Prostate cancer (PCa) is heterogeneous containing phenotypically diverse cells. It is unclear whether these phenotypically different PCa cells are functionally distinct and possess divergent tumorigenic potential. Androgen signaling plays important roles in differentiation and survival of malignant PCa cells, and prostate specific antigen (PSA) as one of the androgen signaling target genes is used as a biomarker of AR signaling to assess tumor progression and evaluate therapeutic efficiency in clinic. Here we present evidence for discordant AR and PSA expression resulting in AR⁺/PSA⁺, AR⁺/PSA⁻, AR⁻/PSA⁻, and AR⁻/PSA⁺ PCa cells in human tumors. We also show that prostate tumor PSA mRNA levels inversely correlate with poor clinical outcomes and patient survival. By employing a lentiviral reporter system, we have fractionated bulk PCa cells into PSA⁺ and PSA⁻[superscript '/lo'] cell populations, with the former being AR⁺/PSA⁺ and the latter containing both AR⁺/PSA⁻ and AR⁻/PSA⁻ cells. The PSA⁺ and PSA⁻[superscript '/lo'] PCa cells demonstrate distinct molecular, cellular, and tumor-propagating properties. PSA⁻[superscript '/lo'] PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division to generate PSA⁺ cells. Of great clinical interest, PSA⁻[superscript '/lo'] PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and they harbor highly tumorigenic castration resistant PCa cells. In contrast, PSA⁺ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division, and are sensitive to castration. Systemic androgen levels dynamically regulate the relative abundance of PSA⁺/PSA⁻[superscript '/lo'] PCa cells in the tumors, which in turn impact the kinetics of tumor growth. Further studies reveal that the PSA⁻[superscript '/lo'] PCa cell population harbors several overlapping but nonidentical tumorigenic subsets including ALDH⁺, CD44⁺, and [alpha]2[beta]1⁺ cells and ALDH⁺CD44⁺[alpha]2[beta]1⁺ can further enrich castration resistant PCa cells. These observations together suggest that heterogeneous PCa cells are organized as a tumorigenic hierarchy. Our results have important implications in understanding how different subpopulations of PCa cells manifest differential responses to current androgen deprivation therapy (ADT). / text

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18856号 / 医博第3967号 / 新制||医||1007(附属図書館) / 31807 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 小川 誠司, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Introdução: O câncer de próstata metastático resistente à castração apresenta sobrevida inferior a 30% em cinco anos, e o único tratamento disponível para os pacientes até pouco tempo atrás era o docetaxel. Com o maior entendimento dos mecanismos de resistência desse câncer às terapias utilizadas, novas drogas foram desenvolvidas, entre elas a abiraterona, que atua no bloqueio da enzima 17-? desidrogenase-hidroxiesteroide e a enzalutamida que age diretamente nos receptores de androgênios. Foi realizada uma revisão sistemática dos estudos que avaliaram a eficácia e segurança da abiraterona mais prednisona e da enzalutamida em pacientes com CPMRC, tanto previamente quanto posteriormente ao tratamento com docetaxel. Métodos: A pesquisa bibliográfica foi realizada em março de 2016 nas bases da Pubmed, Google Acadêmico e ClinicalTrials.gov. Os seguintes termos de pesquisa foram utilizados \"prostate cancer metastatic resistent\", \"prostate cancer\", \"abiraterone\" e enzalutamide\", restringido a estudos clínicos randomizados fase III, duplo cego e multicêntrico, publicados nos idiomas inglês, espanhol. Os estudos selecionados foram analisados de forma independente por LRM e AAN. Os critérios para análise foram a sobrevida global (SG), sobrevida livre de progressão (SLP) e o tempo até a progressão do PSA (TP PSA), previamente e após o uso de docetaxel. Resultados: Foram identificados 53 estudos. Aplicando os critérios de inclusão foram selecionados quatro estudos que juntos somaram uma população de 5.199 (2.394 pacientes após docetaxel e 2.805 pacientes previamente ao uso