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Caracterización Del Mecanismo De Acción De Los ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials dʼinvestigació i docència en els termes establerts a lʼart. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix lʼautorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No sʼautoritza la seva reproducció o altres formes dʼexplotació efectuades amb finalitats de lucre ni la seva comunicació pública des dʼun lloc aliè al servei TDX. Tampoc sʼautoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. 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The access to the contents of this doctoral thesis and its use must respect the rights of the author. It can be used for reference or private study, as well as research and learning activities or materials in the terms established by the 32nd article of the Spanish Consolidated Copyright Act (RDL 1/1996). Express and previous authorization of the author is required for any other uses. In any case, when using its content, full name of the author and title of the thesis must be clearly indicated. Reproduction or other forms of for profit use or public communication from outside TDX service is not allowed. Presentation of its content in a window or frame external to TDX (framing) is not authorized either. These rights affect both the content of the thesis and its abstracts and indexes. Universidad Autónoma de Barcelona Departamento de Medicina Facultad de Medicina Programa de Doctorado en Medicina CARACTERIZACIÓN DEL MECANISMO DE ACCIÓN DE LOS PAN-INHIBIDORES SELECTIVOS DEL RECEPTOR DEL FACTOR DE CRECIMIENTO FIBROBLÁSTICO E IDENTIFICACIÓN DE POTENCIALES BIOMARCADORES PREDICTIVOS DE RESPUESTA MEDIANTE LA UTILIZACIÓN DE XENOINJERTOS DERIVADOS DE PACIENTES CON ALTERACIONES EN ESTA VÍA MOLECULAR Tesis doctoral para optar al grado de Doctor Cinta Hierro Carbó Directores de la tesis: Jordi Rodón Ahnert Violeta Serra Elizalde Tutor de la tesis: Francesc Bosch Albareda Barcelona, 2020 “Y una vez que la tormenta termine, no recordarás cómo lo lograste, cómo sobreviviste. Ni siquiera estarás seguro de si la tormenta ha terminado realmente. Pero una cosa si es segura. Cuando salgas de esa tormenta, no serás la misma persona que entró en ella” Haruki Murakami A Gara AGRADECIMIENTOS Al Dr. Josep Tabernero, por la confianza depositada en mí y por ofrecerme esta gran oportunidad en mi carrera. Al Dr. Jordi Rodón y la Dra. Violeta Serra, ambos directores de esta tesis. Porque nunca dos mentores tan antagónicos tuvieron un efecto tan sinérgico, a ellos les debo haber sacado lo mejor de mí como investigadora. Echaré de menos nuestras teleconferencias en franjas horarias imposibles, y la fuga de ideas que apuntar en mi libreta. A Mònica Sánchez-Guixé, por su dedicación en el laboratorio y por compartir conmigo la ilusión de este proyecto. Ha sido un lujazo trabajar juntas. A la Dra. Elena Garralda y todo el equipo humano que vertebra la UITM, por el apoyo a todo este proyecto; en especial, gracias a Laura Maynes, la mejor coordinadora que el FGFR 360º RESISTANCE podría haber tenido. A la Dra. Ana Vivancos, el Dr. Paolo Nuciforo, el Dr. Rodrigo Dienstmann y sus respectivos equipos, cuyo trabajo ha hecho posible esta tesis. Al Prof. José Jiménez, por su inestimable ayuda con la gestión de muestras. Definitivamente, si no existiera tendrían que inventarlo. A las Dras. Cristina Saura y Mafalda Oliveira, por entender como nadie que para el éxito de los proyectos es imprescindible colaborar. Definitivamente, todas las direcciones siempre me han llevado a la mama, aunque yo me haya resistido. Al Dr. Ricard Mesía y la Dra. Maica Galán, por enseñarme ese algo más de la Oncología, y por haber creído siempre en mí. 1 A los pacientes y sus famílias, por recordarme a diario porqué elegí esta profesión. A mi tribu de amigos, mi gran família elegida, por estar ahí 24/7/365 desde las antípodas o en medio de una pandemia mundial: #Este gato é una mielda, #Pasajeritos confinados, #Sukiyaki friends, #Sinó a Bcn a SF, #AlbaRipoll, #Meprecipitodelavida, #You’ll never walk alone, #Gossip girls, #Pirri the ripper is back, #Ebre connection, #Tu pelo tu pelooo. A mi padres, Tere y Fermín, por su cariño y valores inculcados, pero sobretodo, por su apoyo total a pesar de no siempre entender mis decisiones. A mi hermana Maite y Ismael, luchadores como nadie y cómplices en la