Platinum-based anticancer drugs, such as cisplatin, carboplatin, and oxaliplatin, have been approved for clinical use worldwide for decades. Despite their enormous success, their widespread application is hindered by either cross-resistance or toxic side effects, including nephrotoxicity and neurotoxicity. The need to overcome these drawbacks has stimulated the search for new platinum-based drugs. This dissertation will start with the accidental discovery of cisplatin, followed by an introduction of other platinum-based anticancer agents, including the action mechanism, general structures, and development history. Picoplatin is a newer generation of platinum-based anticancer agent. The bulky 2-methylpyridine as a non-leaving group on picoplatin could reduce the detoxification effect caused by thiol-containing species, such as glutathione and metallothionein, thus may grant picoplatin the ability to overcome cisplatin resistance. A convenient synthesis route for picoplatin derivatives has been developed. 11 new picoplatin derivatives have been designed by varying the bulkiness of the non-leaving amine group. All complexes have been characterized by different instrumentations, including MS, 1H NMR, 13C NMR, 195Pt NMR, HMQC, X-ray crystallography, and elemental analysis. Different bioassays, such as DNA binding, cell viability, and cellular accumulation, have been applied to evaluate their efficacy on cisplatin-sensitive ovarian cancer cell line A2780 and cisplatin-resistant ovarian cancer cell line A2780cis. The newly designed picoplatin derivatives show comparable efficacy with that of picoplatin and less resistance compared with cisplatin. The study of picoplatin derivatives laid the foundation toward the research of bifunctional platinum-based anticancer agents by incorporating histone deacetylase (HDAC) inhibition. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are a pair of important enzymes in epigenetic regulation. They work in harmony to acetylate and deacetylate histone lysine residues, resulting in a more relaxed or more condensed chromatin structure, respectively. HDAC has been found to be overexpressed in some cancer cells. Since 2006, 5 HDAC inhibitors (HDACi) have entered clinical use for cancer treatment. 19 new HDACi with additional coordination sites on the phenyl cap have been designed, synthesized, and evaluated. A few of the new HDACi show comparable or even better HDAC inhibition than that of Vorinostat (SAHA, the first FDA approved HDACi). A logical design would involve the installation of HDACi on the platinum center as a non-leaving group ligand. When the bifunctional drug reaches the cancer cell, the synergistic effect could be maintained as the relaxed chromatin structure makes DNA more susceptible to be attacked by the platinum centers, thus increase the anticancer activity and possibly selectivity toward cancer cells. 6 Pt-HADCi conjugates have been designed and synthesized. Dual functions of the new Pt-HDACi have been confirmed by DNA electrophoresis assay and HDAC inhibition assay. One of the Pt-HDACi (CF-101) shows comparable cytotoxicity with cisplatin and less resistance, which could be used as the lead compound for further structural modification and in vivo studies.

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O envelhecimento dos eletrocatalisadores utilizados em cátodos de células a combustível de eletrólito polimérico (PEMFCs) é um dos principais fatores que restringem sua aplicação como conversores de energia em larga escala. Esse trabalho visa contribuir para o aprimoramento da estabilidade de nanopartículas de platina (NPs de Pt) por meio da modificação do suporte catalítico aos quais encontram-se impregnadas. Desse modo, foram realizadas sínteses de suportes catalíticos baseados em óxidos de molibdênio (MoO3 e MoO2) ancorados em carbono Vulcan® XC72-R, sendo os materiais produzidos caracterizados física, estrutural e eletroquimicamente antes e após a impregnação de NPs de Pt. Para investigar a estabilidade dos eletrocatalisadores, foi realizado um teste de degradação eletroquímico acelerado, o qual consistiu em aplicar os ciclos de potenciais entre 0,6 e 1,0 V vs. ERH por curto período de tempo. Os resultados mostraram que os métodos de síntese utilizados foram satisfatórios, levando a formação dos catalisadores com as proporções bem próximas das requeridas. O catalisador Pt/MoO3-C apresentou a maior atividade específica frente a reação de redução de oxigênio (RRO), atribuída a efeitos sinérgicos metal/suporte. Quando investigada a estabilidade dos materiais frente ao teste de degradação eletroquímico acelerado, observou-se que, a princípio, nenhum dos óxidos de molibdênio diminui a extensão da degradação da platina. Analisando-se as atividades específicas frente à RRO para cada catalisador antes e após o envelhecimento eletroquímico, foi