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UCSF UC San Francisco Electronic Theses and Dissertations Title Exploring the Dysregulation of Iron Metabolism in Cancer: Leveraging Fenton Chemistry for Selective Drug Delivery Permalink https://escholarship.org/uc/item/0tr3v78n Author Spangler, Benjamin Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Exploring the Dysregulation of Iron Metabolism in Cancer; Leveraging Fenton Chemistry for Selective Drug Delivery Pi by Benjamin Spangler DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry and Chemical Biology in the Copyright (2016) by Benjamin Spangler ii Dedications and Acknowledgements I would like to thank everyone who has helped me make it to this point. It is a long list. From my parents who raised me to always ask questions, strive for knowledge, and work hard for the things I cared about, to all those who have taught me along my academic progression; I am here because of you. So thank you, for taking the time to help me learn and grow. Special thanks are due to the following people for helping me along my way in this project: • Dr. Adam Renslo and Dr. James Wells: for being excellent P.I.’s and steering me towards success in so many ways. • Dr. Michelle Arkin and Dr. Martin McMahon for their excellent input and advice as members of my thesis committee. • Dr. Shaun Fontaine: for sharing intermediates, many useful discussions of chemistry, and being an all-around great guy. • Dr. Charles Morgan: for many useful discussions and contributing towards the cell culture work presented in Chapter 2 by assisting in the development of the high-throughput immunofluorescence assay, help with qRT-PCR, and preforming knock-downs and over-expressions for studies of the reactive iron pool. • Dr. Byron Hann and the preclinical therapeutics core at UCSF: for their assistance planning and executing all of the mouse studies presented here. iii • Dr. Samantha Zeitlin: for helping me remember how to do cell culture when I started. • Mr. Steven Chen: for assistance with automated imaging and image analysis • Dr. Yihui Shi: for preforming the toxicity experiments across a panel of the NCI 60 cell lines presented in Chapter 3. • Dr. Tetsuya Matsuguchi for assistance with qRT-PCR experiments. • Dr. Alan Wolfe for the calculation of pharmacokinetic parameters. Aspects of Chapter 2 were adapted from a manuscript currently under review with Nature Chemical Biology: Spangler, B. et al., A reactivity-based probe of the intracellular labile ferrous iron pool. Manuscript submitted for publication. (2015). Aspects of Chapter 3 were adapted from a manuscript in preparation. Spangler, B. et al., Leveraging the reactive iron pool for selective drug delivery in cancer. Manuscript in preparation. (2015). The work presented in Chapter 4 was done in collaboration with Sutro Biopharma (Toni Kline, Xiaofan Li, Jeff Hanson, Sihong Zhou, Krishna Bajjuri, Gang Yin, Alexander Steiner, and Aaron Sato) which provided materials for chemistry and preformed all antibody conjugations and cell culture experiments. This manuscript is dedicated to my amazing fiancée Naomi Yonis who has somehow managed to handle the stresses of these last few months while taking care of me as I have floundered my way through completing a PhD. I could not have done it without you. iv Exploring the Dysregulation of Iron Metabolism in Cancer: Leveraging Fenton Chemistry for Selective Drug Delivery Benjamin Spangler Abstract Most cancer chemotherapeutics are administered at or near their maximum tolerated dose, yet poor efficacy and insufficient therapeutic index remain major causes of attrition in oncology drug development. New pharmacological approaches that selectively target tumor cells are therefore of significant interest. Emerging evidence suggests that an augmented pool of intracellular labile Fe(II) is a metabolic signature of many cancers and thus may represent a targetable chemical environment. We have leveraged Fe(II)-dependent, Fenton-type reactivity of the 1,2,4-trioxolane ring to develop highly selective, reactivity-based probes of the ferrous iron pool and a prototypical scaffold for Fe(II)-dependent drug delivery of chemotherapeutics. These probes reveal higher reactive Fe(II)-pools in cancer cells as compared to non-tumorigenic cells, changes that can be linked to alteration of iron metabolism. Our findings suggest that many cancers alter iron metabolism to increase intracellular Fe(II)-pools and these changes can be exploited for cell- v selective drug delivery. By using this scaffold to mask a highly potent DNA-alkylator we illustrate that this prodrug system is capable of stabilizing and selectively delivering such potent cytotoxins in vivo. Overall our results establish that Fe(II)- dependent prodrug/delivery strategies can be used to enhance the therapeutic index of cancer chemotherapeutics. Encouraged by these results further efforts were made to apply trioxolane-based systems as novel, tumor-selective cleavable linkers for antibody-drug conjugate strategies. Preliminary results indicate trioxolane-based linkers are capable of efficiently releasing drugs from ADC’s in cancer cells but optimization will be required before further development. vi Short-hand and abbreviations used in this text: ADC: antibody-drug conjugate BCN: bicyclo[6.1.0]nonyne BME: β-mercaptoethanol Bpy: bipyridy CBI: cyclopropylbenzindoline CMB: combretastatin CTG: CellTiter-Glo® DBCO: Dibenzocyclooctyl DCM: dichloromethane DFO: desferrioxamine DMS: dimethylsulfide FAC: ferric ammonium citrate FAS: ferrous ammonium sulfate GSH: glutathione hTf: holo-transferrin IRE: iron responsive element MMAE/F: Monomethyl auristatin E/F MOA: mechanism of action NAC: N-acetyl cysteine PK: pharmacokinetics Puro: puromycin ROS: reactive oxygen species TAP: tumor-activated prodrug TEA: trimethylamine TPP: triphenylphosphine Trx: 1,2,4-trioxolane UTR: untranslated region vii Table of Contents Dedications and Acknowledgements ............................................................................................. iii Abstract ...................................................................................................................................................... v Short-hand and abbreviations used in this text: ...................................................................... vii Table of Contents ................................................................................................................................ viii List of Figures, Schemes, and Tables ............................................................................................... x Chapter 1: Iron Metabolism and Cancer ........................................................................................ 1 Regulation of iron metabolism in mammalian cells ............................................................. 1 Dysregulation of iron metabolism in cancer cells ................................................................. 5 Currently available tools to study the labile iron pool ........................................................ 7 Chapter 2: Development of trioxolane-derived reactivity-based probes of the reactive iron(II) pool. ......................................................................................................................... 11 Sterically hindered endoperoxides .......................................................................................... 11 Synthesis of a trioxolane-based probe for intracellular reactive Fe(II) .................... 21 Validation of trioxolane-conjugates as reactivity-based probes of the intracellular labile Fe(II) pool .............................................................................................................................. 25 Profiling cell-type specific changes the labile pool of ferrous iron ............................. 31 Understanding the consequences of iron-metabolism dysregulation on the presence of intracellular reactive Fe(II)-species: ............................................................... 34 Genetic Alterations to the Labile Fe(II) pool ........................................................................ 35 In vivo applications of trioxolane-derived, reactivity-based probes of the labile Fe(II) pool in a PC-3 tumor xenograft model ....................................................................... 39 Discussion .......................................................................................................................................... 41 Chapter 3: Leveraging the dysregulation of iron-metabolism in cancer as a trigger for selective drug delivery ................................................................................................................ 44 Selective drug release strategies in cancer ........................................................................... 45 Trioxolane-mediated delivery of cytotoxic agents to cancer cells ............................... 49 Profiling the effects of oncogenic transformation on iron metabolism and sensitivity to trioxolane-conjugates ........................................................................................ 52 Development of trioxolane-conjugates of highly potent DNA alkylators ................. 54 Pharmacokinetics and safety of trioxolane-drug conjugates ......................................... 57 viii Studying the fate of the cyclohexenone byproduct ...........................................................
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