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Novel treatment targets in high-grade brain tumors

Mir, S.E.

2016

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citation for published version (APA)Mir, S. E. (2016). Novel treatment targets in high-grade brain tumors.

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Download date: 16. Feb. 2021

Neurocosmic Insight: Constellation of diverse neuronal images living in color by Anum Zahra

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Appendices

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About the author: CV & PhD Portfolio

Curriculum VitaeShahryar Mir was born on July 6, 1981 in Rotterdam, the Netherlands. In 2000, he completed secondary education (VWO) at the Libanon Lyceum in Rotterdam. The same year he started his studies in biomedical sciences and cultural anthropology at the VU University in Amsterdam. In 2001 he was selected through a decentralized procedure to start medical school at the same university, while continuing his study in biomedical sciences in parallel. From the beginning he was interested in

bridging the gap between clinical practice and fundamental research. In his second year he enrolled into the VU Honors Program, a three-year research program for medical students. The overall aim of this program was to motivate medical students in combining clinical practice with medical research as medical doctors. During this period he started research at the Pediatric Oncology division at the VU University Medical Center, which consequently lead to his PhD. In 2006 he secured a personal PhD grant from the VU University after competing for the NWO-Mosaic program. He graduated as a Medical Doctor at the Faculty of Medicine of the VU University in 2008, after which he officially started this PhD program at the newly established Neuro-Oncology Research Group in the Cancer Center Amsterdam. Before his Pediatrics training started in 2010, he had achieved his second research grant from the Dutch Cancer Society for combining his residency with a PhD program. During his PhD project he has won several awards including the Tom Voûte young investigator award, the Maarten Kapella award, and the Chris Meijer award. His residency program in Pediatrics was supervised by prof. dr. R.J.B.J. Gemke at the VU University Medical Center and by dr. K.M. Dolman at the OLVG hospital Amsterdam location West. The final year of his residency was spent at the Erasmus University Medical Center in Rotterdam, where he further specialized in neonatology and pediatric genetics & dysmorphology (supervised by prof. dr. M. de Hoog). After registering as a board certified pediatrician in 2015, he started as a consultant in the Waterland hospital in Purmerend. Currently he works as a general pediatrician with special focus on pediatric genetics & dysmorphology. Owning to his passion for research he has recently initiated an outreach program in Pakistan together with his fellow medical doctor and wife Anum Zahra, in which they are striving to identify novel genetic mutations for neural tube defects in multiplex consanguineous families.

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PhD portfolio Shahryar Mir

Brief project descriptionIn the project ‘Novel treatment targets in high-grade brain tumors’, I aimed to identify novel targets for the most common aggressive brain tumors, medulloblastoma and glioblastoma. Using various cell/molecular biological analysis and in vivo experiments I have provided compelling evidence for an important role of H3K27 trimethylation during cerebellar development and in medulloblastoma, aberrant angiogenesis in glioblastoma is driven by a VEGF/miR-101/EZH2 axis and resistance for conventional therapy in glioblastoma is dictated by WEE1 overexpression.

Laboratory techniquesAmongst others; Primary tumor cell culturing, Colony forming assays, PCR, RT-PCR, Western blotting, Immunohistochemistry, Fluorescence microscopy, Cyto-toxicity assays, Flow cytometry, Development of orthotopic mouse brain tumor models and subcutaneous xenograft mouse models.

In-depth courses– Laboratory Animal Science (Article 9 certified) – Working with Radioactivity/Radiation Protection (level 5B certified)

Didactic skills– Supervision of BSc, MSc and MD thesis students (2008-2010)

Grants– 2006: VU University, personal PhD grant for minorities from the VU University after

competing for the NWO-Mosaic program (The Netherlands Organization for Scientific Research)

– 2009: Dutch Cancer Society, personal research funding for residents combining clinical training with fundamental research

Awards– 2005: Award for best oral presentation VU Honors Program Honor, VU University Medi-

cal Center Amsterdam– 2011: Chris Meijer Award. Best PhD student in Oncology at the Cancer Center Amster-

dam/VU University Medical Center Amsterdam– 2011: Maarten Kapella Award. Best fundamental research paper in the field of Pediatrics– 2012: Tom Voûte Young Investigator Award. Best PhD research in the field of Pediatric

Oncology

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(Inter)national functions– Associate member AACR, American Association for Cancer Research– Associate member EACR, European Association for Cancer Research– Associate member NVK, Dutch Society for Pediatrics – Associate member ESHG, European Society of Human Genetics

Lectures/Conference presentations– 2005: Oral presentation, EZH2 overexpression in medulloblastoma, Honour class VUMC– 2008: Poster presentation, EZH2 overexpression in brain tumors, AACR San Diego– 2008: Poster presentation, Role of WEE1 in glioblastoma, SNO Las Vegas– 2009: Lecture innovative therapy for glioblastoma, UMC st Radboud Nijmegen – 2010: Oral presentation, The WEEing of glioblastoma, KWF project adaption by Stichting

Mont Ventoux Ruinerwold– 2011: Oral presentation, WEE1 overexpression in glioblastoma, Maarten Kapella Award,

NvK annual meeting Veldhoven– 2011: Oral presentation, The role of WEE1 and EZH2 in brain tumors, Chris Meijer Award,

VUmc Amsterdam– 2012: Oral presentation, WEE1 overexpression in glioblastoma, Tom Voûte Young Inves-

tigator Award, SKION annual meeting Utrecht

List of publicationsMir SE*, De Witt Hamer PC*, Krawczyk PM, Balaj L, Claes A, Niers JM, Van Tilborg AA, Zwinderman AH, Geerts D, Kaspers GJ, Peter Vandertop W, Cloos J, Tannous BA, Wesseling P, Aten JA, Noske DP, Van Noorden CJ, Würdinger T. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell. 2010 Sep 14;18(3):244-57. PubMed PMID: 20832752.