observado que Pt/MoO2-C apresentou-se como o material mais estável dentre os demais. / The aging of Pt based electrocatalysts used in the polymer electrolyte fuel cell (PEMFC) cathodes is one of the main issues that restrict its wide application as energy converters. This work aims to contribute to the improvement of the stability of platinum nanoparticles (Pt NPs) by modification of the catalyst support at which they are impregnated. Thus, syntheses of catalyst supports based on molybdenum oxide (MoO3 and MoO2) anchored on Vulcan® XC72-R carbon were carried out and the produced materials were characterized physically, structurally and electrochemically prior and after impregnation of the Pt NPs. To investigate their stability, an electrochemical accelerated degradation test was performed, which consisted of applying a large number of short duration potential cycling steps between 0.6 and 1.0 V vs. RHE. The results showed that the synthetic methods used here were satisfactory, leading to the formation of catalysts with compositions near to those expected. The Pt/MoO3-C catalyst showed the highest specific activity toward the oxygen reduction reaction (ORR), and this was attributed to metal/support synergistic effects. When the stability against electrochemical accelerated degradation test of the materials was investigated, it was observed that, in principle, none of the molybdenum oxides really decreases the extent of platinum degradation. However, comparing the specific activities towards the ORR for each catalyst, before and after electrochemical aging, it is concluded that Pt/MoO2-C is the most stable material among all others.

O envelhecimento dos eletrocatalisadores utilizados em cátodos de células a combustível de eletrólito polimérico (PEMFCs) é um dos principais fatores que restringem sua aplicação como conversores de energia em larga escala. Esse trabalho visa contribuir para o aprimoramento da estabilidade de nanopartículas de platina (NPs de Pt) por meio da modificação do suporte catalítico aos quais encontram-se impregnadas. Desse modo, foram realizadas sínteses de suportes catalíticos baseados em óxidos de molibdênio (MoO3 e MoO2) ancorados em carbono Vulcan® XC72-R, sendo os materiais produzidos caracterizados física, estrutural e eletroquimicamente antes e após a impregnação de NPs de Pt. Para investigar a estabilidade dos eletrocatalisadores, foi realizado um teste de degradação eletroquímico acelerado, o qual consistiu em aplicar os ciclos de potenciais entre 0,6 e 1,0 V vs. ERH por curto período de tempo. Os resultados mostraram que os métodos de síntese utilizados foram satisfatórios, levando a formação dos catalisadores com as proporções bem próximas das requeridas. O catalisador Pt/MoO3-C apresentou a maior atividade específica frente a reação de redução de oxigênio (RRO), atribuída a efeitos sinérgicos metal/suporte. Quando investigada a estabilidade dos materiais frente ao teste de degradação eletroquímico acelerado, observou-se que, a princípio, nenhum dos óxidos de molibdênio diminui a extensão da degradação da platina. Analisando-se as atividades específicas frente à RRO para cada catalisador antes e após o envelhecimento eletroquímico, foi observado que Pt/MoO2-C apresentou-se como o material mais estável dentre os demais. / The aging of Pt based electrocatalysts used in the polymer electrolyte fuel cell (PEMFC) cathodes is one of the main issues that restrict its wide application as energy converters. This work aims to contribute to the improvement of the stability of platinum nanoparticles (Pt NPs) by modification of the catalyst support at which they are impregnated. Thus, syntheses of catalyst supports based on molybdenum oxide (MoO3 and MoO2) anchored on Vulcan® XC72-R carbon were carried out and the produced materials were characterized physically, structurally and electrochemically prior and after impregnation of the Pt NPs. To investigate their stability, an electrochemical accelerated degradation test was performed, which consisted of applying a large number of short duration potential cycling steps between 0.6 and 1.0 V vs. RHE. The results showed that the synthetic methods used here were satisfactory, leading to the formation of catalysts with compositions near to those expected. The Pt/MoO3-C catalyst showed the highest specific activity toward the oxygen reduction reaction (ORR), and this was attributed to metal/support synergistic effects. When the stability against electrochemical accelerated degradation test of the materials was investigated, it was observed that, in principle, none of the molybdenum oxides really decreases the extent of platinum degradation. However, comparing the specific activities towards the ORR for each catalyst, before and after electrochemical aging, it is concluded that Pt/MoO2-C is the most stable material among all others.

