Enhanced resistance to radiation could be caused by both chronic hypoxia and acute hypoxic which has been reported in prostate cancer in various studies. Therefore currently used dose prescriptions (70Gy in 35 fractions) for external beam radiation therapy (EBRT) of prostate cancer has been suggested insufficient to provide optimum clinical outcome. In this study, we propose a Biologically Guided Radiation Therapy approach to boost dose in hypoxic prostate tumor regions while sparing the urethra. A previously proposed hypoxia model was modified for prostate cancer and incorporated into treatment plan optimization. The concept of equivalent uniform dose (EUD) was used in the optimization and evaluation of results. CT data from 25 prostate cancer patients who recently received EBRT at the British Columbia Cancer Agency (BCCA) and hypothetical hypoxic regions manually drawn on these CT scans were selected for this study. The results show that our methods could boost dose in target volume to substantially higher levels. EUD of planning target volume increased to more than 80Gy, despite accounting for effects of hypoxia. This increase was achieved with only minor changes in dose in normal tissues, typically less than 5Gy. Notably, urethra sparing was excellent with a EUD around 64Gy. Robustness of the proposed approach is verified against various hypoxic settings. EUD comparison between RT plans in biological guided and conventional approaches using the same RT technique (Volumetric Modulated Arc Therapy) also suggests that biologically guided radiation therapy (BGRT) approach is more suitable for dose painting purposes with the advantage of delivering sufficient dose to hypoxia region in different scenarios and sparing normal tissue better. Furthermore, we also investigated the impact of inter-fraction patient set-up error and intra-fraction organ motion on the high dose gradients achieved with this proposed dose painting method and explored the feasibility of adapting geometrical uncertainties (represented as systematic error and random error) into treatment planning. Image error obtained from EPID images are used to derive systematic uncertainty and random uncertainty. During the geometrical uncertainty adapted optimization, dose matrix in PTV is shifted based on systematic error and convolved with a Gaussian kernel which is pre-calculated using random error. CT sets and organ contours from five patients who enrolled in the previous dose painting i study are selected. For each of them, seven plans are generated using cumulated uncertainty data which was collected after every five fractions. We also present the outcome in terms of equivalent uniform dose (EUD). For four of the patients, EUD history of all seven plans suggests using the proposed optimization method with uncertainty data from the first five fractions, it is possible to achieve the same target coverage of static treatment plans (difference in EUD less than 1Gy). Meanwhile, the elimination of PTV margin also leads to a significant dose reduction (more than 15Gy) in rectum. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

<div>Prostate cancer (PCa) is the second leading cause of cancer related deaths in American men. In this study, I identify two combinational therapeutics to treat PCa – the combination of enzalutamide and simvastatin, and the combination of GSK126 and metformin, both of which strongly suppress PCa cell growth in vitro and in vivo via inhibiting androgen receptor (AR), an important oncogenic driver for the PCa progression. Simvastatin leads to more AR degradation when combined with enzalutamide. For the combination of GSK126 and metformin, the interaction between enhance of zeste homolog2 (EZH2) and AR is interrupted by GSK126, re-sensitizing EZH2 to metformin. Meanwhile, GSK126 inhibits EZH2’s activity. </div><div><br></div><div>Polo-like kinase 1 (PLK1), a cell cycle regulator, is usually overexpressed in non-small-cell lung cancer (NSCLC). Here, we report that PLK1 overexpression promotes the development of Kras^G12D and Trp53^fl/fl (KP)-driven lung adenocarcinoma (LADC). KP mice harboring transgenic PLK1 (KPPI) display heavier tumor burden, poorer tumor differentiation, and lower survival than KP mice. Mechanistically, PLK1 overexpression enhances the activity of MAPK pathway, via upregulating RET expression in a kinase-dependent manner. Supporting our findings, PLK1 knockout in KP mice reduces RET gene expression, inhibits MAPK pathway activity, and strongly delays LADC development. Therefore, these data reveal that PLK1 functions as an oncogene in KP-driven LADC.</div><div> </div><div><br></div>

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Whether to screen for prostate cancer in aging men is a topic that is fairly well researched, but recommendations are controversial, because the evidence supporting any recommendation is equivocal. The evidence clearly does not support routine screening of all average-risk men, but for men aged 55 to 69 years, either not routinely screening, or engaging each man in shared decision making for his individual preference on screening, is reasonable and consistent with the evidence. Many organizations, including the American Cancer Society, have not yet reassessed their guidelines, in response to the US Preventative Services Task Force revised guideline.

Jamaican males are a high-risk population for aggressive prostate cancer (PrCa) due to genetic influences, and identifying empirical data on treatments, which provide survival benefits is a prime challenge for clinicians who manage Jamaican PrCa patients. Thus, the purpose of this investigation was to elucidate treatment effects of brachytherapy and ERBT in the survival of a Jamaican PrCa cohort. Differences in survival outcomes of brachytherapy and ERBT treated Jamaican, and White U.S.-born PrCa patients with localized PrCa were compared. The mechanism of radiation programmed cell death in PrCa carcinogenesis explained in the oxidative stress theory, was the theoretical base for interpreting the research questions. A retrospective cohort design was used, and included survival analysis of secondary data from the Surveillance Epidemiology and End Results database. The sample size was 10,752 Jamaican and White U.S.-born prostate cancer patients diagnosed between 1992 and 2011. Kaplan-Meier and Cox proportional hazard regression models confirmed that brachytherapy resulted in enhanced survival benefits to the Jamaicans, HR 0.63, 95% CI [0.55, 0.73], p < .001, but ERBT did not, HR 1.6, 95% CI [1.38, 1.84] p < .001. Hence, brachytherapy may be an appropriate treatment option for Jamaican PrCa patients. Clinicians and health care planners can utilize the results for policy decisions aimed at increasing access to brachytherapy treatments to Jamaicans. Improving access to efficient PrCa treatments could reduce the morbidity and mortality rates of PrCa among Jamaicans, decrease years of potential life lost from PrCa, and enhance the life expectancy of the Jamaican male population.

