Tumour hypoxia has been demonstrated to cause development of an aggressive tumour phenotype and is associated with increased patient mortality and poorer response to treatments such as chemotherapy and radiotherapy. Previous studies have established that hypoxia exists within a nidus of prostate cancer. Based on the importance of the tumour microenvironment, especially hypoxia, in prostate cancer, the major aims of this thesis were to establish: (a) the role of a novel putative survival factor, dermcidin, in prostate cancer survival under hypoxia/oxidative stress; and (b) the effect of nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDS), a new class of drugs, on the killing of prostate cancer cells subjected to hypoxia. A wide-range of confirmatory, cellular and molecular biology techniques were employed in this thesis. The PC-3 hormone-insensitive prostate cancer cell line was used for the majority of studies as this cell line represents hormone-independent prostate cancer, treatment of which is currently palliative. Cell incubation at 0.2% oxygen for 48 hours was established as suitable conditions to stimulate the development of the hypoxia response. Upregulation of nuclear hypoxia-inducible factor-1α protein was the main marker used to assess the hypoxia response. Dermcidin messenger RNA production was found to occur in a range of prostate cancer cell lines; was upregulated in cell lines by both hypoxic and oxidative stress; and found to act as a proliferation, survival and pro-invasion factor under hypoxia and oxidative stress in immortalised prostate cancer cell lines. Furthermore, the portion of the dermcidin molecule responsible for the survival advantage was localised to the proteolysis-inducing factor core peptide subunit. However, subsequent analysis of primary cancer samples from prostate cancer patients revealed that dermcidin was not expressed in these tumours, although dermcidin mRNA was identified in analysis of other primary tumours. As such, the role of dermcidin in prostate cancer was not evaluated further in this thesis. Investigation of NO-sulindac (a NO-NSAID drug) in hypoxic PC-3 cells showed that these agents were significantly more pro-necrotic, pro-apoptotic and anti-invasive than traditional, unnitrated sulindac. NO-sulindac was found to downregulate the hypoxia response mounted by PC-3 cells under hypoxia via the Akt signalling pathway. Finally, analysis of the role of NO-sulindac in radiosensitising hypoxic PC-3 cells showed that NO-sulindac caused significant radiosensitisation under normoxia, but particularly in hypoxic conditions. As such, NO-NSAIDs show great promise as neoadjuvant, concurrent and adjuvant treatments for patients with hypoxic prostate cancer. The findings of this thesis illustrate several potential novel strategies for treatment of hormone-independent prostate cancer.

Background: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double-blind, placebo-controlled, prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo). At the time of the trial's development, NIH had invested substantial resources in evaluating the potential benefits of these antioxidants. To capitalize on the knowledge gained from following a large cohort of healthy, aging males on the effects of selenium and/or vitamin E, ancillary studies with other disease endpoints were solicited. Methods: Four ancillary studies were added. Each drew from the same population but had independent objectives and an endpoint other than prostate cancer. These studies fell into two categories: those prospectively enrolling and following participants (studies of Alzheimer's disease and respiratory function) and those requiring a retrospective medical record review after a reported event (cataracts/age-related macular degeneration and colorectal screening). An examination of the challenges and opportunities of adding ancillary studies is provided. The impact of the ancillary studies on adherence to SELECT was evaluated using a Cox proportional hazards model. Results: While the addition of ancillary studies appears to have improved participant adherence to the primary trial, this did not come without added complexity. Activation of the ancillary studies happened after the SELECT randomizations had begun resulting in accrual problems to some of the studies. Study site participation in the ancillary trials varied greatly and depended on the interest of the study site principal investigator. Procedures for each were integrated into the primary trial and all monitoring was done by the SELECT Data and Safety Monitoring Committee. The impact of the early closure of the primary trial was different for each of the ancillary trials. Conclusions: The ancillary studies allowed study sites to broaden the research opportunities for their participants. Their implementation was efficient because of the established infrastructure of the primary trial. Implementation of these ancillary trials took substantial planning and coordination but enriched the overall primary trial.

CTCs have emerged as a potential source of clinical significance. But with numerous isolating systems currently available, the numbers of captured CTCs vary widely. At this point, CellSearch remains the only FDA-approved system with clinical significance whereby the results could be used to monitor patients with metastatic colon, breast, or prostate cancer. However, its inability to isolate CTCs from non-high risk prostate cancer patients or CTCs that are EpCAM-negative has led to criticism. In this study, we have shown that size-based filtration successfully isolates CTCs from patients with localized and metastatic prostate cancer. We have also shown that CTCs can be successfully isolated from low and intermediate risk groups. Additionally, clusters of CTCs were preserved and isolated in all localized risk groups and metastatic patients. Furthermore, we enumerated the isolated CTCs using automated and manual methods in low risk, intermediate risk, high risk, and metastatic prostate cancer. The automated and manual counts were comparable. Moreover, the amounts of clusters and the size of clusters correlated with the status and stage of prostate cancer. / October 2016