Abstract : Glioblastoma is the most common and aggressive brain cancer in adults. The current standard-of-care treatment includes surgical resection, radiation therapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy. However, the addition of TMZ to radiation therapy only increased the median survival time (MeST) by 2.5 months. This limited improvement is partially attributable to the low accumulation of chemotherapeutic drugs in the brain tumor due to the blood-brain barrier (BBB). Thus, new delivery methods such as intra-arterial, BBB disruption and convection-enhanced delivery (CED) have been proposed to overcome this limitation. Besides, timing tumor irradiation to coincide with the maximal concentration of platinum-DNA adducts could result in improved tumor control. In this study, CED of cisplatin and oxaliplatin, their respective liposomal formulations Lipoplatin™, Lipoxal™, and carboplatin with or without 15 Gy of radiation therapy has been carried out in F98 glioma bearing Fischer rats to assess their toxicity and MeST. The amount of platinum-DNA adducts in the tumor at 4 h and 24 h after CED was measured and irradiation was administered at these two different time periods to test the concomitant effect. In addition, four liposomal carboplatin formulations with different chemo-physical properties were prepared and their toxicity and MeST were also evaluated in this animal model. Among the tested platinum drugs, carboplatin and Lipoxal™ demonstrated a highest maximum-tolerated dose of 25 µg and 30 µg respectively. CED of carboplatin showed the longest MeST of 38.5 days, and increased to 54.0 days with the addition of 15 Gy radiation therapy. However, radiation at 4 h after CED of either oxaliplatin or carboplatin did not show any survival improvement when compared to radiation at 24 h, although the quantity of platinum-DNA adducts at 4 h was higher than at 24 h after CED. In the four liposomal carboplatin formulations, anionic pegylated liposomal carboplatin showed the longest MeST of 49.5 days, due to its longer tumoral retention time and probably larger distribution volume in the brain. / Résumé : Le glioblastome est le cancer primaire du cerveau le plus courant et agressif chez l’adulte. Le traitement standard comprend la résection chirurgicale, la radiothérapie et la chimiothérapie concomitante et adjuvante avec le témozolomide(TMZ). L'addition de TMZ combinée la radiothérapie a augmenté la survie médiane (MeST) de 2,5 mois. Cette faible amélioration est partiellement due à l'accumulation limitée de médicaments chimiothérapeutiques dans la tumeur cérébrale à cause de la barrière hémato-encéphalique (BBB). Ainsi, de nouvelles méthodes comme l’injection intraartérielle, la rupture osmotique de la barrière hémato-encéphalique, la livraison augmentée par convection (CED) ont été suggérées pour surmonter ce problème. En plus, l’optimisation de l’irradiation de la tumeur lorsque le maximum d’adduits platine-ADN est atteint pourrait aboutir à un meilleur contrôle de la tumeur. Dans cette étude, nous avons injecté par CED le cisplatine, l’oxaliplatine, avec leur formulation liposomale Lipoplatin™, Lipoxal™ ainsi que le carboplatine avec ou sans radiation de 15 Gy. La toxicité et le temps de MeST ont été mesurés chez des rats Fischer porteurs du gliome. La quantité d'adduits platine-ADN dans la tumeur a été mesurée 4 h et 24 h après CED. L’irradiation de la tumeur a été effectuée à ces deux temps pour tester l'effet concomitant. En plus, quatre formulations liposomales de carboplatine avec différentes propriétés chimiophysiques ont été préparées et leur toxicité et MeST combiné à la radiation ont également été évalués. Parmi les drogues de platine testées, le carboplatine et Lipoxal™ ont démontré respectivement la dose maximale tolérée la plus élevée, soit 25 µg et 30 µg. La MeST du carboplatine était la plus longue avec 38,5 jours qui a augmenté à 54,0 jours avec l’addition de 15 Gy de radiothérapie. Toutefois, l’irradiation à 4 h après CED effectuée avec l'oxaliplatine et le carboplatine n'a pas amélioré la MeST comparé à l’irradiation à 24 h, bien que la quantité d'adduits platine-ADN à 4 h était supérieure à celle mesurée à 24 h après CED. Pour les quatre formulations liposomales de carboplatine, celle pégylée négatif a démontré la plus longue MeST, soit 49,5 jours.