vida. A Ismael e Iván, por querer a su tía de forma incondicional. A Juanjo y Susana, por recargarme las pilas siempre que ha hecho falta, y a Marta, por aceptar el reto de compartir conmigo el título de aventurera de la família. A Pilar, Álvaro y Mariona, por tener la gran suerte de haber encontrado en ellos la a otra mitad de mis imprescindibles. A J. J. Carbó, mi genial abuelo pintor que impregnó mi infancia de pasión cromática. Por enseñarme a ir contracorriente, no conformarme nunca con nada y cuestionarlo todo siempre. Creo que estaría orgulloso. A Joan, mi perfecto compañero de viaje. Por entender como nadie lo que significa ser médico, e intentar superarse cada día en el empeño de hacerlo mejor. Por ser mi crítico más duro y al mismo tiempo, mi mayor fan durante todo este proyecto. Gracias por no dejarme tirar la toalla nunca. A mis hijas, por enseñarme el verdadero significado de la resiliencia humana. Y por último, a la ciudad de Melbourne. Por estar allí cuando más la necesitaba. Sin ella, esta tesis nunca hubiera visto la luz. 2 LISTADO DE ABREVIACIONES FGFR: del inglés Fibroblast Growth Factor Receptor FGF: del inglés Fibroblast Growth Factor MTKI: del inglés Multi-Tyrosin Kinase Inhibitor ORR: del inglés Overall Response Rate DCR: del inglés Disease Control Rate ALK: del inglés Anaplastic Lymphoma Kinase NTRK: del inglés Neutrotrophic Tyrosin Receptor Kinase MSI-H: del inglés MiscroSatellite Instability High dMMR: del inglés deficient in MisMatch Repair PTEN: del inglés Phosphatase and TENsin homolog EGFR: del inglés Epidermal Growth Factor Receptor IGFR: del inglés Insulin Growth Factor Receptor VEGFR: del inglés Vascular Endothelial Growth Factor Receptor PDGFR: del inglés Platelet Derived Growth Factor Receptor MAPK: del inglés Mitogen-Activated Pathway Kinase PI3K: del inglés PhosphatidylInositol-4,5-bisphosphate-3-Kinase BRAF: del inglés v-Raf murine sarcoma viral oncogene homolog B1 HER: del inglés Human Epidermal Receptor EMT: del inglés Epithelial-Mesenchymal Transition ADCC: del inglés Antibody-Dependent Cellular-mediated Cytotoxicity IRB: del inglés Institutional Review Board FDA: del inglés Food and Drug Administration NCCN: del inglés National Comprehensive Cancer Network WMA: del inglés World Medical Association RECIST: del inglés Response Evaluation Criteria In Solid Tumors CR: del inglés Complete Response PR: del inglés Partial Response SD: del inglés Stable Disease PD: del inglés Progressive Disease mRNA: Ácido RiboNucleico mensajero 3 ADN: Ácido DesoxirriboNucleico CNA: del inglés Copy Number Alteration NGS: del inglés Next Generation Sequencing FACT: del inglés Functional Annotation for Cancer Treatment qRT-PCR: del inglés Reverse Transcription-Polymerase Chain Reaction WES: del inglés Whole Exome Sequencing RNAseq: del inglés RiboNucleic Acid sequencing EGFP: del inglés Enhanced Green Fluorescent Protein ROC: del inglés Receiver Operating Characteristics TMB: del inglés Tumor Mutational Burden ICI: del inglés Immune Checkpoint Inhibitors PBMCs: del inglés Peripheral Blood Mononuclear Cell 4 LISTADO DE FIGURAS Figura 1. Identificación de poblaciones de pacientes seleccionados molecularmente y aplicación de protocolos traslacionales. Figura 2. Esquema de la vía del FGFR:FGF. Figura 3. Potenciales biomarcadores predictivos a los FGFRinh y métodos de detección. Figura 4. Potenciales mecanismos de resistencia a los FGFRinh. Figura 5. Protocolo de generación de PDXs y líneas celulares FGFR-alteradas y su utilidad como herramienta investigacional. Figura 6. Bloqueo de la angiogénesis en modelos PDXs FGFR-alterados. Figura 7. Proyecto traslacional FGFR 360º RESISTANCE. Figura 8. Esquema de la generación de PDXs FGFR:FGF-amplificados de cáncer de mama seleccionados para experimentos in vivo y caracterización molecular. Figura 9. Porcentaje de cambio en las lesiones diana en casos con FGFRamp/mRNAh según el subtipo tumoral y características moleculares de los pacientes. Figura 10. Correlación entre ClinBen a FGFRinh y nivel de amplificación génica del FGFR en el subgrupo pacientes FGFRamp. Figura 11. Porcentaje de cambio en las lesiones diana en casos con FGFRmut según el subtipo tumoral y características moleculares de los pacientes. Figura 12. Predicción in vitro de la actividad oncogénica de las mutaciones FGFR detectadas en el subgrupo de pacientes FGFRmut.
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