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Targeting Mitosis in Ovarian Cancer

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ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en TARGETING MITOSIS IN OVARIAN CANCER: THE STUDY OF BORA AS A FUTURE THERAPEUTIC AVENUE PhD thesis presented by Alfonso Parrilla Ocón To obtain the degree of PhD for the Universitat Autònoma de Barcelona (UAB) PhD thesis carried out at the Cell Cycle and Cancer Laboratory within the Biomedical Research Group in Gynecology, at Vall d'Hebron Research Institute (VHIR) Thesis affiliated to the Department of Biochemistry and Molecular Biology from the UAB, in the PhD program of Biochemistry, Molecular Biology and Biomedicine Universitat Autònoma de Barcelona, September 12th 2019 Doctorate Director Tutor Alfonso Parrilla Ocón Dr. Anna Santamaria Margalef Dr. Ana Meseguer Navarro TARGETING MITOSIS IN OVARIAN CANCER The study of BORA as a future therapeutic avenue Alfonso Parrilla PhD Thesis 2019 CLINICAL RELEVANCE OF THIS THESIS Clinical management of ovarian cancer remains a challenge due to the failure to obtain long-lasting benefits and the development of resistance to current standard therapies. Since the mitotic spindle is a validated target against cancer, using an integrative global transcriptional profiling we searched for novel actionable mitotic candidates, focusing our attention on BORA. This thesis provides the first evidence of unanticipated oncogenic functions of BORA in addition to its previously described role in mitosis. Our data pinpoints BORA as prognostic biomarker and as essential mediator of tumor cell survival. BORA overexpression enhanced tumorigenicity in vivo whereas its ablation attenuated tumor growth in vivo and compromised the viability of patient-derived tumor cells ex vivo, rendering a potential therapeutic target. Furthermore, exploring the BORA silencing landscape led us to identify downstream effectors that can be currently used as targeted therapies for ovarian cancer management. A mi familia, en especial a mi padre ABSTRACT Ovarian cancer is the most lethal gynecology malignancy, frequently diagnosed at advanced stages with disseminated disease. The genomic and genetic heterogeneity described in ovarian cancer contributes to the development of tumor resistance, hampers effective treatments and ultimately causes disease recurrence. However, it also offers novel potential vulnerabilities that can enhance the effectiveness of existing therapies. In this regard, as the mitotic spindle is a classical target for treating cancer, chromosomal instability-exploiting therapies are emerging in the landscape of anti-cancer therapeutic tools yielding better clinical outcomes. In the present thesis we have identified a number of mitotic-enriched genes overexpressed in ovarian cancer associated with poor overall survival. We further characterized the role of Aurora Borealis (BORA), previously described as a mitotic protein essential in spindle assembly and key activating the master kinase, PLK1. Gain and loss of function assays in mouse models and ex vivo patient-derived ascites cultures grown in 3D, together with a whole genome transcriptome analysis in clinically representative cells lines, revealed an oncogenic role of BORA in tumor development modulating survival, dissemination and inflammatory related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA, such BCL-2 and CDK6, offered promising results in ovarian cancer models. Collectively, the data shown in this thesis depict novel evidence regarding the role of BORA in tumorigenesis and provide novel potential therapeutic opportunities for ovarian cancer management. Key words: Aurora Borealis, ovarian cancer, mitosis, prognosis, pro-oncogene, targeted therapy, PLK1 i RESUMEN DE LA TESIS El cáncer de ovario es la neoplasia maligna ginecológica más letal, frecuentemente diagnosticada en estadios avanzados cuando la enfermedad se encuentra diseminada. La heterogeneidad, tanto genómica como genética, descrita en cáncer de ovario contribuye al desarrollo de resistencia tumoral, dificulta tratamientos efectivos y finalmente causa la recurrencia de la enfermedad. Sin embargo, también ofrece nuevas vulnerabilidades específicas de las células cancerosas que pueden mejorar la efectividad de las terapias existentes. En este sentido, como el huso mitótico es una diana clásica en el desarrollo de terapias contra el cáncer, el uso de agentes que incrementan la inestabilidad cromosómica está emergiendo como nueva herramienta terapéutica aumentando el beneficio clínico de los pacientes. En la presente tesis hemos identificado una serie de genes mitóticos que se encuentran sobre-expresados en cáncer de ovario asociados a una peor supervivencia. En concreto, se ha caracterizado el papel de Aurora Borealis (BORA), previamente descrita como una proteína mitótica esencial en el ensamblaje del huso mitótico y clave en la activación de la quinasa, PLK1. Los ensayos de ganancia y pérdida de función de BORA en modelos de ratón y en cultivos de células de ascitis provenientes de pacientes en 3D, junto con un análisis transcriptómico en líneas celulares clínicamente representativas de cáncer de ovario, revelaron un papel oncogénico de BORA en el desarrollo del tumor que modula la supervivencia celular, la diseminación y las vías inflamatorias. Tratamientos combinados usando inhibidores aprobados en la clínica contra los efectores oncogénicos de BORA, como BCL-2 y CDK6, ofrecieron resultados prometedores en nuestros modelos de cáncer de ovario. En resumen, los datos que se muestran en esta tesis muestran nuevas evidencias sobre el papel de BORA en la tumorigénesis y proporcionan nuevas herramientas terapéuticas para el tratamiento del cáncer de ovario. Palabras clave: Aurora Borealis, cáncer de ovario, mitosis, pronóstico, pro-oncogen, therapia dirigida, PLK1 ii TABLE OF CONTENTS ABSTRACT…………………………………………………………………………….……...i RESUMEN DE LA TESIS…………………………………………………………….…...ii INDEX………………………………………………………….……..…….…………………..iii List of Figures…………………………………………………………………….……………………..iv List of Tables………………………………………………………………………………….………..viii List of Abbreviations and Acronyms………………………………………………………………..…ix 1.2.1 Epidemiology and survival ........................................................................................................ 6 1.2.2 Risk factors: the importance of the genetics .............................................................................. 6 1.2.3 Histology of OC: a heterogeneous disease ................................................................................ 7 1.2.4 Molecular biology of OC: a disease with genomic complexity ..................................................... 8 1.2.5 Etiology .................................................................................................................................... 9 1.2.6 Diagnosis, screening and staging ........................................................................................... 12 1.2.7 Therapeutic options in OC ...................................................................................................... 14 1.2.8 Molecular chemo-sensitive and resistance landscape .............................................................. 17 1.2.9 Targeted therapies in OC ....................................................................................................... 18 1.3.1 Cell cycle: a special focus on mitosis ...................................................................................... 23 1.3.2 Clinical therapeutics targeting the cell cycle ............................................................................ 25 1.3.3 Understanding mitotic death ................................................................................................... 26 1.3.4 Emerging mitotic strategies: CIN-exploiting therapies in cancer ............................................... 27 1.3.5 Targeting cyclin dependent kinase 1 (CDK1) ........................................................................... 28 1.3.6 Targeting kinesins: KIF11 and CENP-E................................................................................... 29 1.3.7 Targeting the spindle assembly checkpoint ............................................................................. 29 1.3.8 Inducing tetraploid: AURORA B and MASTL ........................................................................... 30 1.3.9 Targeting G2/M checkpoint ..................................................................................................... 30 1.4.1 PLK1: controlling mitotic orchestra and beyond ....................................................................... 32 1.4.2 Development of PLK1 inhibitors: from the laboratory to the clinics ............................................ 34 1.5.1 BORA, a multi-phosphorylated protein .................................................................................... 39 1.5.2 BORA, an essential activator of PLK1 ....................................................................................
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