Introduction: Les mutations du gène RAS sont présentes dans plusieurs types de cancers et ont une influence sur la réponse à la chimiothérapie. Excision repair cross- complementation group 1 (ERCC1) est un gène impliqué dans la réparation de l’acide désoxyribonucléique (ADN), et son polymorphisme au codon 118 est également associé à la réponse au traitement. Le peu d’études pronostiques portant sur ces deux gènes dans les cancers oto-rhino-laryngologiques (ORL) ne permet de tirer des conclusions claires. Objectifs: Déterminer l’influence des mutations de K-RAS codons 12 et 13 et du polymorphisme de ERCC1 codon 118 dans le traitement des cancers épidermoïdes avancés tête et cou traités par chimioradiothérapie concomitante à base de sels de platine. Méthode: Extraction de l’ADN provenant de spécimens de biopsie de patients traités par chimioradiothérapie concomitante pour des cancers avancés tête et cou, et ayant un suivi prospectif d’au moins deux ans. Identification des mutations de K-RAS codons 12 et 13 et du polymorphisme de ERCC1 au codon 118 dans les spécimens et corrélation de ces marqueurs avec la réponse au traitement. Résultats: Les mutations de K-RAS codon 12 sont associées à un moins bon contrôle loco-régional par rapport aux tumeurs ne démontrant pas la mutation (32% vs 83% p=0.03), sans affecter pour autant la survie globale. Aucune mutation de K-RAS codon 13 n’a été identifiée. Les différents polymorphismes de ERCC1 n’ont pas eu d’impact sur la réponse au traitement. Conclusion: Les mutations de K-RAS codons 12 et 13 et le polymorphisme de ERCC1 au codon 118 ne semblent pas mettre en évidence les patients qui bénéficieraient d’une autre modalité thérapeutique. / Background: RAS gene mutations have been shown to occur in certain malignancies and have an impact treatment response and overall prognosis. Excision repair cross- complementation group 1 (ERCC1) is a gene implicated in deoxyribonucleic acid (DNA) repair, whose polymorphism at codon 118 has been linked to treatment response. Studies of these two genes in head and neck oncology literature have shown inconsistent results. Objectives: Determine the influence of K-RAS mutations (codons 12 and 13) and the polymorphism of ERCC1 codon 118 in patients with locally advanced head and neck cancer treated with concomitant platinum-based chemoradiation therapy. Methods: DNA extraction from paraffin-embedded biopsy specimens of patients with advanced head and neck squamous cell carcinoma treated with concomitant chemoradiation and followed prospectively for at least two years. Identification of K- RAS mutations (codons 12 and 13) and ERCC1 codon 118 polymorphism in the extracted DNA. Correlation of these markers with treatment response. Results: K-RAS codon 12 mutations were associated with a worse locoregional control than tumors without any mutations (32% vs 83% p=0.03); however, mutational status did not influence overall survival. No K-RAS codon 13 mutation was identified in our specimens. The different ERCC1 polymorphisms did not have an impact on treatment response. Conclusion: K-RAS mutational status (codon 12 and 13) and ERCC1 codon 118 polymorphism does not seem to discriminate between patients for whom another treatment option should be sought in patients with locally advanced head and neck squamous cell carcinoma.