do docetaxel). Em relação a SG, a abiraterona reduziu o risco de morte em 26% após docetaxel (HR 0,74 95% IC 0,64-0,86) e 19% no pré-docetaxel (HR 0,81 95% IC 0,70-0,93), e a enzalutamida reduziu em 37% após (HR 0,63 95% IC, 0,53-0,75) e 23% no pré-docetaxel (HR 0,77 95% IC 0,67-0,88). Em relação a SLPr, abiraterona retardou a progressão da doença em 34% após (HR 0,66 95% IC 0,58-0,76) e 48% na pré-quimio (HR 0,52 95% IC 0,45-0,61), e a enzalutamida em 60% após quimio (HR 0,40 95% IC 0,35-0,47) e 68% na pré-quimio (HR 0,32 95% IC 0,28-0,36). Abiraterona aumentou o tempo até a progressão do PSA em 64% após quimio (HR 0,36 95% IC 0,52-0,78) e 50% na pré-quimio (HR 0,50 95% IC 0,43- 0,58), e a enzalutamida em 75% após quimio (HR 0,25 95% IC 0,20-0,30) e 83% na pré- quimio (HR 0,17 95% IC 0,15-0,20). Conclusão: Tanto abiraterona quanto enzalutamida demonstraram melhores resultados no aumento da SG, da SLPr e do TP PSA no tratamento de pacientes com CPMRC. Não há um estudo comparativo direto e devido a diferenças nos critérios de inclusão e dos grupos comparadores entre esses estudos clínicos, não é possível uma análise indireta entre tais medicamentos. Assim, questões como qual a melhor estratégia de tratamento na pré e pós-quimio e o sequenciamento ideal para enfrentamento do CPMRC não podem ser respondidas. / Introduction: Castrate-resistant metastatic prostate cancer presents survival less than 30% in five years, and the only treatment available to patients until recently was docetaxel. With the greater understanding of the mechanisms of resistance of this cancer to the therapies used, new drugs have been developed, among them abiraterone, which acts in the blockade of the enzyme 17-? dehydrogenase-hydroxysteroid and the enzyme that acts directly on the androgen receptors. A systematic review was made of studies evaluating the efficacy and safety of abiraterone plus prednisone and of enzyme adduct in patients with CPMRC both before and after docetaxel treatment. Methods: The literature search was prepared in March 2016 based on Pubmed, Google Scholar and ClinicalTrials.gov. The following search terms were used \"prostate cancer metastatic resistant\", \"prostate cancer\", \"abiraterone\" and \"enzyme\", restricted to phase III, double blind and multicenter clinical trials published in English, Spanish, Italian and Portuguese. The selected studies were analyze by LRM and AAN. The criteria for analysis were overall survival (OS), progression-free survival (PSA) and time to PSA progression (PS PSA), before and after docetaxel use. Results: Fifty-three studies were identified and, according to the inclusion criteria, four studies were selected that together added a population of 5,199 (2,394 patients after docetaxel and 2,805 patients prior to docetaxel use). In relation to SG, abiraterone reduced the risk of death by 26% after docetaxel (HR 0.74 95% CI 0.64-0.86) and 19% in predocetaxel (HR 0.81 95% CI 0.70- 0.93), and enzyme reductase reduced by 37% (HR 0.63 95% CI, 0.53-0.75) and 23% in pre docetaxel (HR 0.77 95% CI 0.67-0, 88). In relation to SLPr abiraterone delayed disease progression by 34% (HR 0.66 95% CI 0.58-0.76) and 48% in pre-chemotherapy (HR 0.52 95% CI 0.45-0, 61), and enzyme-alpha 60% after chemo (HR 0.40 95% CI 0.35-0.47) and 68% in pre-chemo (HR 0.32 95% CI 0.28-0.36). Abiraterone increased the time until PSA progression by 64% after chemo (HR 0.36 95% CI 0.52-0.78) and 50% in pre-chemo (HR 0.50 95% CI 0.43-0, 58), and enzyme-alpha in 75% after chemo (HR 0.25 95% CI 0.20-0.30) and 83% in pre-chemo (HR 0.17 95% CI 0.15-0.20). Conclusion: Both abiraterone and enzalutamide showed better results in increasing SG, SLPr and TP PSA in the treatment of patients with CPMRC. There is no direct comparative study and, because of differences in inclusion criteria and comparator groups between these clinical studies, indirect analysis of such drugs is not possible. Thus, questions such as the best pre and post chemo treatment strategy and the optimal sequencing for CPMRC coping cannot be answered.

