Antihypertensive drug use and prostate cancer-specific mortality in Finnish men.
ABSTRACT: The aim of this study was to investigate pre- and post-diagnostic use of antihypertensive drugs on prostate cancer (PCa)-specific survival and the initiation of androgen deprivation therapy (ADT). The cohort investigated 8,253 PCa patients with 837 PCa-specific deaths during the median follow-up of 7.6 years after diagnosis. Information on drug use, cancer incidence, clinical features of PCa, and causes of death was collected from Finnish registries. Hazard ratios with 95% confidence intervals were calculated using Cox regression with antihypertensive drug use as a time-dependent variable. Separate analyses were performed on PCa survival related to pre- and post-diagnostic use of drugs and on the initiation of ADT. Antihypertensive drug use overall was associated with an increased risk of PCa-specific death (Pre-PCa: 1.21 (1.04-1.4), Post-PCa: 1.2 (1.02-1.41)). With respect to the separate drug groups, angiotensin II type 1 receptor (ATr) blockers, were associated with improved survival (Post-PCa: 0.81 (0.67-0.99)) and diuretics with an increased risk (Post-PCa: 1.25 (1.05-1.49)). The risk of ADT initiation was slightly higher among antihypertensive drug users as compared to non-users. In conclusion, this study supports anti-cancer effect of ATr blockers on PCa prognosis and this should be investigated further in controlled clinical trials.
Project description:BACKGROUND:Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post-treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers. METHODS:RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal. RESULTS:A number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015). CONCLUSIONS:Here we report on the first "real-time" in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel.
Project description:Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear. To explore the effects of ADT on PCa TIM, RNA sequencing was performed on six paired pre-ADT biopsy and post-ADT PCa lesions, and five paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa. Bioinformatics methods including ESTIMATE and ssGSEA were used to evaluate the stromal immune score and immune cell infiltration in PCa and paracancerous tissues. Weighted correlation network analysis was used to screen hub genes in the ADT-induced immune remodeling process. The results showed differences exist between PCa and paracancerous tissues in response to ADT. Compared with paracancerous tissues, the immune remodeling effect of ADT in PCa was more intense. ZFP36, JUNB, and SOCS3 served as hub genes in the ADT-induced immune remodeling process and were associated with PSA recurrent-free survival in the TCGA and our neoadjuvant ADT cohort. To investigate the joint action of the above three hub genes, an immune signature score was constructed. The results showed that immune signature score-based immune subtypes reveal the heterogeneity of the immune microenvironment of PCa and showed significant differences in patient prognosis, tumor immune infiltration, mutation burden, and landscape.
Project description:J Clin Hypertens (Greenwich). 2009;11:466-474. (c)2009 Wiley Periodicals, Inc.Lower heart failure (HF) rates in individuals taking chlorthalidone vs amlodipine, lisinopril, or doxazosin were unanticipated in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). HF differences appeared early, leading to questions about the possible influence of pre-enrollment antihypertensive drugs. A post hoc study evaluated hospitalized HF events. During year 1479 individuals had HF, with pre-entry antihypertensive medication data obtained on 301 patients (63%). Case-only analysis examined interactive effects (interaction odds ratio [OR, ratio of ORs]) of previous medication and ALLHAT treatment on HF outcomes, eg, did treatment effect differ by pre-entry antihypertensive class? Among cases, 39%, 37%, 17%, and 47% were taking pre-entry diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers, respectively. Interaction OR for year 1 HF for amlodipine vs chlorthalidone for patients taking vs not taking diuretics pre-entry was 1.08 (95% confidence interval [CI], 0.53-2.21; P=.83); for lisinopril vs chlorthalidone, 1.33 (95% CI, 0.65-2.74; P=.44); and for doxazosin vs chlorthalidone, 1.13 (95% CI, 0.57-2.25; P=.73). Controlling for other pre-entry antihypertensives yielded similar results. There was no significant evidence that pre-entry drug type explained observed hospitalized HF differences by ALLHAT treatment.
Project description:Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT?>?TLK1?>?NEK1?>?ATR?>?Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP and TRAMP-C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT).
Project description:Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ?5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan-Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27-70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58-164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103-132). In total, 314 MDTs were performed and 25 patients (13%) received ?3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials.
Project description:Through in vitro kinase assays and docking studies, we report the synthesis and biological evaluation of a phenothiazine analog J54 with potent TLK1 inhibitory activity for prostate cancer (PCa) therapy. Most PCa deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa. Treatments that can suppress the conversion to mCRPC have high potential to be rapidly implemented in the clinics. ADT results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DNA damage response that typically results in temporary cell-cycle arrest of androgen-responsive PCa cells, whereas its abrogation leads to apoptosis. We studied J54 as a potent inhibitor of this axis and as a mediator of apoptosis in vitro and in LNCaP xenografts, which has potential for clinical investigation in combination with ADT. J54 has low affinity for the dopamine receptor in modeling and competition studies and weak detrimental behavioral effects in mice and C. elegans.
Project description:To evaluate Medicare Part D's impact on use of antihypertensive medications among seniors with hypertension.Medicare-Advantage plan pharmacy data from January 1, 2004 to December 12, 2007 from three groups who before enrolling in Part D had no or limited drug benefits, and a comparison group with stable employer-based coverage.Pre-post intervention with a comparison group design was used to study likelihood of use, daily counts, and substitutions between angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers (ARBs).Antihypertensive use increased most among those without prior drug coverage: likelihood of use increased (odds ratio = 1.40, 95 percent confidence interval [CI] 1.25-1.56), and daily counts increased 0.29 (95 percent CI 0.24-0.33). Proportion using ARBs increased from 40 to 46 percent.Part D was associated with increased antihypertensive use and use of ARBs over less expensive alternatives.