Cancer of the prostate (CaP) is the most common malignancy diagnosed in men in the Western society. During the last years, prostate specific antigen (PSA) has been used as a biomarker for CaP, although a high PSA value is not specific for CaP. Thus, there is an urgent need for new and improved diagnostic markers for CaP. In this thesis, the aim was to find a miRNA signature for diagnosis of CaP and to elucidate if differences in behavior between transition zone and peripheral zone tumors are reflected in miRNA expression. One of the major findings is anexpression signature based on nine miRNAs that with high accuracy (85%) could classify normal and malignant tissues from the transition zone of the prostate. The results furthermore show that the major differences in miRNA expression are found between normal and malignant tissues, rather than between the different zones. In addition, tumors arising in the peripheral zone have fewer changes in miRNA expression compared to tumors in the transition zone, indicating that the peripheral zone is more prone to tumor development compared to the transition zone of the prostate. A crucial step in pre-processing of expression data, in order to differentiate true biological changes, is the normalization step. Therefore, an additional aim of this thesis was to compare different normalization methods for qPCR array data in miRNA expression experiments. The results show that data-driven methods based on quantile normalization performs the best. The results also show that in smaller miRNA expression studies, only investigating a few miRNAs, RNU24 is the most suitable endogenous control gene for normalization. Taken together, the results in this thesis show the importance of miRNAs and the possibility of their future use as biomarkers in the field of prostate cancer.

Introduction: Cancer-related fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after activity. Etiologic mechanisms underlying CRF are not well understood. Methods: A literature review was conducted to examine studies that had investigated the association of mitochondrial dysfunction with fatigue. The major conclusion from this review was that alterations in energy metabolism may contribute to fatigue. Therefore, the dissertation study focused on laboratory techniques for measuring mitochondrial oxidative phosphorylation enzymes (complexes I-V) and a mitochondrial-specific oxidative stress marker (superoxide dismutase 2 [SOD2]). The primary aim of the dissertation research was to describe levels of biomarkers of mitochondrial function, fatigue, and health-related quality of life (HRQOL) before and at the completion of external beam radiation therapy (EBRT) in men with nonmetastatic prostate cancer (NM-PC). To achieve this aim a secondary analysis of a descriptive, longitudinal study was conducted (#10-NR-0128). Results: A total of n = 22 men with NM-PC were included in this study. There were significant increases in fatigue and a significant decrease HRQOL from baseline to the completion of EBRT. However, there was no significant change in the biomarkers of mitochondrial function from baseline to EBRT completion. Given the exploratory nature of the study, it was decided to further investigate the patient sample to understand the relationship of fatigue and mitochondrial function in a well-characterized fatigue phenotype. There was preliminary evidence to support the possibility of distinct patterns of mitochondrial enzyme levels between those with a high intensification of fatigue and those with a low intensification of fatigue during EBRT; however, these differences were not statistically significant. Discussion: To our knowledge, this is the first study to describe the relationship between mitochondrial enzymes and fatigue before and during EBRT in men with NM-PC. The most important preliminary finding from this study is the possibility that mitochondrial enzymes might be related to fatigue intensification during EBRT. Future studies will be critical to determine if these preliminary findings are replicable, and if so, whether there are potential therapeutic targets in individuals at highest risk for fatigue intensification during EBRT.

The chemokine receptor CCR5 has been implicated in the pathogenesis of prostate cancer. A novel natural product, anibamine, was isolated and found to be a micromolar inhibitor of the receptor. Anibamine was used as a new anti-prostate cancer lead compound. To discover the pharmacophore, analogs of anibamine were designed using the “deconstruction-reconstruction-elaboration” approach and synthesized. The establishment of a stereoselective route to only one isomer was explored, to increase yield and eliminate elaborate purification procedures. Analogs were found to have anti-prostate cancer activity at levels higher than the parent compound. The molecular modeling studies of the deconstructed analogs indicate that due to the psuedo-symmetry of the parent compound, the binding conformation of the deconstructed analogs may not be very different from each other. All this information together may help identify a next generation lead compound for anti-prostate cancer treatment.

