Table Of ContentPersonalizing 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