Introduction: Les mutations du gène RAS sont présentes dans plusieurs types de cancers et ont une influence sur la réponse à la chimiothérapie. Excision repair cross- complementation group 1 (ERCC1) est un gène impliqué dans la réparation de l’acide désoxyribonucléique (ADN), et son polymorphisme au codon 118 est également associé à la réponse au traitement. Le peu d’études pronostiques portant sur ces deux gènes dans les cancers oto-rhino-laryngologiques (ORL) ne permet de tirer des conclusions claires. Objectifs: Déterminer l’influence des mutations de K-RAS codons 12 et 13 et du polymorphisme de ERCC1 codon 118 dans le traitement des cancers épidermoïdes avancés tête et cou traités par chimioradiothérapie concomitante à base de sels de platine. Méthode: Extraction de l’ADN provenant de spécimens de biopsie de patients traités par chimioradiothérapie concomitante pour des cancers avancés tête et cou, et ayant un suivi prospectif d’au moins deux ans. Identification des mutations de K-RAS codons 12 et 13 et du polymorphisme de ERCC1 au codon 118 dans les spécimens et corrélation de ces marqueurs avec la réponse au traitement. Résultats: Les mutations de K-RAS codon 12 sont associées à un moins bon contrôle loco-régional par rapport aux tumeurs ne démontrant pas la mutation (32% vs 83% p=0.03), sans affecter pour autant la survie globale. Aucune mutation de K-RAS codon 13 n’a été identifiée. Les différents polymorphismes de ERCC1 n’ont pas eu d’impact sur la réponse au traitement. Conclusion: Les mutations de K-RAS codons 12 et 13 et le polymorphisme de ERCC1 au codon 118 ne semblent pas mettre en évidence les patients qui bénéficieraient d’une autre modalité thérapeutique. / Background: RAS gene mutations have been shown to occur in certain malignancies and have an impact treatment response and overall prognosis. Excision repair cross- complementation group 1 (ERCC1) is a gene implicated in deoxyribonucleic acid (DNA) repair, whose polymorphism at codon 118 has been linked to treatment response. Studies of these two genes in head and neck oncology literature have shown inconsistent results. Objectives: Determine the influence of K-RAS mutations (codons 12 and 13) and the polymorphism of ERCC1 codon 118 in patients with locally advanced head and neck cancer treated with concomitant platinum-based chemoradiation therapy. Methods: DNA extraction from paraffin-embedded biopsy specimens of patients with advanced head and neck squamous cell carcinoma treated with concomitant chemoradiation and followed prospectively for at least two years. Identification of K- RAS mutations (codons 12 and 13) and ERCC1 codon 118 polymorphism in the extracted DNA. Correlation of these markers with treatment response. Results: K-RAS codon 12 mutations were associated with a worse locoregional control than tumors without any mutations (32% vs 83% p=0.03); however, mutational status did not influence overall survival. No K-RAS codon 13 mutation was identified in our specimens. The different ERCC1 polymorphisms did not have an impact on treatment response. Conclusion: K-RAS mutational status (codon 12 and 13) and ERCC1 codon 118 polymorphism does not seem to discriminate between patients for whom another treatment option should be sought in patients with locally advanced head and neck squamous cell carcinoma.

This work deals with studying a molecular mechanism of anticancer effect of a new platinum - based drug. The qualities of still unknow dinuclear platinum komplex (BBR3571-DACH) were parallelly studied together with clinically time-tested and used mononuclear platinum complex DACH. Earlier essays demostrated, that DNA is the critical target for the cytostatic activity of platinum compounds. Altered properties of DNA and binding characteristics of these two platinum compounds were monitored by several different bioanalytical methods (differential pulse polarography, UV-VIS spectrophotometry, fluorescence spectrophotometry, CD spectroscopy and electrophoresis) after modification of DNA by both of platinum complexes. For the compounds BBR3571-DACH and DACH it was determined that the DNA binding is rapid and bifunctional. The stabilizing effect on DNA was significant particularly after modification of DNA by dinuclear komplex, while denaturating effect wasn´t proved at all. The results also indicate that dinuclear platinum complex BBR3571-DACH probably does not participate on formation of long-range cross-links like other early studied polynuclear platinum complexes.

