Abstract Glucocorticoid receptor (GR) is emerging as a key driver of prostate cancer (PCa) progression and therapy resistance in the absence of androgen receptor (AR) signaling. Acting as a bypass mechanism, GR activates AR-regulated genes, although GR-target genes contributing to PCa therapy resistance remain to be identified. Emerging evidence also shows that African American (AA) men, who disproportionately develop aggressive PCa, have hypersensitive GR signaling linked to cumulative stressful life events. Using racially diverse PCa cell lines (MDA-PCa-2b, 22Rv1, PC3, and DU145) we examined the effects of glucocorticoids on the expression of two stress oncoproteins associated with PCa therapy resistance, Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75). We observed that glucocorticoids upregulated LEDGF/p75 and CLU in PCa cells. Blockade of GR activation abolished this upregulation. We also detected increased GR transcript expression in AA PCa tissues, compared to European American (EA) tissues, using Oncomine microarray datasets. These results demonstrate that glucocorticoids upregulate the therapy resistance-associated oncoproteins LEDGF/p75 and CLU, and suggest that this effect may be enhanced in AA PCa. This study provides an initial framework for understanding the contribution of glucocorticoid signaling to PCa health disparities.
Prostate cancer (PCa) is the second most frequently diagnosed malignancy and the second leading cause of death in men worldwide, after adjusting for age. According to the International Agency for Research on Cancer, continents such as North America and Europe report higher incidence of PCa; however, mortality rates are highest among men of African ancestry in the western, southern, and central regions of Africa and the Caribbean. The American Cancer Society reports, African Americans (AAs), in the United States, have a 1.7 increased incidence and 2.4 times higher mortality rate, compared to European American’s (EAs). Hence, early population history in west Africa and the subsequent African Diaspora may play an important role in understanding the global disproportionate burden of PCa shared among Africans and other men of African descent. Nonetheless, disparities involved in diagnosis, treatment, and survival of PCa patients has also been correlated to socioeconomic status, education and access to healthcare. Although recent studies suggest equal PCa treatments yield equal outcomes among patients, data illuminates an unsettling reality of disparities in treatment and care in both, developed and developing countries, especially for men of African descent. Yet, even after adjusting for the effects of the aforementioned factors; racial disparities in mortality rates remain significant. This suggests that molecular and genomic factors may account for much of PCa disparities.
Abstract Prostate Cancer (PCa) is the number one diagnosed cancer among Black men (BM) in the United States. Diagnosed earlier, with more aggressive disease, BM are dying at higher rates than other race/ethnic groups. Family history of PCa and lack of access to annual screenings are known contributors to the development of lethal disease. In addition, over 70% of BM are vitamin D deficient (VDD), which promotes tumor aggressiveness, and generally have little knowledge of their family history of PCa. When detected at an early stage, BM have higher survival rates for PCa than other racial/ethnic group. As a result, the American Cancer Society recommends that men with a higher risk of developing PCa should receive information about the benefits and limitations of screening between 40 and 50 years of. Community-based screening (CBS) interventions have been shown to increase early detection and increase knowledge of PCa risk for BM). The purpose of this study is to better understand the feasibility of CBS interventions in reducing PCa disparities among BM. Methodology: Participants were recruited between 2018-2020 from CBS events in Southern California. The men completed a 48-item questionnaire prior to receiving a Prostate-Specific Antigen (PSA) test. Vitamin-D levels were also measured. The survey included questions on demographics, general health, cancer history, and family history of cancer. Inclusion criteria involved BM over the age of 40, without a family history of PCa, with PSA scores greater than 4 ng/ml (abnormal screening result), and Vitamin-D values less than 20 ng/ml (Vitamin D deficiency level). Survey data was analyzed using SPSS Version 25. Results: Our participants (n=497) included 68.8% (n=342) BM, 10% (n=50) White, 11.9% (n=59) Latino, 6.8% (n=34) Asian, and 2.4% (n=12) other. 