Personalizing Anti-Cancer Treatment from Genetic and Pharmacokinetic Perspective Het personaliseren van de behandeling tegen kanker vanuit genetisch en farmacokinetisch oogpunt Sander Bins Personalizing Anti-Cancer Treatment from Genetic and Pharmacokinetic Perspective Het personaliseren van de behandeling tegen kanker vanuit genetisch en farmacokinetisch oogpunt Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op Woensdag 15 februari 2017 om 13.30 uur Sander Bins geboren te Voorburg Colofon ISBN: 978-94-6299-502-4 Printed by: Ridderprint BV © Sander Bins, 2016 Allrights reserverd. No parts of this book may be reproduced or transmitted, in any form or by any means, without writen permision of the author. P e r d s o n a l i z i n g A n t i - C a n c e r T r e a t m e n t f r o m G e n e t i c a n Pharmacokinetic Perspective Het personaliseren van de behandeling tegen kanker vanuit genetisch en farmacokinetisch oogpunt Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op Woensdag 15 februari 2017 om 13.30 uur Sander Bins geboren te Voorburg Colofon ISBN: 978-94-6299-502-4 Printed by: Ridderprint BV © Sander Bins, 2016 Allrights reserverd. No parts of this book may be reproduced or transmitted, in any form or by any means, without writen permision of the author. Promotiecommissie Promotoren: Prof.dr. S. Sleijfer Hoe verder men keek, Prof.dr. A.H.J. Mathijssen hoe groter het leek. J.A. Deelder Overige leden: Prof.dr. R.H.N. van Schaik Prof.dr. A.D.R. Huitema Prof.dr. E.E. Voest Promotiecomisie Promotoren: Prof.dr. S. Sleijfer Hoe verder men keek, Prof.dr. A.H.J. Mathijssen hoe groter het leek. J.A. Deelder Overige leden: Prof.dr. R.H.N. van Schaik Prof.dr. A.D.R. Huitema Prof.dr. E.E. Voest Contents Chapter 1 Introduction 9 Chapter 2 Implementation of a multicenter biobanking 17 collaboration for next-generation sequencing-based biomarker discovery based on fresh frozen pre- treatment tumor biopsies Oncologist. 2016 Sep 23 [Epub ahead of print] Chapter 3 The time to progression ratio: a new individualized 43 volumetric parameter for the early detection of clinical benefit of targeted therapies Ann. Oncol. 2016;27(8):1638-1643 Chapter 4 Conventional dosing of anticancer agents: precisely 61 wrong or just inaccurate? Clin. Pharmacol. Ther. 2014;95(4):361-364 Chapter 5 Influence of OATP1B1 Function on the Disposition of 69 Sorafenib-β-D-Glucuronide Submitted Chapter 6 Polymorphisms in SLCO1B1 and UGT1A1 are 95 associated with sorafenib-induced toxicity Pharmacogenomics 2016;17(14):1483-1490 Chapter 7 Prospective Analysis in GIST Patients on the Role of 111 Alpha-1 Acid Glycoprotein in Imatinib Exposure Clin Pharmacokinet. 2016 Jul 26 [Epub ahead of print] Chapter 8 Individualized pazopanib dosing: a prospective 125 feasibility study in cancer patients Clin. Cancer Res. 2016;22(23):5738-5746 Chapter 9 Development and clinical validation of an LC-MS/MS 145 method for the quantification of pazopanib in DBS. Bioanalysis. 2016;8(2):123-134 Chapter 10 Discussion 167 Chapter 11 Dutch summary 181 Appendices 187 Contents Chapter 1 Introduction 9 Chapter 2 Implementation of a multicenter biobanking 17 collaboration for next-generation sequencing-based biomarker discovery based on fresh frozen pre- treatment tumor biopsies Oncologist. 2016 Sep 23 [Epub ahead of print] Chapter 3 The time to progression ratio: a new individualized 43 volumetric parameter for the early detection of clinical benefit of targeted therapies Ann. Oncol. 2016;27(8):1638-1643 Chapter 4 Conventional dosing of anticancer agents: precisely 61 wrong or just inaccurate? Clin. Pharmacol. Ther. 2014;95(4):361-364 Chapter 5 Influence of OATP1B1 Function on the Disposition of 69 Sorafenib-β-D-Glucuronide Submitted Chapter 6 Polymorphisms in SLCO1B1 and UGT1A1 are 95 associated with sorafenib-induced toxicity Pharmacogenomics 2016;17(14):1483-1490 Chapter 7 Prospective Analysis in GIST Patients on the Role of 111 Alpha-1 Acid Glycoprotein in Imatinib Exposure Clin Pharmacokinet. 2016 Jul 26 [Epub ahead of print] Chapter 8 Individualized pazopanib dosing: a prospective 125 feasibility study in cancer patients Clin. Cancer Res. 2016;22(23):5738-5746 Chapter 9 Development and clinical validation of an LC-MS/MS 145 method for the quantification of pazopanib in DBS. Bioanalysis. 