[ES] El curso natural de los tumores va acompañado de la acumulación progresiva de alteraciones genómicas, propiciando una cadena de eventos que resultan en inestabilidad genómica (IG). Éste fenómeno, caracterizado por alteraciones en el número de copias, constituye un hallmark genómico con impacto pronóstico más allá de la histología y otras características moleculares del tumor. En el ámbito de la investigación en oncología ginecológica, la IG ha ganado fuerza en los últimos años, permitiendo la estratificación de pacientes de acuerdo al pronóstico y la respuesta a agentes que dañan el ADN, como las terapias basadas en platinos y los inhibidores de PARP. En el cáncer de ovario, en particular, se ha descrito un subgrupo molecular caracterizado por alta incidencia de alteraciones en el número de copias relacionado con un mejor pronóstico y respuesta a quimioterapia. Esta correlación presenta la IG como un buen marcador predictivo y pronóstico. Así, un modelo basado en la IG trasladable a la práctica clínica constituirá una herramienta útil para la optimización de la toma de decisiones. La era de la medicina personalizada llegó de la mano de los estudios integrativos, donde las técnicas de alto rendimiento se aplican de manera combinada para obtener una visión molecular global de los tumores, completando y complementando la caracterización clásica a nivel anatómico e histológico. Esta tesis propone un estudio global de la IG como biomarcador pronóstico y predictivo de respuesta en cáncer ginecológico, haciendo hincapié en el cáncer de ovario seroso de alto grado y cáncer de endometrio. A través de la aplicación de estrategias basadas en NGS con la adaptación de pipelines de análisis disponibles obtuvimos los perfiles de IG de muestras de tejido fijadas en formol y embebidas en parafina, de una manera fiable, portable y coste efectiva, combinando herramientas de machine learning para ajustar modelos predictivos y pronósticos. Partiendo de esta premisa, ajustamos y validamos, en cohortes clínicas bien caracterizadas, tres modelos a partir de los datos ómicos individuales y un modelo integrativo (Scarface Score) que demostró la capacidad de predecir la respuesta a agentes que dañan el ADN en un escenario clínico concreto de pacientes con cáncer de ovario seroso de alto grado. Paralelamente, desarrollamos y validamos un algoritmo basado en el perfil de mutaciones, con impacto pronóstico, en cáncer de endometrio. Este algoritmo consiguió una estratificación que respondía al perfil de IG de los pacientes. Finalmente, se caracterizó un panel de líneas celulares de cáncer de ovario a nivel de respuesta, genético y genómico. Se interrogó el estatus de la vía de recombinación homóloga y su asociación a patrones de IG, completando el perfil molecular y estableciendo las bases para futuros estudios preclínicos y clínicos. Los resultados obtenidos en esta tesis doctoral presentan herramientas de gran valor para el manejo clínico en cuanto a la búsqueda de una medicina personalizada. Adicionalmente, diferentes estudios para trasladar el modelo predictivo a otros escenarios clínicos pueden ser explorados, usando como base el planteado, pero restableciendo puntos de corte nuevos y específicos. / [CA] El curs natural dels tumors va acompanyat de l'acumulació progressiva d'alteracions genòmiques, propiciant una cadena d'esdeveniments que resulten en inestabilitat genòmica (IG). Aquest fenomen, caracteritzat per la presencia de alteracions en el nombre de cópies, constitueix un hallmark genòmic amb impacte pronòstic més enllà de la histologia i altres característiques moleculars del tumor. En l'àmbit de la recerca en oncologia ginecològica, la IG ha guanyat força en els últims anys, permetent l'estratificació de pacients d'acord amb el pronòstic i la resposta d'agents que danyen l'ADN, com les teràpies basades en platins i els inhibidors de PARP. En el càncer d'ovari en particular, s'ha descrit un subgrup molecular caracteritzat per una alta incidència d'alteracions en el nombre de còpies relacionat amb un millor pronòstic i resposta a quimioteràpia. Aquesta correlació presenta la IG com un marcador predictiu i pronòstic adeqüat. Així, un model basat en la IG traslladable a la pràctica clínica constituirà una eina útil per a l'optimització de la presa de decisions. L'era de la medicina personalitzada va arribar de la mà dels estudis integratius, on les tècniques d'alt rendiment s'apliquen de manera combinada per a obtenir una visió molecular global dels tumors, completant i complementant la caracterització clàssica a nivell anatòmic i histològic. Aquesta tesi proposa un estudi global de la IG com a biomarcador pronòstic i predictiu de resposta en càncer ginecològic, posant l'accent en el càncer d'ovari serós d'alt grau i càncer d'endometri. A través de la aplicación d'estratègies basades en NGS amb l'adaptació de pipelines d'anàlisis disponibles, vam obtenir els perfils de IG de mostres de teixit fixades en formol i embegudes en parafina d'una manera fiable, portable i cost efectiva, combinant eines de machine learning per a ajustar models