Embed Size (px)
Citation preview
UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Towards personalised medicine for cancer
Molenaar, R.J.
Link to publication
Citation for published version (APA):Molenaar, R. J. (2017). Towards personalised medicine for cancer: From initial therapy to follow-up
General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.
Download date: 09 Jul 2018
Towards Personalised M
edicine for Cancer: From Inial Therapy to Follow
-Up Rem
co J. Molenaar
TOWARDS PERSONALISED MEDICINE FOR CANCER:
FROM INITIAL THERAPY TO FOLLOW-UP
BY
REMCO J. MOLENAAR
Towards Personalised Medicine for Cancer: From Initial Therapy to Follow-Up Academic Thesis, University of Amsterdam, Amsterdam, The Netherlands ISBN: 978-94-6299-812-4 Author: Remco Molenaar Layout: Remco Molenaar Cover illustration: www.clipartof.com (rights-free) Printing: Ridderprint, Ridderkerk Copyright 2017 © by R.J. Molenaar, Amsterdam, The Netherlands. All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without prior admission of the author. Financial support for printing this thesis was kindly provided by the Academic Medical Center, ABN AMRO, Abbott, AstraZeneca, Bayer, Celgene, Chipsoft, Greiner, Novartis, Sanofi, Sigma-Aldrich and Servier. This thesis is accompanied by an electronic supplementary file that supports the data and conclusions that are presented in this print version. This electronic supplement can be retrieved from the internet via http://www.tumormetabolism.eu/es.pdf or by scanning the QR code on the right with your mobile device.
TOWARDS PERSONALISED MEDICINE FOR CANCER:
FROM INITIAL THERAPY TO FOLLOW-UP
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus
prof. dr. ir. K.I.J. Maex
ten overstaan van een door het College voor Promoties ingestelde commissie,
in het openbaar te verdedigen in de Aula der Universiteit
op vrijdag 22 december 2017, te 13:00 uur
door
Remco Jurriaan Molenaar
geboren te Amsterdam
Promotiecommissie:
Promotores: Prof. dr. C.J.F. van Noorden AMC-UvA Prof. dr. W.P. Vandertop AMC-UvA en
Vrije Universiteit Amsterdam Copromotores: Dr. F.E. Bleeker AMC-UvA Dr. J.W. Wilmink AMC-UvA Overige leden: Prof. dr. P.M.M. Bossuyt AMC-UvA Prof. dr. S. Leenstra Erasmus Universiteit Rotterdam Prof. dr. M.H.J. van Oers AMC-UvA Prof. dr. C.J.A. Punt AMC-UvA Prof. dr. L.J.A. Stalpers AMC-UvA Prof. dr. T. Würdinger Vrije Universiteit Amsterdam Faculteit der Geneeskunde
Voor mijn ouders
Table of contents
Prologue: Cancer as a redox disease? – The Lancet 2014 ......................................................................................... 8
Chapter 1: General introduction ......................................................................................................................................... 9
PART ONE: IDH1/2 MUTATIONS, CANCER BIOLOGY AND CELLULAR METABOLISM ............................ 11
Chapter 2: The driver and passenger effects of IDH1 and IDH2 mutations in oncogenesis, metabolic rewiring and survival prolongation – Biochimica Biophysica Acta Reviews on Cancer 2014 ................. 12
Chapter 3: In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma – Oncotarget 2017 ....... 22
Chapter 4: Metabolic mapping: quantitative enzyme cytochemistry and histochemistry to determine the activity of dehydrogenases in cells and tissues – Journal of Visualized Experiments 2017 ............. 33
Chapter 5: IDH1-mutated gliomas rely on glutamate to compensate for defective isocitrate processing: consequences for studies on IDH1 function – Submitted ............................................................. 42
Chapter 6: Tumour cells in search for glutamate: an alternative explanation for increased invasiveness of IDH1-mutated glioma – Neuro Oncology 2014 .......................................................................... 57
Chapter 7: Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation – Submitted ............................................................................................................................................................................... 59
Chapter 8: Study protocol of a phase Ib/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours – British Medical Journal Open .......................................... 69
PART TWO: THE EFFECTS OF IDH1/2 MUTATIONS ON ANTI-CANCER THERAPY RESPONSE .......... 81
Chapter 9: The therapy-sensitizing effects of IDH1 and IDH2 mutations in cancer – Oncogene 2017 ....................................................................................................................................................................................................... 82
Chapter 10: Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms – Leukemia 2015 ................................................................................................. 91
Chapter 11: The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone – Neuro Oncology 2014 ......................................... 102
Chapter 12: Robustness of IDH1/2 mutations, TERT mutations, and 1p/19q codeletions as prognostic tools in lower-grade glioma – Submitted ................................................................................................................... 113
Chapter 13: Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198 – Cancer Research 2015 .................................................................................................................................................... 122
