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Redirect Repurposing of Drugs: Innovative Revision of Cancer Treatment

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Redirect Repurposing of Drugs: Innovative Revision of Cancer Treatment KU Leuven Biomedical Sciences Group Faculty of Pharmaceutical Sciences Department of Pharmaceutical and Pharmacological Sciences ReDIReCT Repurposing of Drugs: Innovative Revision of Cancer Treatment Ciska Verbaanderd Ciska VERBAANDERD Ciska VERBAANDERD Jury: SupervisorCiska VERBAANDERDProf. Isabelle Huys Co-Supervisors Prof. Ilse Rooman Dr. Greet Musch Chair Prof. Pieter Annaert Dissertation presented in Jury membersCiska VERBAANDERD Prof. Eric Van Cutsem partial fulfilment of the Prof. Jeroen Luyten requirements for the Dr. Denis Lacombe degree of Doctor in Dr. Daniel O’Connor Pharmaceutical Sciences Ciska VERBAANDERD Dissertation presented in Ciska VERBAANDERD partial fulfilment of the Jury: September 2020 Supervisor Prof. Isabelle Huys requirements for the degree of Doctor in Co-Supervisors Prof. Ilse Rooman Dr. Greet Musch Pharmaceutical Sciences Ciska VERBAANDERD Chair Prof. Pieter AnnaertSeptember 2020 Jury members Prof. Jeroen Luyten Prof. Eric Van Cutsem Dissertation presented in Prof. x partial fulfilment of the Ciska VERBAANDERDProf. x September 2020 requirements for the degree of Doctor in Aan mijn liefste papa Van wie we afscheid hebben moeten nemen tijdens dit onderzoeksproject DANKWOORD Een doctoraat wordt vaak (terecht) beschreven als een traject met veel hoogtepunten maar ook uitdagingen en beproevingen. Gelukkig heb ik dit traject niet alleen moeten afleggen en werd ik omringd door een heleboel gemotiveerde mensen. Ik zou daarom graag iedereen willen bedanken die mij de voorbije vier jaar gesteund en geholpen heeft. Ten eerste zou ik graag mijn promotor en copromotoren willen bedanken voor hun enorme steun en bijdrage aan dit project. Isabelle, bedankt voor het vertrouwen en voor alle kansen die je mij gegeven hebt. Jij hebt mij onvoorwaardelijk gesteund de afgelopen vier jaar, niet alleen op professioneel maar ook op persoonlijk vlak. Jouw onuitputbaar enthousiasme motiveerde mij steeds om te blijven doorzetten. Ik heb enorm veel bewondering voor de manier waarop jij alles combineert en toch ook steeds tijd maakt voor een warm gesprek of ontspannende activiteit. Ook ben ik mijn copromotoren, Ilse en Greet, heel dankbaar voor de steun, kritische blik en constructieve feedback. Jullie professionele bijdrage was een meerwaarde die ik als zeer leerrijk heb ervaren. I would like to thank the members of my examining committee: Prof. Pieter Annaert, Prof. Jeroen Luyten, Prof. Eric Van Cutsem, Dr. Denis Lacombe and Dr. Daniel O’ Connor. Thank you for taking the time to review and evaluate this dissertation and for providing constructive feedback to strengthen the final manuscript. Your input is much appreciated and added significant value to this work. I would also like to thank everyone that contributed to the studies included in this dissertation. A special thanks to all people that participated in the interviews and focus group discussions for sharing their valuable time, opinions and perspectives. Uiteraard ben ik het Antikankerfonds enorm dankbaar, niet alleen en vooral omdat ze dit onderzoeksproject financieel gesteund hebben maar ook omdat ze mij met open armen verwelkomd hebben in hun fantastisch team. Bedankt aan alle collega’s voor de gezellige babbels, de leuke teamactiviteiten, de leerrijke gesprekken en vooral ook de steun op momenten dat het wat moeilijker ging. Een speciaal woord van dank gaat uit naar Lydie Meheus met wie ik nauw heb mogen samenwerken de afgelopen vier jaar. Lydie, ik heb heel veel van jou geleerd en ik heb enorm veel bewondering voor jouw doorzettingsvermogen en jouw toewijding aan de zoektocht naar betere behandelingsopties voor kankerpatiënten. Bedankt voor het vertrouwen dat je in mij stelde en voor alle kansen die je mij gegeven hebt. I would also like to thank Gauthier Bouche and Pan Pantziarka for sharing their experience and their profound knowledge about drug repurposing in oncology with me. Gauthier and Pan, I learned a lot from both of you and I really appreciated your insightful contributions. Daarnaast wil ik ook alle collega’s aan de KU Leuven bedanken voor de ontspannende gesprekken, de leuke teamactiviteiten en afterworks, de fijne samenwerkingen en de leerrijke ervaringen. Ik kwam steeds met veel plezier naar Gasthuisberg! Een speciale vermelding gaat naar de doctoraatstudenten die al bezig waren of die samen met mij aan hun traject begonnen zijn en met wie ik ook veel tijd heb doorgebracht: Elfi, Eline, Evelien, Laurenz, Liese, Niki, Rosanne en Stefanie. Bedankt voor jullie hulp en steun doorheen de jaren, maar vooral ook voor alle leuke en memorabele momenten die we samen hebben beleefd. In het bijzonder wil ik Liese bedanken omdat zij altijd klaarstond