Project description:BACKGROUND:SLCO-encoded transporters have been associated with progression to castration-resistant prostate cancer (CRPC) after initiation of androgen deprivation therapy (ADT). Although expressed at lower levels than in CRPC tissues, SLCO-encoded transporters may also play a role in response of primary prostate cancer (PCa) to ADT and biochemical recurrence. METHODS:We systematically explored expression of the 11 human SLCO genes in a large sample of untreated and ADT-treated normal prostate (NP) and primary PCa tissues, including tumors treated with neoadjuvant abiraterone. RESULTS:Transporters with the most recognized role in steroid uptake in PCa, including SLCO2B1 (DHEAS) and 1B3 (testosterone), were consistently detected in primary PCa. SLCO1B3 was nearly 5-fold higher in PCa vs NP with no difference in Gleason 3 vs 4 and no change with ADT. SLCO2B1 was detected at 3-fold lower levels in PCa than NP but was nearly 7-fold higher in Gleason 4 vs Gleason 3 and increased 3-fold following ADT (p?<?0.05 for all). CONCLUSIONS:We observed clear differences in SLCO expression in PCa vs NP samples, in Gleason 4 vs Gleason 3 tumors, and in ADT-treated vs untreated tissues. These findings are hypothesis generating due to small sample size, but suggest that baseline and ADT-induced changes in PCa OATP expression may influence steroid uptake and response to ADT, as well as uptake and response to drugs such as abiraterone and docetaxel which are also subject to OATP-mediated transport and are now being routinely combined with ADT in the metastatic castration sensitive setting.
Project description:The transition from CKD to ESRD can be particularly unstable, with high rates of death and hospitalizations. Few studies have examined medication use during this critical period. We examined patterns of antihypertensive medication use from the four quarters before and eight quarters after incident ESRD treated with maintenance dialysis.We used the US Renal Data System to identify patients aged ?67 years initiating dialysis for ESRD between January 2008 and December 2010 with Medicare Part D and a low-income subsidy. We ascertained the incidence of AKI and hyperkalemia during each quarter on the basis of having at least 1 payment claim for the condition. We used Poisson regression with robust SEMs to formally test for changes in the trend and level of antihypertensive medication use in a series of intervention analyses.The number of antihypertensive drugs used increased as patients neared ESRD, peaking at an average of 3.4 in the quarter immediately preceding dialysis initiation, then declining to 2.2 medications by 2 years later. Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use was stable at approximately 40%, even among patients with coronary disease and systolic heart failure, and did not correlate with AKI or hyperkalemia. Dialysis initiation was associated with a 40% (95% confidence interval, 38% to 43%) lower adjusted level of diuretic use, which continued to decline after ESRD. Three- and four-drug combinations that included a diuretic were most common before ESRD, whereas after ESRD, one- and two-drug ?-blocker or calcium-channel blocker-based combinations were most common.The use of antihypertensive medications, particularly angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and diuretics, may be suboptimal during the transition from CKD to ESRD, especially in patients with coronary disease or systolic heart failure. Future studies are needed to identify strategies to increase the appropriate use of antihypertensive medications during this critical transition period.
Project description:Androgen deprivation therapy (ADT) is a widely used treatment for patients with hormone-sensitive prostate cancer (PCa). However, duration of treatment response varies, and most patients eventually experience disease progression despite treatment. Leuprorelin is a luteinizing hormone-releasing hormone (LHRH) agonist, a commonly used form of ADT. Prostate-specific antigen (PSA) is a biomarker for monitoring disease progression and predicting treatment response and survival in PCa. However, time-dependent profile of tumor regression and growth in patients with hormone-sensitive PCa on ADT has never been fully characterized. In this analysis, nationwide medical claims database provided by Humana from 2007 to 2011 was used to construct a population-based disease progression model for patients with hormone-sensitive PCa on leuprorelin. Data were analyzed by nonlinear mixed effects modeling utilizing Monte Carlo Parametric Expectation Maximization (MCPEM) method in NONMEM. Covariate selection was performed using a modified Wald's approximation method with backward elimination (WAM-BE) proposed by our group. 1113 PSA observations from 264 subjects with malignant PCa were used for model development. PSA kinetics were well described by the final covariate model. Model parameters were well estimated, but large between-patient variability was observed. Hemoglobin significantly affected proportion of drug-resistant cells in the original tumor, while baseline PSA and antiandrogen use significantly affected treatment effect on drug-sensitive PCa cells (Ds). Population estimate of Ds was 3.78 x 10-2 day-1. Population estimates of growth rates for drug-sensitive (Gs) and drug-resistant PCa cells (GR) were 1.96 x 10-3 and 6.54 x 10-4 day-1, corresponding to a PSA doubling time of 354 and 1060 days, respectively. Proportion of the original PCa cells inherently resistant to treatment was estimated to be 1.94%. Application of population-based disease progression model to clinical data allowed characterization of tumor resistant patterns and growth/regression rates that enhances our understanding of how PCa responds to ADT.