Indiana University-Purdue University Indianapolis (IUPUI) / Continual and recalcitrant inflammation is an extremely common condition in the human prostate and has been found to be associated with a number of prostatic diseases including prostate cancer and benign prostatic hyperplasia (BPH). While much has been described regarding prostate disease resulting from oxygen and nitrogen radicals during inflammation, proliferative mechanisms associated with repair and regeneration are less understood. The Inhibitor of Apoptosis (IAP) family member survivin has been found to be overexpressed during inflammation and associated with prostate cancer progression. Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein that is essential in activating inflammatory transcription factors. Because APE1/Ref-1 is expressed and elevated in prostate cancer, we sought to characterize APE1/Ref-1 expression and activity in human prostate cancer cell lines and determine the effect of selective reduction-oxidation (redox) function inhibition on prostate cancer cells in vitro and in vivo. Due to the role of inflammatory transcriptional activators NFĸB and STAT3 in survivin protein expression, and APE1/Ref-1 redox activity regulating their transcriptional activity, we assessed selective inhibition of APE1/Ref-1’s redox function as a novel method to halt prostate cancer cell growth and survival. Our study demonstrates that survivin and APE1/Ref-1 are significantly higher in human prostate cancer specimens compared to noncancerous controls and that APE1/Ref-1 redox specific inhibition with small molecule inhibitors APX3330 and APX2009 decreases prostate cancer cell proliferation and induces cell cycle arrest. Inhibition of APE1/Ref-1 redox function significantly reduced NFĸB transcriptional activity, survivin mRNA and survivin protein levels. These data indicate that APE1/Ref-1 is a key regulator of survivin and a potentially viable target in prostate cancer.

Indiana University-Purdue University Indianapolis (IUPUI) / Despite therapeutic advancements, prostate cancer remains the second most common cause of cancer-related mortality in men. Docetaxel is the first cytotoxic agent to show modest improvements in overall survival rate in patients with metastatic prostate cancer. Unfortunately, over half of these patients do not respond to treatment and ultimately all develop resistance. The mechanism mediating docetaxel resistance remains unknown. Survivin has a classical biological role in cancer, in fact survivin has been shown to be overexpressed in almost every solid tumor and is associated with drug resistance and clinically aggressive disease. In these studies I demonstrate that docetaxel resistant cells have overexpression of survivin compared to sensitive parental cells, knockdown of survivin decreases docetaxel resistance, and stable overexpression of survivin increases resistance to docetaxel. The data in these studies suggest that survivin is likely implicated in docetaxel resistance and treatment with a direct survivin inhibitor may sensitize resistant cells to docetaxel. To this end the evaluation and optimization of two different backbones of survivin inhibitors was performed. One such inhibitor identified is LQZ-7-3 which decreases survivin level via proteasome degradation, leads to apoptosis of cells, and showed efficacy in a prostate cancer xenograft model in vivo when given in an oral formulation. LQZ- 7-3 showed strong specificity to survivin versus other IAP family members at the protein level. Another inhibitor, LQZ-7F-1, demonstrated nanomolar inhibition of cancer cell growth and similar effects on survivin. Both compounds synergized with docetaxel in vitro warranting future in vivo efficacy studies as a combinatorial therapy. Overall, our findings indicate survivin is a significant contributor to docetaxel resistance in metastatic prostate cancer at the molecular level and survivin inhibitors may prove efficacious as a new therapy to sensitize cancer cells to chemotherapies.

On average, 65 Canadian men will be diagnosed with prostate cancer (PC) every day, making it the most common male cancer in Canada. Despite the prevalence, the etiology of PC is unknown. Evidence nonetheless supports the role of prostate cancer stem cells (PCSCs) in PC initiation and metastasis. In spite of almost a decade worth of research on PCSCs our knowledge on their biology remains fragmented. By taking advantage of the availability of DU145 cell-derived PCSCs in our laboratory, this thesis research focuses on investigating the unique properties of PCSCs and their function in promoting PC tumorigenesis. We identified two PCSC-specific proteins, ALDH3A1 and CNTN1. In mouse models of xenograft tumors, ALDH3A1 was expressed at higher levels in PCSC-derived tumors than in DU145 non-PCSC-produced tumors and in lung metastases than local tumors. In clinical settings, elevation of ALDH3A1expression was observed from normal prostate tissues to carcinomas and from local PCs to the paired lymph node metastases. Additionally, ALDH3A1 was clearly detected in bone metastases. Similar to ALDH3A1, CNTN1 expression associates with PC progression and biochemical recurrence following radical prostatectomy. The clear presence of CNTN1 in lymph node and bone metastases was also demonstrated. Furthermore, CNTN1 expression promoted PC metastasis to the lungs and tumor initiation in NOD/SCID mice. Mechanistically, CNTN1 increased AKT activation and reduced E-cadherin expression. Collectively, our research revealed important roles of both PCSC proteins in promoting PC tumorigenesis and progression. PC develops chemotherapy resistance in which PCSCs play a major role. In supporting this knowledge, we demonstrated that PCSCs are innately more resistant to the chemotherapeutic drugs, etoposide and docetaxel and that this resistance was in part attributable to their enhanced DNA damage response. Taken together, the findings of this thesis advances our knowledge on two specific PCSC markers and their association with prostate cancer progression and metastasis. As well as to the mechanism whereby PCSCs promote resistance to chemotherapeutic drugs. / Thesis / Doctor of Philosophy (PhD)

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