om mij op te beuren met een warm gesprek of een leuk verzetje. Liese, bedankt om er steeds voor mij te zijn. II DANKWOORD Graag wil ik ook mijn vrienden en familie bedanken die mij door dik en dun gesteund hebben gedurende de afgelopen vier jaar. Zij zorgden voor amusement en gezelligheid, maar stonden ook steeds klaar om mij een hart onder de riem te steken op momenten dat het wat moeilijker ging. Dikke merci allemaal! Helaas heb ik ongeveer anderhalf jaar geleden plots afscheid moeten nemen van een van de belangrijkste personen in mijn leven, mijn papa. Papa, ik ben je enorm dankbaar voor je eindeloze steun, je wijze woorden, je warme knuffels, je constante aanmoedigingen en je vertrouwen in mijn kunnen. Je leerde mij hoe belangrijk het is om mijn grenzen te verleggen en je spoorde mij aan om elke uitdaging met volle overtuiging aan te gaan, inclusief dit doctoraat. Ik mocht je altijd lastigvallen met een vraag of probleem en telkens nam je uitgebreid de tijd om mij met raad en daad bij te staan. Hoewel je me steeds aanmoedigde om goed te studeren en hard te werken, leerde jij mij ook hoe belangrijk het is om te genieten van het leven en om tijd te maken voor familie en vrienden. Ik kan niet beschrijven hoe trots ik ben om je dochter te zijn, je zal altijd mijn grote voorbeeld blijven. Ik heb je ontzettend hard gemist tijdens de laatste stappen van dit traject, maar jij bent de reden dat ik ben blijven doorzetten tot het eind. Bedankt voor alles, liefste papa. Ook wil ik mijn mama bedanken voor alle kansen die ze mij gegeven heeft. Mama, zonder jouw steun, en geloof in mij had ik hier vandaag niet gestaan. Ik heb enorm veel bewondering voor je kracht en je doorzettingsvermogen. Je hebt mij geleerd om nooit op te geven en steeds mijn dromen na te streven. Daarnaast ben ik ook mijn zus enorm dankbaar om altijd in mij te blijven geloven. Zusje, heel erg bedankt voor de steun, de vele dikke knuffels en de motiverende berichtjes. Tot slot wil ik heel graag Adrian bedanken voor zijn onvoorwaardelijke steun, vertrouwen, liefde en oeverloze geduld. Adrian, vanaf het begin van dit traject stond je steeds voor mij klaar en vooral tijdens de voorbije maanden was je mijn baken. Je hebt mij bijgestaan op momenten dat ik het overzicht even kwijt was en je hebt mij gemotiveerd om door te blijven gaan. Je hebt mij geholpen bij het brainstormen, nalezen en lay-outen van dit proefschrift. Daarnaast zorgde je voor de welkome ontspanning en haalde je mij af en toe weg van mijn bureau voor een fietstochtje of een gezellige wandeling. Adrian, ik ben je enorm dankbaar. Dankzij jou heb ik dit traject kunnen waarmaken. III IV TABLE OF CONTENTS TABLE OF CONTENTS DANKWOORD .................................................................................................................................................. II TABLE OF CONTENTS ........................................................................................................................................ V LIST OF ABBREVIATIONS ................................................................................................................................. VII LIST OF TABLES ................................................................................................................................................ IX LIST OF FIGURES .............................................................................................................................................. XI PART 1 GENERAL INTRODUCTION & OBJECTIVES ............................................................................................. 1 CHAPTER 1 GENERAL INTRODUCTION ........................................................................................................................ 3 CHAPTER 2 OBJECTIVES & RESEARCH DESIGN ............................................................................................................ 15 PART 2 RESEARCH AND DEVELOPMENT OF REPURPOSED MEDICINES ........................................................... 19 CHAPTER 3 DATA SHARING AND PARTNERSHIP INITIATIVES TO FACILITATE DRUG REPURPOSING RESEARCH ............................. 21 CHAPTER 4 INNOVATIVE MECHANISMS TO FUND CLINICAL DRUG REPURPOSING RESEARCH ................................................. 41 PART 3 CLINICAL IMPLEMENTATION OF REPURPOSED MEDICINES................................................................. 59 CHAPTER 5 REGULATORY FRAMEWORK AND RECOMMENDATIONS TO BRING REPURPOSED MEDICINES TO CANCER PATIENTS ..... 61 CHAPTER 6 DRUG REPURPOSING CANDIDATES IN ONCOLOGY - PILOT STUDIES FOR A EUROPEAN REPURPOSING FRAMEWORK ... 77 CHAPTER 7 PATIENT AND HCP PERSPECTIVES ON CLINICAL ADOPTION OF REPURPOSED MEDICINES IN BELGIUM .................... 99 PART 4 CONCLUDING DISCUSSION .............................................................................................................
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