predictius i pronòstics. Partint d'aquesta premissa, vam ajustar i validar, en cohortes clíniques ben caracteritzades, tres models a partir de les dades omiques individuals i un model integratiu (Scarface Score) que va demostrar la capacitat de predir la resposta a agents que danyen l'ADN en un escenari clínic concret de pacients amb càncer d'ovari serós d'alt grau. Paral·lelament, desenvoluparem i validarem un algoritme basat en el perfil de mutacions amb impacte pronòstic en càncer d'endometri. Aquest algoritme va aconseguir una estratificació que responia al perfil de IG dels pacients. Finalment, es va caracteritzar un panell de línies cel·lulars de càncer d'ovari a nivell de resposta, genètic i genòmic. Es varen interrogar l'estatus de la via de recombinació homòloga i la seua associació a patrons de IG, completant el perfil molecular i establint les bases per a futurs estudis preclínics i clínics. Els resultats obtinguts en aquesta tesi doctoral presenten eines de gran valor per al maneig clínic en quant a la cerca d'una medicina personalitzada. Addicionalment, diferents estudis per a traslladar el model predictiu a altres escenaris clínics poden ser plantejats, usant com a base el propost però restablint punts de tall nous i específics. / [EN] The natural course of tumors matches the progressive accumulation of genomic alterations, triggering a cascade of events that results in genomic instability (GI). This phenomenon includes copy number alterations and constitutes a genomic hallmark that defines specific outcomes beyond histology and other molecular features of the tumor. In the context of gynaecologic oncology research, GI has gained strength in the last years allowing the stratification of patients according to prognosis and response to certain DNA-damaging agents, such as platinum-based therapies and PARP inhibitors. Particularly in ovarian and endometrial cancers, it has been described a molecular subgroup characterized by high copy number alterations (CNA) related to good prognosis and better response to chemotherapy. This relationship highlights GI as a predictive and prognostic biomarker. Hence, a GI-based model translated into clinical practice would constitute a tool for optimizing clinical decision-making. The era of personalised medicine arrived together with the coming of integrative studies, where results of high-throughput techniques are combined to obtain a comprehensive molecular landscape of the diseases, bringing a new paradigm to characterize the tumors beyond classical anatomic and histological characteristics. This thesis proposes a global study of the phenomenon of GI as a prognostic and predictive biomarker of treatment response in gynaecological cancers, mainly focused on high-grade ovarian cancer and endometrial cancer. Through the development of an NGS-based strategy with the adaptation of available pipelines of analysis, we obtained GI profiles on formalin-fixed paraffin-embedded samples in a reliable, portable, and cost-effective approach, with the combination of Machine Learning tools to fit prognostic and predictive models based on the integration of omic data. Based on that premise, we fit and validated, in well-characterized clinical cohorts, three single-source models and an integrative ensemble model (Scarface Score) that proved to be able to predict response to DNA-damaging agents in a clinical scenario of High-Grade Serous Ovarian Cancer. In addition, a mutational-based algorithm (12g algorithm) with prognostic impact was developed and validated for endometrial cancer patients. This algorithm achieved a GI-based stratification of patients. Finally, a panel of ovarian cancer cell lines was characterized at the response, genetic and genomic level, interrogating homologous recombination repair pathway status and its associated GI profiles, completing the molecular landscape, and establishing the basis and breeding ground of future preclinical and clinical studies. The results reported in this Doctoral Thesis provide valuable clinical management tools in the accomplishment of a reliable tailored therapy. Additionally, future studies in different tumor types and drugs for implementation of the predictive model can be planned, using as a base the defined one but re-establishing new and specific cut-offs. / The present doctoral thesis was partially funded by GVA Grants “Subvencions per a la realització de projectes d’i+d+i desenvolupats per grups d’investigació emergents (GV/2020/158)” and “Ayudas para la contratación de personal investigador en formación de carácter predoctoral” (ACIF/2016/008), “Beca de investigación traslacional Andrés Poveda 2020” from GEICO group and Phase II clinical trial (POLA: NCT02684318, EudraCT 2015-001141-08, 03.10.2015). This study was awarded the Prize “Antonio Llombart Rodriguez-FINCIVO 2020” from the Royal Academy of Medicine of the Valencian Community / López Reig, R. (2023). Genomic instability as a predictive biomarker for the application of DNA-damaging therapies in gynecological cancer patients [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/199026