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- MicroRNAs and Drug Resistance in Prostate Cancer. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 17.
Prostate cancer is the second leading cause of cancer related death in American men. Androgen deprivation therapy (ADT) is used to treat patients with aggressive prostate cancers. After androgen deprivation therapy, prostate cancers slowly progress to an androgen-independent status. Taxanes (e.g. docetaxel) are used as standard treatments for androgen-independent prostate cancers. However, these chemotherapeutic agents will eventually become ineffective due to the development of drug resistance. A microRNA (miRNA) is a small non-coding RNA molecule which can regulate gene expression at the post-transcription level. miRNAs elicit their effects by binging to the 3'-untranslated region (3'-UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNAs. miRNAs have received increasing attention as targets for cancer therapy, as they can target multiple signaling pathways related to tumor progression, metastasis, invasion, and chemoresistance. Emerging evidence suggests that aberrant expression of miRNAs can lead to the development of resistant prostate cancers. Here, we discuss the roles of miRNAs in the development of resistant prostate cancers and their involvement in various drug resistant mechanisms including androgen signaling, apoptosis avoidance, MDR transporters, epithelialmesenchymal transition (EMT), and cancer stem cells (CSCs). In addition, we also discuss strategies for treating resistant prostate cancers by targeting specific miRNAs. Different delivery strategies are also discussed with focus on those have been successfully used in human clinical trials.
- Patterns of androgen deprivation therapies among men diagnosed with localised prostate cancer: A population-based study. [JOURNAL ARTICLE]
- Eur J Cancer 2014 Apr 12.
Many men diagnosed with localised prostate cancer will eventually be treated with androgen deprivation therapy (ADT). ADT is associated with adverse effects and its timing is controversial. Data on patterns of use are scarce. We describe patterns of ADT use, defined as castration (medical and surgical) or antiandrogen monotherapy initiated after primary treatment, in a population-based cohort.Data were extracted from the population-based Prostate Cancer data Base Sweden (PCBaSe). Totally 45,147 men diagnosed between 1997 and 2009 with clinical stage T1-2, N0-NX, M0-MX and prostate specific antigen (PSA)<50ng/ml without primary ADT were included. Outcomes in the period 2006 through 2010 were analysed using a period analysis approach.The cumulative incidence of castration at 10years after diagnosis was 11.6% (95% confidence interval (CI), 11.0-12.2%). The corresponding proportion of antiandrogen monotherapy was 10.8% (95% CI, 10.2-11.4%). Castration was the dominant therapy among men on deferred treatment. The probability of receiving castration rather than antiandrogen monotherapy increased with age. Estimated median durations of castration ranged from 4years in the deferred treatment high-risk group to 17years in the prostatectomy low-risk group. The main limitation was the lack of information on progression to metastatic disease and PSA at the time for initiation of ADT.When initiated early after curative treatment, the duration of castration can be decades. The findings indicate that more accurate tools are necessary to guide which men should be selected for ADT as secondary treatment.
- The Influence of Age and Comorbidity on the Benefit of Adding Androgen Deprivation to Dose-escalated Radiation in Men With Intermediate-risk Prostate Cancer. [JOURNAL ARTICLE]
- Am J Clin Oncol 2014 Apr 11.
Androgen deprivation therapy (ADT) can improve outcomes for men with intermediate-risk prostate cancer (IR-PrCa) receiving external-beam radiotherapy (EBRT). Older men and men with significant comorbidity may be more susceptible to the harms of ADT, therefore we aimed to determine whether these men benefit from ADT.The adult comorbidity evaluation-27 index categorized severity of comorbidity in 636 men treated for IR-PrCa with dose-escalated EBRT (>75 Gy). The cohort was dichotomized at median age of 70. Multivariate Cox proportional hazard analysis evaluated the association of ADT with failure-free survival (FFS) for each age and comorbidity subgroup.A total of 48% of men were 70 years and above. After adjustment for tumor characteristics, the addition of ADT to EBRT was associated with improved FFS for both men below 70 years of age (adjusted hazard ratio [AHR] 0.44; 95% confidence interval [CI], 0.19-0.99; P=0.046) and men 70 years and above (AHR 0.23; 95% CI, 0.06-0.91; P=0.035). ADT improved FFS for men below 70 years who had no or mild comorbidity (AHR 0.25; 95% CI, 0.09-0.73; P=0.011) but not for men below 70 years who had moderate or severe comorbidity (AHR 1.62; 95% CI, 0.35-7.49; P=0.537). Similarly, in men 70 years and above, there was a trend for improved FFS with ADT in healthy men (AHR 0.10; 95% CI, 0.01-1.08; P=0.058) but not in men with moderate to severe comorbidity (AHR 0.38; 95% CI, 0.06-2.56; P=0.318).The addition of ADT to dose-escalated EBRT can improve outcomes for both younger and older men with IR-PrCa. This benefit was more pronounced in healthy men.