Introdução: O câncer de próstata metastático resistente à castração apresenta sobrevida inferior a 30% em cinco anos, e o único tratamento disponível para os pacientes até pouco tempo atrás era o docetaxel. Com o maior entendimento dos mecanismos de resistência desse câncer às terapias utilizadas, novas drogas foram desenvolvidas, entre elas a abiraterona, que atua no bloqueio da enzima 17-? desidrogenase-hidroxiesteroide e a enzalutamida que age diretamente nos receptores de androgênios. Foi realizada uma revisão sistemática dos estudos que avaliaram a eficácia e segurança da abiraterona mais prednisona e da enzalutamida em pacientes com CPMRC, tanto previamente quanto posteriormente ao tratamento com docetaxel. Métodos: A pesquisa bibliográfica foi realizada em março de 2016 nas bases da Pubmed, Google Acadêmico e ClinicalTrials.gov. Os seguintes termos de pesquisa foram utilizados \"prostate cancer metastatic resistent\", \"prostate cancer\", \"abiraterone\" e enzalutamide\", restringido a estudos clínicos randomizados fase III, duplo cego e multicêntrico, publicados nos idiomas inglês, espanhol. Os estudos selecionados foram analisados de forma independente por LRM e AAN. Os critérios para análise foram a sobrevida global (SG), sobrevida livre de progressão (SLP) e o tempo até a progressão do PSA (TP PSA), previamente e após o uso de docetaxel. Resultados: Foram identificados 53 estudos. Aplicando os critérios de inclusão foram selecionados quatro estudos que juntos somaram uma população de 5.199 (2.394 pacientes após docetaxel e 2.805 pacientes previamente ao uso do docetaxel). Em relação a SG, a abiraterona reduziu o risco de morte em 26% após docetaxel (HR 0,74 95% IC 0,64-0,86) e 19% no pré-docetaxel (HR 0,81 95% IC 0,70-0,93), e a enzalutamida reduziu em 37% após (HR 0,63 95% IC, 0,53-0,75) e 23% no pré-docetaxel (HR 0,77 95% IC 0,67-0,88). Em relação a SLPr, abiraterona retardou a progressão da doença em 34% após (HR 0,66 95% IC 0,58-0,76) e 48% na pré-quimio (HR 0,52 95% IC 0,45-0,61), e a enzalutamida em 60% após quimio (HR 0,40 95% IC 0,35-0,47) e 68% na pré-quimio (HR 0,32 95% IC 0,28-0,36). Abiraterona aumentou o tempo até a progressão do PSA em 64% após quimio (HR 0,36 95% IC 0,52-0,78) e 50% na pré-quimio (HR 0,50 95% IC 0,43- 0,58), e a enzalutamida em 75% após quimio (HR 0,25 95% IC 0,20-0,30) e 83% na pré- quimio (HR 0,17 95% IC 0,15-0,20). Conclusão: Tanto abiraterona quanto enzalutamida demonstraram melhores resultados no aumento da SG, da SLPr e do TP PSA no tratamento de pacientes com CPMRC. Não há um estudo comparativo direto e devido a diferenças nos critérios de inclusão e dos grupos comparadores entre esses estudos clínicos, não é possível uma análise indireta entre tais medicamentos. Assim, questões como qual a melhor estratégia de tratamento na pré e pós-quimio e o sequenciamento ideal para enfrentamento do CPMRC não podem ser respondidas. / Introduction: Castrate-resistant metastatic prostate cancer presents survival less than 30% in five years, and the only treatment available to patients until recently was docetaxel. With the greater understanding of the mechanisms of resistance of this cancer to the therapies used, new drugs have been developed, among them abiraterone, which acts in the blockade of the enzyme 17-? dehydrogenase-hydroxysteroid and the enzyme that acts directly on the androgen receptors. A systematic review was made of studies evaluating the efficacy and safety of abiraterone plus prednisone and of enzyme adduct in patients with CPMRC both before and after docetaxel treatment. Methods: The literature search was prepared in March 2016 based on Pubmed, Google Scholar and