University of Groningen Sigma receptor ligands Rybczynska, Anna A. IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2012 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Rybczynska, A. A. (2012). Sigma receptor ligands: novel applications in cancer imaging and treatment. s.n. Copyright Other than for strictly personal use, it 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), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. 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Cover design: Robert Łotocki (www.bitmap-brothers.pl) Printed by: CPI Wöhrmann Print Service, Zutphen © 2012, A.A. Rybczynska. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanically, by photocopying, recording, or otherwise, without permission of the author. ISBN: 978-90-367-5309-8 (hardcopy) 978-90-367-5310-4 (electronic version) Sigma Receptor Ligands: Novel Applications in Cancer Imaging and Treatment Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op woensdag 29 februari 2012 om 12.45 uur door Anna Agnieszka Rybczynska geboren op 20 april 1982 te Bielsko-Biala, Poland Promotores: Prof. Dr. R.A.J.O. Dierckx Prof. Dr. P.H. Elsinga Copromotor: Dr. A. van Waarde Beoordelingscommissie: Prof. Dr. K. Ishiwata Prof. Dr. C. van de Wiele Prof. Dr. A.G.J. van der Zee ISBN: 978-90-367-5309-8 (hardcopy) 978-90-367-5310-4 (electronic version) EXPERIENCE On the open sea I’ve been fishing - Finding my own water sliver; To catch a great fish I’ve been running, I’ve met once in a mountain river. Paranimfen: Dawid J. Rybczyński Paul de Bruyn Table of contents Introduction Chapter 1 Scope and overview of the thesis 9 Chapter 2 Sigma receptors in oncology: therapeutic and diagnostic 25 applications of sigma ligands Diagnostic Applications Chapter 3 Steroid hormones affect binding of the sigma receptor 69 ligand, 11C-SA4503, in tumor cells and tumor-bearing rats Chapter 4 MicroPET with sigma receptor ligand, 11C-SA4503, 87 detects spontaneous pituitary tumors in rodents Therapeutic Applications Chapter 5 Cytotoxicity of sigma receptor ligands is associated with 107 major changes of cellular metabolism and complete occupancy of the sigma-2 subpopulation Chapter 6 In vivo responses of human A375M melanoma 125 to a sigma ligand: FDG-PET imaging Chapter 7 Melanoma-associated Chondroitin Sulfate Proteo- 145 glycan (MCSP)-targeted delivery of sTRAIL potently inhibits melanoma outgrowth in vitro and in vivo Chapter 8 Cell cycle inhibition by sigma receptor ligands enhances 171 anti-MCSP:TRAIL-induced apoptosis in human melanoma cells: monitoring synergy with FDG and FLT Chapter 9 Treatment of ovarian carcinoma with sigma receptor 191 ligands: preliminary data and perspectives Summary, Conclusions and Perspectives Chapter 10 Summary 199 Chapter 11 Conclusions and perspectives 213 Chapter 12 Nederlandse samenvatting / Streszczenie po polsku 225 Acknowledgements 243 List of Abbreviations 247 Scope and overview of the thesis Chapter 1 10 Scope and overview of the thesis Chapter 1 Cancer is a disease of modern civilization and the second leading cause of human deaths [1,2]. This is mainly due to the aging population and the current lifestyle [3]. Specifically, GLOBCAN 2008 estimated that 7.6 million people died from cancer worldwide in 2008 accounting for a 11% risk of dying from cancer before the 75-year of age [2,4]. With these numbers in mind, the prospect of curing cancer might seem daunting. However, specific knowledge of the molecular hallmarks of cancer has already enabled us to develop better tools for prevention, detection and treatment. Here, I will first provide a brief overview of these hallmarks of cancer, followed by the current available treatment and diagnostic options. This overview will hopefully help to localize the research presented in the further chapters of this thesis in the current trends in oncology. Hallmarks of cancer Cancer is a complex disease due to its heterogeneous origins. For example, almost every cell type can generate a cancer cell and all these cancers manifest themselves with varying symptoms. This process of tumorigenesis includes four development phases shared by all cancers, namely initiation, promotion, progression, and conversion [5] (Fig. 1). In all these phases of development, cancer cells acquire many adaptations to avoid elimination by the body’s defense mechanisms and to acquire a selective advantage over neighboring cells [6]. Among the most characteristic cancer adaptations are self- sufficiency in providing growth signals, insensitivity to growth inhibition, evasion of apoptosis (programmed cell death), sustained angiogenesis (vascularization), tissue invasion and metastasis, and the potential for unlimited self-replication [5,6] (Fig. 1). Acquisition of selective advantages is usually the result of genome instability that enables cancers to stratify mutations in genes controlling the aforementioned processes [7,8]. As a result of these mutations, the balance between tumor suppressor genes and oncogenes is disturbed. For instance, self-sufficiency in providing growth signals and insensitivity to growth-inhibitory signals can result from active Harvey rat sarcoma viral oncogene homolog (H-Ras) or loss of the suppressor retinoblastoma protein (Rb), which induces uncontrolled division of cancer cells and, ultimately, cancer promotion and progression [5,7]. Furthermore, evasion of apoptosis, during which apoptotic mechanisms become impaired, may be exemplified by the mutation in the tumor suppressor gene p53 [9]. The p53 mutation is found in more than 50% of cancers, where it contributes to resistance of cancer to apoptosis-inducing treatment [5]. Another example for increased pro-survival signaling and impaired apoptosis is upregulation of the PI3K-Akt pathway. A proto- 11 1 Chapter initiation mutation promotion cell proliferation mutation or epigenetic change proliferation and selection progression mutation or epigenetic change proliferation and selection invasion and metastasis conversion -> self-suciency in providing growth signals -> potential for unlimited self-replication -> insensitivity to growth inhibition -> sustained angiogenesis -> avoidance of immune destruction -> tissue evasion and metastasis -> evasion of apoptosis -> deregulation of cellular energetics Adapted from Pearson Education, Inc 2009 Fig. 1. Phases of cancer development. Tumorigenesis is initiated by multifactor mutations in cell. Disease is promoted if the mutation-burdened cell escapes body’s defense mechanisms, starts to proliferate abnormally and possesses genomic flexibility allowing further mutations and/or epigenetic changes. During tumor progression several adaptation, proliferation and selection cycles take place. This process of acquiring more invasive and resistant phenotype increases tumor survival. Finally, highly motile cancer cells will move from the primary tumor and hatch to distant locations in the body, beginning an advanced stage of the disease. 12 Scope and overview of the thesis Chapter 1 oncogenic phosphatidylinositol-3-kinase (PI3K) is a key cellular signaling coordinator of processes such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking [7,10]. Cancer cells with mutation of the PIK3CA oncogene or mutation/deletion of the PtdIns(3,4,5)P3 phosphatase (PTEN) tumor suppressor gene have hyperactive signaling downstream of PI3K, allowing cancerous transformation [11]. Probably the best known downstream effector from PI3K is Akt kinase [12]. In its active phosphorylated form, Akt kinase stimulates the aerobic glycolysis, regulates cell cycle and facilitates pro-survival mechanisms in cancer. Therefore, cells which develop resistance to apoptosis (via p53, PI3K-Akt or other pathways) will have a selective advantage compared to their neighbors based on their ability to survive e.g. hypoxic environment and acidosis [7]. Surviving hypoxia means stabilization of hypoxia inducible factor 1-alpha (HIF1α) and, possibly consequently,