- Does Statin or ASA Affect Survival When Prostate Cancer Is Treated with External Beam Radiation Therapy? [Journal Article]
- Prostate Cancer 2014.:184297.
Background.Prior studies evaluating the effect of statins or acetylsalicylic acid (ASA) on the survival of men receiving prostate cancer were treatment have reported conflicting results, and have not adjusted for comorbidity. Our aim is to investigate the influence of statins and ASA on prostate cancer survival, when comorbidity is adjusted for, in men treated with external beam radiation therapy (EBRT) for prostate cancer. Methods. A cohort of 3851 patients with prostate cancer treated with curative EBRT ± androgen deprivation therapy (ADT) between 2000 and 2007. Stage, treatment, medication use, and Charlson comorbidity index (CCI) scores were analyzed.
Results.Median followup was 8.4 years. Mean age was 70.3 years. Neoadjuvant ADT was used in 67%. Statins were used in 23%, ASA in 24%, and both in 11%. Comorbidity scores were 0 in 65%, 1 in 25%, and ≥2 in 10% of patients. Statin and ASA use were associated with increased age and comorbidity. Although statin and ASA use were significantly associated with improved prostate cancer specific survival (PCSS) on univariate analysis, neither were on multivariate analysis.
Conclusion.Neither statin nor ASA use impacted PCSS on multivariate competing risks analysis. Survival was impacted by increased comorbidity as well as statin and ASA use.
- Determinants of vitamin D levels in men receiving androgen deprivation therapy for prostate cancer. [JOURNAL ARTICLE]
- J Am Assoc Nurse Pract 2014 Apr 14.
Studies found an association between decreased 25-OH vitamin D blood level and prostate cancer progression. Vitamin D supplementation is controversial and dosage recommendations inconsistent. This study identified factors associated with 25-OH vitamin D levels and whether vitamin D supplementation with 800 IU/day raised vitamin D levels in prostate cancer patients receiving androgen deprivation therapy (ADT).We recruited 108 men treated with ADT for ≥9 months from eight cancer and urology practices. Sections of the NHANES 2005-2006 questionnaire and Canadian Fitness Survey were completed identifying age, ethnicity, length of ADT use, calcium supplementation ≥1000 IU mg/day, body mass index, exercise, alcohol and tobacco use, and vitamin D supplementation ≥800 IU/daily. Blood was collected for 25-OH vitamin D analysis.The majority of men (66%) had blood levels of 25-OH vitamin D <32 ng/mL. Regression analysis showed vitamin D supplementation (β = 6.556, CI 1.463, 11.650; p = .012) and African American ethnicity (β = -7.816, CI -12.996, -2.635; p = .003) is associated with 25-OH vitamin D level after controlling age and tobacco use.Findings support current recommendations for supplementation with ≥800 IU vitamin D/day for men receiving ADT. Nurse practitioners caring for prostate cancer patients receiving ADT should include vitamin D monitoring and supplementation.
- Weight Gain on Androgen Deprivation Therapy: Which Patients Are at Highest Risk? [JOURNAL ARTICLE]
- Urology 2014 Apr 8.
To identify factors associated with weight gain at 1 year from initiation of androgen deprivation therapy (ADT).A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT for at least 6 months. Outcome associations were tested using 2-tailed t tests and linear regression.Men in our cohort had significant weight gain (+1.32 kg, P = .0005) in the 1 year after ADT initiation. Three risk factors for weight gain on ADT were identified as follows: age <65 years (2.72 kg gained, P = .001), body mass index (BMI) <30 (1.98 kg gained, P = .00002), and nondiabetic status (1.56 kg gained, P = .0003). Multivariable regression found both age <65 years (beta = 4.01, P = .02) and BMI <30 (beta = 3.57, P = .03) to be independently predictive of weight gain, whereas nondiabetic status was nonsignificantly predictive of weight gain (beta = 2.14, P = .29). Weight change was further stratified by the total number of risk factors present (risk score): scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of -1.10, +0.41, +1.34, and +3.79 kg, respectively (P-trend = .0005).Age <65 years and BMI <30 were both independently associated with weight gain 1 year after starting ADT. Increasing weight gain was also strongly associated with increasing number of baseline risk factors present. Despite traditional concerns about ADT in unhealthy men, these data suggest younger, healthier patients may be at higher risk for gaining weight on ADT and should be counseled accordingly.
- Unrecognized kinetics of serum testosterone: impact on short-term androgen deprivation therapy for prostate cancer. [Journal Article]
- Yonsei Med J 2014 May 1; 55(3):570-5.