2016;8(2):123-134 Chapter 10 Discussion 167 Chapter 11 Dutch summary 181 Appendices 187 CHAPTER 1 Introduction CHAPTER 1 Introduction 10 | Chapter 1 Introduction | 11 Cancer treatment has been subject of discussion for centuries. Surgery was already oncogenes) or inhibition of anti-proliferative signaling (tumor suppressor genes). A 1 practiced (unsuccessfully) back in ancient Egypt, but until recent ages every type of schematic description of these processes is depicted in Figure 1. cancer was deemed incurable, if detected at all. Whereas methods of surgery and th th radiotherapy were evolving in a revolutionary way during the 19 and early 20 century, A B systemic anti-cancer treatment only found its way into the clinic in the second half of the (Proto)oncogenes Tumor suppressor genes previous century. After World War I, the myelotoxic effect of mustard gas was noticed and 2 translated into the first chemotherapy: nitrogen mustard. Since then, many other Physiological state KRAS Proliferation P53 systemic anti-cancer agents have been developed for the treatment of many different Proliferation types of cancer. The first group of patients that benefited from systemic anti-cancer treatment were those with hematological cancers. Nowadays, many leukemia and Aberrant state KRAS PROLIFERATION P53 lymphoma patients can even be cured by systemic treatment sometimes combined with PROLIFERATION radiotherapy. However, except for patients with germline tumors and for the use in adjuvant or neoadjuvant setting, systemic therapies still rarely cure patients with solid tumors. This indicates that, despite all progress that has been made, there is much to win Figure 1. A schematic depiction of oncogenes and tumor suppressor genes. (A) Proto-oncogenes are in this field of medicine. physiologically involved in the normal process of cell cycle regulation. Mutated proto-oncogenes can become oncogenes and become constitutively activated, which leads to continuous proliferative Although there is still much to be learned, the biological behavior of tumors has signaling. (B) Tumor suppressor genes are physiologically involved in suppressing cell proliferation. been scrutinized in parallel to the advent of chemotherapy. Since the 1950s, many When mutated, they can lose their suppressive function, which leads to increased proliferative researchers have examined cancer cells and have – successfully – found ways to stop signaling. these cells from proliferating. One of the earliest examples of the translation of increasing 3 biological understanding into anti-cancer drugs is the group of fluoropyrimidines. Basic Just as for the anti-hormonal agents, drugs are being developed to specifically target these research had shown that rat hepatoma cells take up much more uracil than other aberrant proliferative signals. This has resulted broad spectrum of targeted anti-cancer (healthy) tissue. By attaching the toxic atom fluorine to an uracil base, resulting in 5- drugs with different mechanisms of decreasing intracellular signaling: tyrosine kinase fluorouracil (5-FU), the cytostatic effects of this drug are predominantly, but not inhibitors (TKIs) prevent the phosphorylation of intracellular proteins, monoclonal exclusively, localized in cancer cells. Despite its age, 5-FU is currently still standard of care antibodies (mABs) target extracellular receptors that initiate the intracellular signaling, for the treatment of several cancer types. and there are many other examples such as drugs that inhibit mammalian target of Accordingly, the increasing biological knowledge has led to the discovery of many rapamycin (mTOR-inhibitors). other ways to kill cancer cells. Hormones appeared to stimulate cancer cell growth, which could be stopped by inhibiting this hormonal signaling, e.g. with the famous selective Precision Medicine estrogen receptor modulator tamoxifen. Similarly, many other (non-hormonal) signaling The first – and still the most impressive – example of a targeted anti-cancer agent is the pathways have been identified. Currently, a number of genes have been described that, TKI imatinib. In 1996, imatinib was found to inhibit the growth of chronic myelogenous when mutated or overexpressed, cause either activation of proliferative signaling (proto- 4 leukemia (CML) cells that contained the BCR-ABL translocation. Patients with BCR-ABL