Associations Between Polymorphisms in Genes Related to Oxidative Stress and DNA Repair, Interactions With Serum Antioxidants, and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Serum markers, obesity and prostate cancer risk: results from the prostate cancer prevention trial

Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor-1 (IGF-1) pathways. We investigated the association of circulating serum markers (e.g., androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF-1 axis analytes. Logistic regression estimated odds ratio and 95% confidence intervals (CIs) for risk of overall, low-grade (Gleason 2–6), and high-grade (Gleason 7–10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF-1 axis significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF-1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments.

Mechanistic Insights into the Link between Obesity and Prostate Cancer

Obesity is a pandemic of increasing worldwide prevalence. There is evidence of an association between obesity and the risk of prostate cancer from observational studies, and different biologic mechanisms have been proposed. The chronic low-level inflammation within the adipose tissue in obesity results in oxidative stress, activation of inflammatory cytokines, deregulation of adipokines signaling, and increased circulating levels of insulin and insulin-like growth factors (IGF). These mechanisms may be involved in epithelial to mesenchymal transformation into a malignant phenotype that promotes invasiveness, aggressiveness, and metastatic potential of prostate cancer. A thorough understanding of these mechanisms may be valuable in the development of effective prostate cancer prevention strategies and treatments. This review provides an overview of these mechanisms.

The Influence of Finasteride on the Development of Prostate Cancer

This chapter describes the design, main findings, relevance, and limitations of the landmark Prostate Cancer Prevention Trial (PCPT), which randomized men to finasteride versus placebo and followed them for 7 years. It found a major reduction in prostate cancer incidence but also a higher proportion of high-risk cancer in men diagnosed with prostate cancer. The study did not address the more important oncological outcomes of disease-specific and overall survival. Secondary analyses of PCPT outcomes favored the finasteride arm and suggested that the risk of high-risk cancer is not increased. Linkage analysis of participants from PCPT to Medicare claims data suggested no adverse long-term cardiac, endocrine, or sexual effects.

Targeting androgen receptor signaling with MicroRNAs and Curcumin: a promising therapeutic approach for Prostate Cancer Prevention and intervention

Prostate cancer (PC) is a multifactorial disease characterized by the abrogation of androgen receptor signaling. Advancement in microbiology techniques has highlighted the significant role of microRNAs (miRNAs) in the progression of PC cells from an androgen-dependent to an androgen-independent state. At that stage, prostate tumors also fail to respond to currently practiced hormone therapies. So, studies in recent decades are focused on investigating the anti-tumor effects of natural compounds in PC. Curcumin is widely recognized and now of huge prestige for its anti-proliferative abilities in different types of cancer. However, its limited solubility, compatibility, and instability in the aqueous phase are major hurdles when administering. Nanoformulations have proven to be an excellent drug delivery system for various drugs and can be used as potential delivery platforms for curcumin in PC. In this review, a shed light is given on the miRNAs-mediated regulation of androgen receptor (AR) signaling and miRNA-curcumin interplay in PC, as well as on curcumin-based nanoformulations that can be used as possible therapeutic solutions for PC.

Digital technologies in prostate cancer prevention and early diagnosis

Background. Prostate cancer is one of the most common malignant neoplasms in males. The Russian Federation observed the same patterns: the incidence of prostate cancer is steadily growing, without the tendency to decrease. Currently, no effective methods are available for prostate cancer early diagnosis and screening. Aim. To improve the effectiveness of prostate cancer prevention and early diagnosis with new digital technologies for high-risk cancer group formation Material and methods. Data from the Cancer Registry population in the Altai regional cancer center, Barnaul City was used. The Cancer Registry includes information about 253,000 patients with malignant neoplasms, including 14,482 males suffering from prostate cancer. Based on the targeted prevention method of A.F. Lazarev, Method for determining the risk of prostate cancer (Patent 2692987) and Automated program for early diagnosis of prostate cancer (certificate of state registration of the computer program No. 2019663514) was developed, which simplifies the stage of forming groups of precancerous high oncorisk and increases prostate cancer detection, as well as develops personalized targeted preventive measures for each patient. Results. The study formed a group of 328 patients with precancerous high oncorisk for prostate cancer in the Cancer Registry, wherein an in-depth examination revealed 26 patients with prostate cancer, which was 7.9%. Stages I and II were established in 97.8%. Conclusion. The web application Automated program for early diagnosis of prostate cancer allows the group formation of high-risk patients who are a targeted search for prostate cancer. The testing process allows a large number of patients to be examined in a short time. The automated program for the early diagnosis of prostate cancer allows a statistically significant increased prostate cancer detection, as well as personalized preventive measure suggestions for each patient.

Prostate Cancer Care and Survivorship (CaPCaS) Model for Black Men: An Ethnographical Study of Prostate Cancer Survivors

Background: In 2020, 191,930 men will be diagnosed with prostate cancer. The lives of these men will change dramatically as they go through the prostate cancer care and survivorship process. Black men are especially affected, as they are more likely to get and die from prostate cancer. The primary objective of this study was to explain the experiences of Black men across by developing a prostate cancer care and survivorship (CaPCaS) model. Methods: Based on the principles of community engagement research and employing qualitative methodology, we interviewed Black prostate cancer survivors to document their CaPCaS experiences relative to prostate cancer prevention, detection, diagnosis, treatment, survivorship and advocacy using audio and video recordings. Our data analysis plan included preparing and verifying the narrative data, coding data, and developing an interpretive framework for Black men’s experiences across the prostate cancer care continuum. Results: Thirty-two prostate cancer survivors participated in the study. A CaPCaS model was created with themes specific to the trajectory of prostate cancer prevention, screening, diagnosis, treatment, survivorship, and advocacy. Contextual themes identified were African Diaspora, Masculinity and Socio-demographic factors. Additionally, we identified cross-cutting factors across the CaPCaS process that included Acculturation, Self-efficacy, Health literacy, Patient-provider racial concordance, Stigma and Spirituality. Conclusion: The CaPCaS model is an explanatory model of prostate cancer care and survivorship factors for Black men and will foster better understanding of behaviors associated with improved prostate cancer outcomes in Black men.