62% of participants (n=269) have never been screened for PCa, and 74% (n=313) are between 40 and 88 years old. Of the Black population, 62% (n=163) never received a PSA screening, and 66% (n=175) did not have a family history of PCa. In addition, 36% (n=113) of the BM were VDD. Of the BM with an Abnormal Screening Result (ASR) (n=32), 44% (n=14) have never been screened, and 53% (n=17) did not have a family history of PCa. In addition, 44% (n=14) of the participants with an ASR were VDD. Lastly, of the BM above the age of 40 with an ASR, and VDD, (n=14), 50% have never been screened and 57% did not have a family history of PCa. Discussion: This study aimed to identify the feasibility of a community based PCa screening intervention for BM in Southern California. As a result of our CBS program, we identified high risk men without a family history of PCa and were VDD. This program offers early detection and screening opportunities to further increase awareness of PCa risk factors for BM. Future research should include the impact of CBS interventions for BM at perceived lower risk of developing PCa. Citation Format: Dorothy Galloway, Dede Teteh, Leanne Woods-Burnham, Mya Walker, Rick A. Kittles. Connecting under-resourced populations: A community-based prostate cancer screening intervention [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-023.
Abstract African American (AA) men are more likely to develop and die from prostate cancer (PCa) yet less likely to receive information about screening from physicians. Although guidelines espouse shared decision-making regarding PCa screening and PSA testing, studies reveal lack of consistency. Several studies demonstrate that PCa knowledge strongly influences informed decisions, and that engaging interactions are especially important for AA men who are more likely to progress from early stage to aggressive end-stage PCa at an earlier age and faster rate than other populations. This study evaluated the frequency of physician-patient conversations among AA men and whether this translated into increased PCa knowledge and PSA testing. In this study, self-identified Black men ages 21-85 donated blood and completed a health survey (n=414) via Project C.H.A.N.G.E. (Changing Health in Adult Men with New and Great Experiences), a transdisciplinary cross-sectional study conducted at Loma Linda University. PCa knowledge following physician conversations in light of socio-economic and health care variables was evaluated using univariate, bivariate, and multiple regression analyses. PSA values were measured with ELISA. Our results revealed that 52.7% of participants had never discussed the pros and cons of PCa screening with their physicians. The likelihood of physician-patient conversations increased with age (p.001), and health insurance positively predicted these discussions (p.001). Multiple regression analysis indicated ethnicity and high school education as predictors of improved PCa knowledge (p.001). We found that 38.5% of men who had discussed PCa screening with a physician and 28.5% who had not discussed PCa screening had PSA values that could be considered high-risk for PCa diagnosis. These findings expose a remaining deficiency in physician compliance regarding national guidelines for shared decision-making conversations with high-risk men. This is problematic as a large group of AA men at evident risk for PCa have not ever discussed this disease with their physicians and may be harboring undetected PCa. Encouraging more effective interactions between AA men and their physicians concerning PCa screening and PSA testing has the potential to reduce PCa health disparities. Citation Format: Leanne Woods-Burnham, Laura Stiel, Colwick Wilson, Susanne Montgomery, Carlos A. Casiano. Physician consultations, prostate cancer knowledge, and PSA screening in African American men: Are the conversations effective? [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr A56.
Recent advances in our understanding of racial disparities in prostate cancer (PCa) incidence and mortality that disproportionately affect African American (AA) men have provided important insights into the psychosocial, socioeconomic, environmental, and molecular contributors. There is, however, limited mechanistic knowledge of how the interplay between these determinants influences prostate tumor aggressiveness in AA men and other men of African ancestry. Growing evidence indicates that chronic psychosocial stress in AA populations leads to sustained glucocorticoid signaling through the glucocorticoid receptor (GR), with negative physiological and pathological consequences. Compelling evidence indicates that treatment of castration-resistant prostate cancer (CRPC) with anti-androgen therapy activates GR signaling. This enhanced GR signaling bypasses androgen receptor (AR) signaling and transcriptionally activates both AR-target genes and GR-target genes, resulting in increased prostate tumor resistance to anti-androgen therapy, chemotherapy, and radiotherapy. Given its enhanced signaling in AA men, GR-together with specific genetic drivers-may promote CRPC progression and exacerbate tumor aggressiveness in this population, potentially contributing to PCa mortality disparities. Ongoing and future CRPC clinical trials that combine standard of care therapies with GR modulators should assess racial differences in therapy response and clinical outcomes in order to improve PCa health disparities that continue to exist for AA men.
