostate cancer, individual proportion of European ancestry, number of GGC androgen receptor repeats, and CYP3A4/CYP3A5 haplotype revealed distinct interaction effects from those found in European Americans. For European Americans, the CART model had the highest AUC whereas for African Americans, the LR model with the CART discovered factors had the largest AUC. CONCLUSION AND IMPACT:These results provide new insight into underlying prostate cancer biology for European Americans and African Americans.
| S-EPMC3111844 | biostudies-literature
Project description:ImportanceThe open-label randomized phase 2 LACOG0415 trial evaluated 3 treatment strategies for patients with advanced castration-sensitive prostate cancer (CSPC): androgen deprivation therapy (ADT) plus abiraterone acetate and prednisone (AAP), apalutamide (APA) alone, or APA plus AAP.ObjectiveTo investigate the association of ADT plus AAP, APA alone, or APA plus AAP with health-related quality of life (HRQOL) in patients with advanced CSPC in the LACOG0415 trial.Design, setting, and participantsThe LACOG0415 randomized clinical trial comprised 128 patients with advanced CSPC who were randomized (1:1:1) to 1 of 3 treatment arms from October 16, 2017, to April 23, 2019. Statistical analysis was conducted from March to September 2022.InterventionsPatients were randomized (1:1:1) to 1 of 3 treatment arms: ADT plus AAP, APA alone, or APA plus AAP.Main outcomes and measuresHealth-related quality of life was evaluated using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, including its subscales, completed at baseline and every 4 weeks until week 25. FACT-P scores range from 0 to 156, and higher scores indicate better HRQOL. Mean changes in score from baseline to week 25 were adjusted by baseline score and were calculated to evaluate whether there was a difference according to the treatment arm using a mixed-effect model for repeated measures. Time to deterioration was estimated by Kaplan-Meier curves and compared by stratified log-rank test. Analysis was performed on an intention-to-treat basis.ResultsA total of 128 patients with advanced CSPC were randomized to receive ADT plus AAP (n = 42; median age, 69.8 years [IQR, 58.9-71.6 years]), APA alone (n = 42; median age, 69.5 years [IQR, 59.8-72.6 years]), or APA plus AAP (n = 44; median age, 71.0 years [IQR, 63.0-72.3 years]). Metastatic disease was present in 95 patients (74.2%), high-risk biochemical recurrence disease in 22 (17.2%), and locally advanced disease in 11 (8.6%). There was no significant difference in baseline mean (SD) FACT-P total scores and subscales among the 3 treatment arms (FACT-P total score: ADT plus AAP arm, 118.5 [24.3]; APA alone arm, 116.1 [23.9]; AAP plus APA arm, 114.9 [18.1]; P = .69). Health-related quality of life was maintained during treatment period, and there were no statistically significant differences at 25 weeks in mean (SD) FACT-P total scores or subscales between treatment arms (FACT-P total score: ADT plus AAP arm, 122.3 [20.4]; APA alone arm, 119.5 [16.4]; AAP plus APA arm, 119.9 [20.3]). The APA alone and AAP plus APA arms were not associated with meaningful improvements in HRQOL compared with the ADT plus AAP arm, except in time to deterioration of the emotional well-being score, which was more favorable in the APA alone arm (reference arm: ADT plus AAP arm; APA alone arm: hazard ratio, 0.37 [0.15-0.85]; P = .02; ADT plus AAP arm: hazard ratio, 0.56 [0.26-1.19]; P = .13). Limitations include short follow-up period and the absence of other questionnaires to capture differences between therapies.Conclusions and relevanceIn this prespecified secondary analysis of a randomized clinical trial of ADT plus AAP, APA alone, or APA plus AAP for patients with advanced CSPC, HRQOL was not statistically different between treatments with APA alone or APA plus AAP as compared with ADT plus AAP. Larger studies with longer follow-up and more specific questionnaires are needed to further evaluate HRQOL with these treatment strategies.Trial registrationClinicalTrials.gov Identifier: NCT02867020.
| S-EPMC11731179 | biostudies-literature
Project description:IntroductionMetastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance.Areas coveredThis review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer.Expert opinionAndrogen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.
| S-EPMC4696015 | biostudies-literature
Project description:Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs) in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC) rs2707765 and rs497844, were significantly (p ≤ 0.009 and q ≤ 0.043) associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ≤ 0.003). Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer.
| S-EPMC5187770 | biostudies-literature
Project description:Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.
| S-EPMC7892335 | biostudies-literature
Project description:Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer.
| S-EPMC9979947 | biostudies-literature
Project description:Recently, mixed forms between adenocarcinoma and neuroendocrine prostate cancer (NEPC) have emerged that are characterized by persistent androgen receptor (AR)-signalling and elevated chromogranin A (CgA) levels. The main aim of this study was to analyze castration-resistant prostate cancer (CRPC) patients treated with abiraterone or enzalutamide, assessing progression-free/overall survival (PFS/OS) in association with circulating AR and CgA. AR aberrations were analyzed by droplet digital PCR in pre-treatment plasma samples collected from two biomarker protocols [197 patients from a retrospective study (REC 2192/2013) and 59 from a prospective trial (REC 6798/2015)]. We subdivided patients into three groups according to CgA by receiver-operating characteristic (ROC) curves. In the primary cohort, plasma AR gain and mutations (p.L702H/p.T878A) were detected in 78 (39.6%) and 16 (8.1%) patients, respectively. We observed a significantly worse PFS/OS in patients with higher-CgA than in patients with normal-CgA, especially those with no AR-aberrations. Multivariable analysis showed AR gain, higher-CgA and LDH levels as independent predictors of PFS [hazard ratio (HR) = 2.16, 95% confidence interval (95% CI) 1.50-3.12, p < 0.0001, HR = 1.73, 95% CI 1.06-2.84, p = 0.026, and HR = 2.13, 95% CI 1.45-3.13, p = 0.0001, respectively) and OS (HR = 1.72, 95% CI 1.15-2.57, p = 0.008, HR = 3.63, 95% CI 2.13-6.20, p < 0.0001, and HR = 2.31, 95% CI 1.54-3.48, p < 0.0001, respectively). These data were confirmed in the secondary cohort. Pre-treatment CgA detection could be useful to identify these mixed tumors and would seem to have a prognostic role, especially in AR-normal patients. This association needs further evaluation in larger prospective cohorts.
| S-EPMC6194135 | biostudies-literature
Project description:ObjectiveTo evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response.Patients and methodsIn a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing.ResultsAt the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less.ConclusionGenetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.
| S-EPMC3538410 | biostudies-literature