Mir SE*, Smits M*, Nilsson J*, van der Stoop PM, Hulleman E, Niers JM, de Witt Hamer PC, Marquez VE, Cloos J, Krichevsky AM, Noske DP, Tannous BA, Würdinger T. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget. 2010 Dec;1(8):710-20. PubMed PMID: 21321380.

Mir SE*, Smits M*, Nilsson RJ, van der Stoop PM, Niers JM, Marquez VE, Cloos J, Breakefield XO, Krichevsky AM, Noske DP, Tannous BA, Würdinger T. Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. PLoS One. 2011 Jan 28;6(1):e16282. PubMed PMID: 21297974. De Witt Hamer PC, Mir SE, Noske D, Van Noorden CJ, Würdinger T. WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe. Clin Cancer Res. 2011 Jul 1;17(13):4200-7. PubMed PMID: 21562035.

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About the author | 153

De Witt Hamer PC, Mir SE, Noske D, Van Noorden CJ, Würdinger T. WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe. Clin Cancer Res. 2011 Jul 1;17(13):4200-7. PubMed PMID: 21562035.

Mir SE, Smits M, Biesmans D, Julsing M, van der Valk P, Aronica E, Kaspers GJ, Cloos J, Wurdinger T, Hulleman E. Trimethylation of H3K27 during human cerebellar development in relation to medulloblastoma. Manuscript under revision.

*: joined first authorship

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Acknowledgments

The journey of doing a PhD project with my residency simultaneously has been tremendous but truly remarkable. This time was marked by numerous ups and downs. It is these personal hardships and genuine challenges that have molded me into the individual I am today. I will take this occasion to thank some very important people in my life whose contributions, mentally and physically, have made this PhD thesis possible.

I am grateful to all my dedicated (co)promotors whose support and encouragement allowed me to steer myself in the right direction. I would like to especially thank prof. dr. G.J.L. Kaspers. Dear Gert-Jan you are the epitome of the saying “a tree laden with fruits, always bends”. I shall forever be thankful for everything you have done for me. Prof. dr. T. Würdinger, dear Tom, I always look back at our intellectually invigorating discussions with great fondness. You brought a unique sense of innovation, youth and zeal to our group. Dr. J. Cloos, dear Jacqueline, you cultivated the imperative and enduring quality of patience in my personality when I first encountered you in the Honors Program as a restless and hyper enthusiastic student. Your support and advice particularly in the beginning phase was certainly invaluable. Dr. E. Hulleman, dear Esther, you have been a guide to me in the concluding stages of my work. The thing that made an indelible impression on me was your upmost regard for maintaining ethical standards in research. It induced a sense of responsibility and pride in me for my work.

I also would like to thank the opposition committee; prof. dr. E. Aronica, prof. dr. S. Leenstra, prof. dr. E.J. Meijers-Heijboer, dr. D.G. van Vuurden and dr. R.W. Stam for dedicating their valuable time and expertise to my thesis manuscript. I am eagerly looking forward to the questions you have in store for me.

I will like to express my sincere gratitude for my co-authors: Michiel, Dennis, Machteld, Paul, Eleonora, Jonas, Petra, Johanna, Victor, Anna, David, Bakhos, Xandra, Jacqueline, Esther, Philip, Przemek, Leonora, An, Angela, Aeilko, Dirk, Peter, Pieter, Jacob, Cornelis, Gert-Jan and Tom. We have indeed burned the midnight oil to ultimately emerge victorious in our task! This arduous phase has indeed been a tremendous learning experience for us all.

I would also like to mention all the PhD candidates, technicians, postdocs and supervisors from all the different departments who facilitated me in my work and enabled me to apply my very best to the tasks. Thank you all for your support.

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Acknowledgments | 155

I will also like to thank my colleagues in the clinic for accommodating me at work when I had too much on my plate. You have undeniably been a great help in enabling me to maintain a balance between my research and clinical work.

A heartily thanks to a special group of people who are unquestionably the biggest influence on my life; my dear family. My parents who have not only brought me into this world but also provided me with the right tools to live a meaningful life. I am infinitely indebted to my parents for setting up the right priorities for me from the very beginning. I really thank you for all the endeavors you have faced to provide me with the prospects of advancement in life. The passing away of my father in 2007 is by far the biggest loss I have suffered in my life. Your presence alone incessantly inspired me to become the best version of myself! I will forever miss you daddy. It is for these reasons that I dedicate this book to my parents. The unwavering solace offered by you has enabled me to conquer it all.

When thanking family it is a felicitous moment to thank my new family living in Pakistan who despite the distance have never been closer. Thank you for all your love and support.

I would also like to thank my brothers for very different reasons. Afzaal, Waqas and Nagam thanks for bearing my scientific mumbo jumbo when you had no idea what on earth I was talking about. I know you will always have my back because brothers don’t let each other wander alone in the dark.

Lastly I would like to thank my wife Anum. Thank you for spreading the beauty of your art with all its vivacious colors in this book, in our home and in my life. It is only after meeting you that I feel so complete, content and utterly blessed. Thank you for opening the doors of perpetual happiness to my life.

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