<p>The androgen receptor (AR) signaling axis is a well-established therapeutic target in prostate cancer, due to its central role in tumor maintenance and progression. Although patients respond initially to androgen deprivation therapies and AR antagonists, they invariably progress to a castration-resistant state. Consequently, there is an unmet need for agents that target the AR signaling axis in a unique manner. </p><p>Histone deacetylase (HDAC) inhibitors repress AR signaling and prostate cancer growth in cellular and xenograft models. However, HDAC inhibitors also induce epithelial to mesenchymal (EMT) and neuroendocrine differentiation, both of which are associated with prostate cancer progression and aggressiveness. Given that 18 different HDAC isoforms have been identified in humans, and non-selective or Class I (HDAC1, 2, 3, and 8) HDAC inhibitors have been used in most of these studies, the relative contribution of individual HDAC isoforms to AR transcriptional activity and prostate cancer pathophysiology remains to be elucidated. The overarching goals of this study were to (1) determine the role of individual Class I HDACs in AR transcriptional activity and prostate cancer growth, (2) identify selective HDAC inhibitors that have reduced adverse profiles to the treatment of prostate cancer, and (3) identify potential HDAC-interacting proteins that regulate AR target gene transcription and prostate cancer growth. </p><p>Using genetic knockdown studies and pharmacological inhibitors with isoform selectivity, we identified that HDAC3 was required for AR transcriptional activity and proliferation in cellular models of androgen-sensitive and castration-resistant prostate cancer (CRPC). Additionally, we found that RGFP966, an HDAC3-selective inhibitor, attenuated the growth of a xenograft model of CRPC. Furthermore, non-selective HDAC inhibitors induced EMT and neuroendocrine markers in prostate cancer cells, but RGFP966 treatment did not. These studies provide rationale for selective inhibition of HDAC3 for the treatment of CRPC, and could provide an explanation for the lack of success using non-selective HDAC inhibitors in clinical trials for prostate cancer.</p><p>We also assessed the role of REV-ERB alpha, an HDAC3-interacting protein, in the regulation of AR transcriptional activity and prostate cancer growth. Using siRNA knockdown studies, REV-ERB inhibitors, and overexpression studies, we concluded that REV-ERB alpha; was required for AR target gene induction and prostate cancer growth, including models of CRPC. These studies also provide rational for targeting REV-ERB alpha; for the treatment of CRPC.</p><p>Taken together, these studies identify two novel targets in the HDAC signaling axis for the treatment of prostate cancer: HDAC3 and REV-ERB alpha. Our studies provide greater insight into AR transcriptional regulation and prostate cancer pathophysiology.</p> / Dissertation

Background: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. Methods: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. Results: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile (1 vs. Quartile) (4) = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile (4) = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m(2)), but not among men with high BMI (>= 27.8 kg/m(2)). Interactions of race and BMI with vitamin D intake were significant (P-Interaction < 0.05). Conclusion: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

Upplevelsen av livskvalitet hos män med prostatacancer – en litteraturstudie                                         Abstrakt Bakgrund: Prostatacancer är den vanligast förekommande cancerformen bland män i Sverige. Många män lever med biverkningar efter behandlingen, vilket kan påverka deras liv negativt och hur de upplever sin livskvalitet. Syfte: Syftet var att belysa upplevelsen av livskvalitet hos män med prostatacancer. Metod: En litteraturstudie där åtta vetenskapliga artiklar med kvalitativ ansats har granskats, sammanställts och analyserats. Resultat: Tre huvudkategorier med sex kategorier identifierades: Bemästrande av situationen – Strävan efter väbefinnande genom kontroll, Insikt i sjukdomens påverkan. Adaption till livssituation – En förändringsprocess i livet, En kamp för sinnesro. Manlig identitet – Den förändrade sexualiteten påverkar identiteten, Relationer som stöd.   Konklusion: Upplevelsen av livskvalitet varierar från individ till individ och påverkas av bl.a. biverkningar efter behandling och synen på sin livssituation. Författarna tror att litteraturstudien kan medvetandegöra sjuksköterskor om vilken påverkan prostatacancer har på männens livskvalitet. Genom att ställa personliga frågor kan sjuksköterskan ge god vård utifrån varje persons individuella behov.   Nyckelord: Prostatacancer, livskvalitet, män, anpassning / The experience of quality of life in men with prostate cancer – A literature study   Abstract Background: Prostate cancer is the most common cancer among men in Sweden. Many men live with treatment related side effects which can cause a negative effect on their lives and the experience of their quality of life. Aim: The aim was to illuminate the experience of the quality of life in men with prostate cancer. Method: A literature study of eight articles with qualitative approach. The articles result have been reviewed, compiled and analyzed. Results: Three main categories and six categories were identified: Control of the situation – quest for wellbeing through control, insight in the impact of the disease. Adaptation to life situation – a reconstruction of life, a struggle for peace of mind. Male identity – the altered sexuality affects the identity, the support of relationships. Conclusion: The experience of quality of life varies between individuals and is affected by side effects after treatment and the way they are looking at their life situation. The authors believe that this literature study can raise awareness among nurses regarding the impact prostate cancer has on men’s quality of life. By asking personal questions the nurse can provide good nursing care based on each person’s individual need.   Keywords: Prostate cancer, quality of life, men, adaptation

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