ClinicalTrials.gov. The following search terms were used \"prostate cancer metastatic resistant\", \"prostate cancer\", \"abiraterone\" and \"enzyme\", restricted to phase III, double blind and multicenter clinical trials published in English, Spanish, Italian and Portuguese. The selected studies were analyze by LRM and AAN. The criteria for analysis were overall survival (OS), progression-free survival (PSA) and time to PSA progression (PS PSA), before and after docetaxel use. Results: Fifty-three studies were identified and, according to the inclusion criteria, four studies were selected that together added a population of 5,199 (2,394 patients after docetaxel and 2,805 patients prior to docetaxel use). In relation to SG, abiraterone reduced the risk of death by 26% after docetaxel (HR 0.74 95% CI 0.64-0.86) and 19% in predocetaxel (HR 0.81 95% CI 0.70- 0.93), and enzyme reductase reduced by 37% (HR 0.63 95% CI, 0.53-0.75) and 23% in pre docetaxel (HR 0.77 95% CI 0.67-0, 88). In relation to SLPr abiraterone delayed disease progression by 34% (HR 0.66 95% CI 0.58-0.76) and 48% in pre-chemotherapy (HR 0.52 95% CI 0.45-0, 61), and enzyme-alpha 60% after chemo (HR 0.40 95% CI 0.35-0.47) and 68% in pre-chemo (HR 0.32 95% CI 0.28-0.36). Abiraterone increased the time until PSA progression by 64% after chemo (HR 0.36 95% CI 0.52-0.78) and 50% in pre-chemo (HR 0.50 95% CI 0.43-0, 58), and enzyme-alpha in 75% after chemo (HR 0.25 95% CI 0.20-0.30) and 83% in pre-chemo (HR 0.17 95% CI 0.15-0.20). Conclusion: Both abiraterone and enzalutamide showed better results in increasing SG, SLPr and TP PSA in the treatment of patients with CPMRC. There is no direct comparative study and, because of differences in inclusion criteria and comparator groups between these clinical studies, indirect analysis of such drugs is not possible. Thus, questions such as the best pre and post chemo treatment strategy and the optimal sequencing for CPMRC coping cannot be answered.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21995号 / 医博第4509号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸井 雅和, 教授 万代 昌紀, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Yes / The aldo-keto reductase 1C3 (AKR1C3) enzyme is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) because of its role in the biosynthesis of androgens. Flufenamic acid, a non-selective AKR1C3 inhibitor, has previously been subjected to bioisosteric modulation to give rise to a series of compounds with the hydroxytriazole core. In this work, the hit compound of the previous series has been modulated further, and new, more potent, and selective derivatives have been obtained. The poor solubility of the most active compound (cpd 5) has been improved by substituting the triazole core with an isoxazole heteronucleous, with similar enzymatic activity being retained. Potent AKR1C3 inhibition is translated into antiproliferative effects against the 22RV1 CRPC cellular model, and the in-silico design, synthesis and biological activity of new compounds is described herein. Compounds have also been assayed in combination with two approved antitumor drugs, abiraterone and enzalutamide. / This research was financially supported by the University of Turin (Ricerca Locale grants BOSD_RILO_20_01, LOLM_RILO_21_01, PIPA_RILO_20_01 and PIPA_RILO_21_01), Fondazione Cassa di Risparmio di Torino (Grant BOSD_CRT_17_2) and TUBITAK (The Scientific and Technological Research Council of Turkey-2219 program).

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13517号 / 論医博第2267号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 遊佐 宏介, 教授 戸井 雅和, 教授 小川 誠司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.