To evaluate the kinetics of serum testosterone (T) recovery following short-term androgen deprivation therapy (ADT), as the understanding thereof is essential for the proper management of prostate cancer (PCa), especially intermittent ADT.This prospective analysis included male sex offenders who voluntarily received leuprolide acetate in order to alleviate sexual aberrance. Thirty-three and 25 patients who received 3 and 6 months of ADT were assigned to Group A and Group B, respectively. Serum T levels were obtained every week during the on-cycle period, then monthly during the off-cycle period for at least 12 months.The kinetics of serum T during the on-cycle period were similar in both groups. After flare reaction at week 2, a nadir of 0.45±0.29 ng/mL was achieved. In Group A, an abrupt rebound-upsurge was observed during the first 2 month off-cycle period, which surpassed the baseline level and reached a plateau level of 8.74±2.11 ng/mL during the flare (p<0.001). This upsurge was followed by a gradual decline back to baseline over the following 10 months. In Group B, a gradual increase was observed, and a baseline level of 7.26±1.73 ng/mL was reached at 5 months. Thereafter, an ongoing upsurge that surpassed baseline levels was observed until 12 months (8.81±1.92 ng/mL; p=0.002).The kinetics of serum T recovery during the off-cycle period varied according to the duration of ADT. Serum T should be monitored beyond normalization, as an excessive rebound may improve quality-of-life, but hamper the treatment efficacy of PCa.
- Reconsideration of progression to CRPC during androgen deprivation therapy. [REVIEW]
- J Steroid Biochem Mol Biol 2014 Apr 6.
Androgen blockade-naïve prostate cancer (PCa) develops into CRPC during androgen deprivation therapy (ADT) by various genetic actions. The androgen-AR signaling axis plays a key role in this development. PCa cells mainly adapt themselves to the environment of lower androgen concentrations and change into androgen-hypersensitive cells or androgen-independent cells. Androgens of adrenal origin and their metabolites synthesized in the microenvironment in an intracrine/paracrine fashion act on surviving PCa cells and secrete prostate specific antigen (PSA). Total androgen deprivation (TAD) (castration, antiandrogen, and CYP17A1 inhibitor) can become an effective therapeutic strategy concerning the androgen signaling axis-related pathway. However, it is important to ascertain whether elevation of serum PSA results from AR activation or from an androgen-independent tumor volume effect. Then, clinicians can judge it adequately using the imaging studies such as CT or bone scan as well as PSA and bone metabolic markers, an approach which is necessary to judge which treatment is most suitable for the CRPC patients. This article is part of a Special Issue entitled 'Essential role of DHEA'.
- Reporting combined outcomes with Trifecta and survival, continence, and potency (SCP) classification in 337 patients with prostate cancer treated with image-guided hypofractionated radiotherapy. [JOURNAL ARTICLE]
- BJU Int 2013 Oct 29.
To report the image-guided hypofractionated radiotherapy (hypo-IGRT) outcome for patients with localised prostate cancer according to the new outcome models Trifecta (cancer control, urinary continence, and sexual potency) and SCP (failure-free survival, continence and potency).Between August 2006 and January 2011, 337 patients with cT1-T2N0M0 prostate cancer (median age 73 years) were eligible for a prospective longitudinal study on hypo-IGRT (70.2 Gy/26 fractions) in our Department. Patients completed four questionnaires before treatment, and during follow-up: the International Index of Erectile Function-5 (IIEF-5), the International Prostate Symptom Score (IPSS), and the European Organization for Research and Treatment of Cancer prostate-cancer-specific Quality of Life Questionnaires (QLQ) QLQ-PR25 and QLQ-C30. Baseline and follow-up patient data were analysed according to the Trifecta and SCP outcome models. Cancer control, continence and potency were defined respectively as no evidence of disease, score 1 or 2 for item 36 of the QLQ-PR25 questionnaire, and total score of >16 on the IIEF-5 questionnaire. Patients receiving androgen-deprivation therapy (ADT) at any time were excluded.Trifecta criteria at baseline were met in 72 patients (42% of all ADT-free patients with completed questionnaires). Both at 12 and 24 months after hypo-IGRT, 57% of the Trifecta patients at baseline were still meeting the Trifecta criteria (both oncological and functional success according to the SCP model). The main reason for failing the Trifecta criteria during follow-up was erectile dysfunction: in 18 patients after 6 months follow-up, in 12 patients after 12 months follow-up, and in eight patients after 24 months. Actuarial 2-year Trifecta failure-free survival rate was 44% (95% confidence interval 27-60%). In multivariate analysis no predictors of Trifecta failure were identified. Missing questionnaires was the main limitation of the study.The Trifecta and SCP classifications can be used as tools to report RT outcome.
- Natural history of untreated prostate specific antigen radiorecurrent prostate cancer in men with favorable prognostic indicators. [Journal Article]
- Prostate Cancer 2014.:912943.