Chapter 14: IDH1/2 mutations sensitise acute myeloid leukaemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors – Clinical Cancer Research 2017 ..................................................... 135
Chapter 15: Myeloid neoplasia mutation rates differ in primary cases versus cases arising after cancers treated or not with radiation and/or chemotherapy – Submitted ................................................ 148
PART THREE: EARLY AND LATE ADVERSE EFFECTS OF RADIATION THERAPY ................................... 153
Chapter 16: Haematopoietic stem cell niches, leukaemic cells and propagation of therapy-related myeloid neoplasms – Biochimica Biophysica Acta Reviews on Cancer 2017 ............................................... 154
Chapter 17: Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with irradiation – Leukemia 2016 ................................................................................................... 158
Chapter 18: Risk of haematologic malignancies following radioiodine treatment for well-differentiated thyroid cancer – Journal of Clinical Oncology 2017 .................................................................. 172
Chapter 19: Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine – Leukemia 2017 ............................................................................... 184
Chapter 20: Breast cancer tumour size and subsequent risks of acute myeloid leukaemia in patients treated with chemotherapy and radiotherapy – Submitted .............................................................................. 195
Chapter 21: Risk of developing second haematological malignancies after irradiation and/or chemotherapy in adolescents and young adults – Submitted ........................................................................... 205
Chapter 22: Absence of increased risks for glioma after contemporary radiation therapy for cancer in childhood and adolescents – Submitted ..................................................................................................................... 217
Chapter 23: Early and late risks of heart disease-related mortality after irradiation for oesophageal cancer: a population-based study among oesophageal cancer survivors – Submitted .......................... 225
Chapter 24: General discussion ..................................................................................................................................... 239
Chapter 25: Summary ........................................................................................................................................................ 242
Chapter 26: Nederlandse samenvatting .................................................................................................................... 244
Appendix: PhD portfolio ................................................................................................................................................... 246
Appendix: Authors and affiliations .............................................................................................................................. 251
Appendix: Curriculum Vitae ........................................................................................................................................... 252
Appendix: Dankwoord ...................................................................................................................................................... 254
Appendix: Reference list .................................................................................................................................................. 255
8
Prologue: Cancer as a redox disease? Based on: Molenaar RJ, van Noorden CJ. Type 2 diabetes and cancer as redox diseases? The Lancet 2014; 384 (9946): 853.1 We have read with great interest the hypothesis postulated by James Watson that diabetes, dementias, cardiovascular disease, and some cancers are accelerated or even caused by shortages in cellular reactive oxygen species (ROS).2 Watson reasons that physical activity prevents these diseases by generating ROS, which are needed for redox potentials to correctly fold proteins in the endoplasmatic reticulum. Remarkably, physical activity can not only contribute to cancer prevention,3 but also prolong survival and delay recurrence in patients with cancer.4 Therefore, Watson’s hypothesis resonates well with cancer metabolism as a driver of malignancy. By comparison with quiescent cells, proliferating cells decrease nutrient flow through the Krebs cycle and electron transport chain in favour of aerobic glycolysis (known as the Warburg effect). For reductive biosynthetic reactions, cells are in high demand of NADPH.5 Because the electron transport chain is the major generator of ROS and NADPH is an important antioxidant,6 such metabolic rewiring might contribute to ROS shortages. This contribution might non-specifically hamper the stabilisation of tumour suppressor proteins, for example, which can further contribute to oncogenesis. Therefore, we are convinced that Watson’s insights can be elaborated more explicitly into cancer by hypothesising that the therapeutic effect of physical activity in cancer relies on the restoration of the low ROS levels caused by cancerous metabolic rewiring. Watson’s proposal to unravel the molecular basis of physical activity as therapy for diabetes could also benefit cancer research and patients with cancer.
