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.

Les cancers moléculaires apocrines sont un sous-groupe de cancer du sein caractérisé par l'expression du récepteur aux androgènes (RA), l'absence du récepteur aux oestrogènes (RE) et l'expression paradoxale de nombreux gènes typiquement exprimés dans les tumeurs RE positives. Une proportion significative de ces patientes va récidiver sous forme de métastases dont la prise en charge repose sur des traitements non spécifiques (chimiothérapies). En préclinique, la lignée cellulaire MDA-MB-453 a été identifiée comme ayant un profil transcriptomique similaire à ce sous-groupe tumoral. En clinique, les essais réalisés dans ce sousgroupe tumoral avec différents anti-androgènes, dont l’abiratérone (inhibiteur de la synthèse des androgènes), retrouvent un bénéfice clinique chez environ 25% des patientes. L’objectif de cette thèse est d’améliorer les connaissances et les prises en charge thérapeutiques spécifiques de ces tumeurs. Nos données précliniques comparatives montrent que l'ODM-201, nouvel antiandrogène, ne présente pas une efficacité supérieure par rapport aux antiandrogènes déjà étudiés. Afin de contourner les limites des lignées cellulaires identifiées dans ce premier projet, nous avons démontré la nécessité de développer de nouveaux modèles : les Patient-Derived-Xenograft orthotopiques. Notre deuxième projet est en faveur d’une meilleure sélection des patientes à traiter par abiratérone notamment basé sur des caractéristiques immunohistochimiques apocrines. Chez les patientes ne présentant pas ces caractéristiques, nous avons isolé CHEK1 comme une cible d’intérêt en combinaison thérapeutique pour majorer les taux de réponse de l’abiratérone en monothérapie. / Molecular apocrine cancers are a subgroup of breast cancer characterized by the expression of the androgen receptor (AR), the absence of the estrogen receptor (ER) and the paradoxical expression of many genes typically expressed in ER positive tumors. A significant proportion of these patients will recur in the form of metastases whose management is based on non-specific treatments (chemotherapy). In preclinical study, the MDA-MB-453 cell line was identified as having a transcriptomic profile similar to this tumor subgroup. Clinical trials in this tumor subgroup testing different antiandrogens, including abiraterone (inhibitor of androgen synthesis), found a clinical benefit in about 25% of patients. The aim of this thesis is to improve the knowledge and the specific therapeutic management of these tumors. Our comparative preclinical data show that ODM-201, a new anti-androgen, does not show superior efficacy compared to previously studied anti-androgens. In order to circumvent the limits of cell lines provided by this first project, we have shown the need to develop new models: orthotopic Patient-Derived-Xenograft. Our second project favors a better selection of patients to be treated with abiraterone, especially based on apocrine immunohistochemical characteristics. In patients without these characteristics, we isolated CHEK1 as a target of interest in combination therapy to increase response rates of abiraterone monotherapy.

Backgroun and aims: Pharmacokinetic variability is of paramount importance for sucessfull pharmacotherapy. The main purpose of this work was to study variability of pharmacokinetics in clinical and non-clinical setting with the aim to predict variability in target population. Specifically, three drugs were chosen, sufentanil, with relativelly narrow therapeutic index, and nabumeton and abirateron, both with known high variability. Methods: The study of pharmacokinetic variability of sufentanil was based on clinical samples taken from patients undergoing surgical cardiac procedure, where the sufentanil was used as a part of the drug coctail used during the procedure. New analytical method was necessary to prepare and validate to measure sufentanil concentrations and obtain pharmacokinetic parameters. These were compared between determined genotype groups of MDR1 and OPRM1. Similarly, clinical study was executed with nabumetone, in which nabumetone was administered in a group of 24 subjects on two separate occassions. Plazma samples were obtained and concentrations of nabumetone and its active metabolite, 6-methoxynaphtylacetic acid (6-MNA), were determined. Obtained pharmacokinetic profiles were compared between female and male volunteers, and genotypes for MDR1 and CYP2D6. Finaly for abiraterone,...

MicroRNAs are a class of small non-coding RNAs involved in post-transcriptional regulation. Their role in almost all processes of the cell, make microRNAs ubiquitary players of cell development, growth, differentiation, cell to cell communication and cell death. Thus, cells’ physiological or pathological conditions are reflected by variations in the levels of expression of microRNAs, enabling them to be used as biomarkers of such states. In the past decade, there has been an exponential increase of studies using microRNAs as potential biomarkers for cancer, neurodegenerative diseases, inflammation and cardiac diseases, from tissues and liquid biopsies. However, none of them has reached the clinics yet, due to inconsistency of results through the literature and lack of assay standardization and reproducibility. Technological limitations of microRNAs detection have been, to date, the biggest challenge for using these molecules in clinical settings. In fact, although microarrays, RT-qPCR and RNA-seq are well-established technologies, they all require complex procedures and trained personnel, for performing RNA extraction, labelling of the target and PCR amplification. All these steps introduce variability and, in addition, since no universally standardized protocol – from sample extraction to analyte detection - has been produced yet, methodological procedures are difficult to reproduce. For this reason, we developed a new platform for the rapid detection of microRNAs in biofluids composed of an innovative silicon-photomultiplier (SiPM) based detector and a new chemistry for nucleic acid testing (Chem-NAT). Chem-NAT exploits a dynamic labelling chemistry which allows the sensitive detection of nucleic acids till single base level. On the other hand, SiPM-based device, compared to normal vacuum photomultipliers, grants miniaturization and higher capacity of fitting in a bench-top solution for clinical settings, among other advantages. The new platform – ODG – has been validated for the direct detection – neither RNA extraction nor PCR amplification needed - of microRNA-21 in plasma of lung cancer patients. In this work, we also explored the use of microRNAs as biomarkers in metastatic castration resistant prostate cancer (mCRPC). We collected plasma samples from mCRPC patients before and after abiraterone acetate treatment – androgen deprivation type of drug – and performed a miRnome analysis for discovering microRNAs predicting the efficacy of the drug. We chose miR-103a-3p and miR-378a-5p and we validated them via TaqMan RT-qPCR. We discovered that the ratio between the two microRNAs is able to predict the efficacy of abiraterone acetate and follow the responsiveness in time. In liquid biopsies, extracellular vesicles are getting increasing importance for diagnostic and prognostic purposes. Therefore, in this work we also explored the expression of some microRNAs in extracellular vesicles from plasma, isolated via nickel-based method. We discovered that microRNA-21 and microRNA-223 are not enriched in vesicles from healthy individuals.

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