Abstract There is no cure for metastatic prostate cancer (PCa), the most commonly diagnosed cancer and third leading cause of cancer mortality among U.S. men. Patients with advanced PCa often develop resistance to conventional therapies resulting in metastatic castration-resistant PCa (mCRPC). Docetaxel (DTX) chemotherapy is the standard-of-care for mCRPC, followed by secondary chemotherapy with cabazitaxel (CBZ), yet chemoresistance and death inevitably occurs. While pharmacological agents targeting single survival pathways have shown promise at the bench side, clinical trials have failed. This is mostly due to the presence of redundant pathways utilized by PCa tumor cells to maintain chemoresistance. Therefore, we are interested in further defining molecular pathways associated with DTX-resistance in order to identify novel therapeutic targets to overcome this resistance. We hypothesized that RNA sequencing (RNAseq) analysis comparing the transcriptomes of chemosensitive and chemoresistant mCRPC cells will reveal potential targets for combinatorial therapies. RNAseq analysis of DTX-sensitive and -resistant PC3 and DU145 cells revealed a number of differentially regulated genes that were either unique to each cell line or common to both. We found that dipeptidyl peptidase 4 (DPP4), fatty acid binding protein 5 (FABP5), nestin (NES), and tetraspanin 8 (TSPAN8) were among the top most robustly and significantly upregulated genes in both DTX-resistant PC3 and DU145 cell lines. In-house qPCR studies validated the RNAseq results for these genes, and Western blotting analysis showed increased expression of these proteins in DTX-resistant cells, which correlated with increased mRNA expression. Interestingly, NES, TSPAN8, DPP4 are genes associated with development of the cancer stem-cell (CSC) phenotype. Other genes associated with CSCs were also upregulated in the DTX-resistant cells, suggesting that in vitro selection of mCRPC cells for DTX resistance may enrich for CSCs. This novel finding is consistent with recent studies implicating CSCs in PCa chemoresistance. Further analysis and validation of our RNAseq data will increase our understanding of DTX-resistance mechanisms in PCa cells, including the yet undefined functional role of CSC-related genes. These studies also reveal potential therapeutic targets to circumvent DTX resistance in PCa. Citation Format: Christina K. Cajigas-Du Ross, Leanne Woods-Burnham, Joshua Ramirez, Xin Chen, Charles Wang, Carlos A. Casiano. RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5902.
Prostate cancer remains a significant health challenge, being the most prevalent non-cutaneous cancer in men worldwide. This review discusses the critical advancements in biomarker discovery using single-omics and multi-omics approaches. Multi-omics, integrating genomic, transcriptomic, proteomic, metabolomic, and epigenomic data, offers a comprehensive understanding of the molecular heterogeneity of prostate cancer, leading to the identification of novel biomarkers and therapeutic targets. This holistic approach not only enhances the specificity and sensitivity of prostate cancer detection but also supports the development of personalized treatment strategies. Key studies highlighted include the identification of novel genes, genetic mutations, peptides, metabolites, and potential biomarkers through multi-omics analyses, which have shown promise in improving prostate cancer management. The integration of multi-omics in clinical practice can potentially revolutionize prostate cancer prognosis and treatment, paving the way for precision medicine. This review underscores the importance of continued research and the application of multi-omics to overcome current challenges in prostate cancer diagnosis and therapy.
