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Efficacy and Mechanistic Evaluation of Tic10, a Novel Antitumor Agent

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Efficacy and Mechanistic Evaluation of Tic10, a Novel Antitumor Agent University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Joshua Edward Allen University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Oncology Commons Recommended Citation Allen, Joshua Edward, "Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent" (2012). Publicly Accessible Penn Dissertations. 488. https://repository.upenn.edu/edissertations/488 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/488 For more information, please contact [email protected]. Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Abstract TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells and is a critical effector in the immune surveillance of cancer. Recombinant TRAIL and TRAIL-agonist antibodies are in clinical trials for the treatment of solid malignancies due to the cancer-specific cytotoxicity of TRAIL. Recombinant TRAIL has a short serum half-life and both recombinant TRAIL and TRAIL receptor agonist antibodies have a limited capacity to perfuse to tissue compartments such as the brain, limiting their efficacy in certain malignancies. To overcome such limitations, we searched for small molecules capable of inducing the TRAIL gene using a high throughput luciferase reporter gene assay. We selected TRAIL-inducing compound 10 (TIC10) for further study based on its induction of TRAIL at the cell surface and its promising therapeutic index. TIC10 is a potent, stable, and orally active antitumor agent that crosses the blood-brain barrier and transcriptionally induces TRAIL and TRAIL-mediated cell death in a p53-independent manner. TIC10 induces a sustained upregulation of TRAIL in tumors and proximal cells that may contribute to the antitumor activity of TIC10 through a bystander effect. Expression profiling of TIC10-induced transcriptional changes revealed changes in FOXO target genes. We found that Foxo3a undergoes a TIC10-induced nuclear translocation, binds to the TRAIL gene promoter in response to TIC10, and is responsible for TIC10-induced cell death and TRAIL production in vitro and in vivo. TIC10 activates Foxo3a through the dual inactivation of Akt and ERK, which normally phosphorylate and inactivate Foxo3a. The induction of TRAIL by TIC10 can be recapitulated using pharmacological inhibitors of Akt and ERK signaling pathways or siRNA. These mechanistic data provide a clear therapeutic strategy for targeting the TRAIL gene and suggest that Foxo3a-mediated TRAIL induction is responsible for the synergy between PI3K/Akt and MAPK pathway inhibitors. TIC10 is a potentially first-in-class antitumor therapy that utilizes the tumor microenvironment to produce TRAIL, acts as a pharmacological delivery vehicle to improve the therapeutic properties of TRAIL, and highlights Foxo3a activation as an attractive opportunity to induce TRAIL-mediated apoptosis that can be harnessed through dual inhibition of the MAPK and PI3K/Akt pathway. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Biochemistry & Molecular Biophysics First Advisor Wafik S. El-Deiry Keywords Foxo3a, small molecule, targeted therapy, TIC10, TRAIL Subject Categories Oncology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/488 EFFICACY AND MECHANISTIC EVALUATION OF TIC10, A NOVEL ANTITUMOR AGENT Joshua E. Allen A DISSERTATION in Biochemistry and Molecular Biophysics in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2012 Supervisor of Dissertation: ________________________________ Wafik S. El-Deiry, M.D. Ph.D. Adjunct Professor of Medicine Rose Dunlap Professor and Chief, Hematology/Oncology, Penn State Hershey Medical Center Graduate Group Chairperson: _______________________________ Kathryn M. Ferguson, Ph.D. Associate Professor, Physiology Dissertation Committee: Trevor Penning, Ph.D., Professor, Pharmacology Charles Abrams, M.D., Professor and Associate Chief, Hematology-Oncology Ronen Marmorstein, Ph.D., Professor, Wistar Institute Xiaolu Yang, Ph.D., Professor, Cancer Biology DEDICATION To my mother who inspired me to pursue this career path and to relentlessly persevere. ii ACKNOWLEDGMENTS I thank my advisor, Wafik El-Deiry, for his enduring support and the opportunities that he has provided me to form the foundation of my career. I would also like to thank all of my previous mentors and teachers throughout my education, as each step has been essential in allowing me to become who I am today. I thank the past and present members of the El-Deiry lab, particularly Dave, who have made my journey possible and pleasant. I would also like to thank Nicole, my family, and my friends who keep my days bright. I would also like to thank my thesis committee members for their feedback and enlightening perspectives. iii ABSTRACT EFFICACY AND MECHANISTIC EVALUATION OF TIC10, A NOVEL ANTITUMOR AGENT Joshua E. Allen Wafik S. El-Deiry, M.D. Ph.D. TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells and is a critical effector in the immune surveillance of cancer. Recombinant TRAIL and TRAIL-agonist antibodies are in clinical trials for the treatment of solid malignancies due to the cancer-specific cytotoxicity of TRAIL. Recombinant TRAIL has a short serum half-life and both recombinant TRAIL and TRAIL receptor agonist antibodies have a limited capacity to perfuse to tissue compartments such as the brain, limiting their efficacy in certain malignancies. To overcome such limitations, we searched for small molecules capable of inducing the TRAIL gene using a high throughput luciferase reporter gene assay. We selected TRAIL-inducing compound 10 (TIC10) for further study based on its induction of TRAIL at the cell surface and its promising therapeutic index. TIC10 is a potent, stable, and orally active antitumor agent that crosses the blood-brain barrier and transcriptionally induces TRAIL and TRAIL- mediated cell death in a p53-independent manner. TIC10 induces a sustained upregulation of TRAIL in tumors and proximal cells that may contribute to the antitumor activity of TIC10 through a bystander effect. Expression profiling of TIC10-induced transcriptional changes revealed changes in FOXO target genes. We found that Foxo3a undergoes a TIC10-induced nuclear translocation, binds to the TRAIL gene promoter in response to TIC10, and is responsible for TIC10-induced cell death and TRAIL production in vitro and in vivo. TIC10 activates Foxo3a through the dual inactivation of Akt and ERK, which normally phosphorylate and inactivate Foxo3a. The induction of TRAIL by TIC10 can be recapitulated using pharmacological inhibitors of Akt and ERK signaling pathways or siRNA. These mechanistic data provide a clear therapeutic iv strategy for targeting the TRAIL gene and suggest that Foxo3a-mediated TRAIL induction is responsible for the synergy between PI3K/Akt and MAPK pathway inhibitors. TIC10 is a potentially first-in-class antitumor therapy that utilizes the tumor microenvironment to produce TRAIL, acts as a pharmacological delivery vehicle to improve the therapeutic properties of TRAIL, and highlights Foxo3a activation as an attractive opportunity to induce TRAIL-mediated apoptosis that can be harnessed through dual inhibition of the MAPK and PI3K/Akt pathway. v TABLE OF CONTENTS Title Page ............................................................................................................................... i Dedication .............................................................................................................................. ii Acknowledgments ................................................................................................................. iii Abstract .................................................................................................................................. iv Table of Contents .................................................................................................................. vi List of Figures ........................................................................................................................ ix CHAPTER 1: INTRODUCTION 1.1 TRAIL Biology ........................................................................................................... 1 1.2 TRAIL-based Therapies as Antitumor Agents ............................................................ 9 1.3 Regulation of the human TRAIL Gene ....................................................................... 13 1.4 Regulation of Foxo3a Activity ..................................................................................... 24 1.5 Scope of This Thesis Research ................................................................................ 28 CHAPTER 2: IDENTIFICATION OF TIC10 AS A SMALL MOLECULE INDUCER OF TRAIL 2.1 Abstract ...................................................................................................................... 32 2.2 Introduction ................................................................................................................ 33 2.3 Materials and Methods ............................................................................................... 34 2.4 Results ......................................................................................................................
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