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Evaluation of Therapeutic Response of Histiocytic Sarcoma Cell Lines to Novel Small Molecule Inhibitors of Receptor Tyrosine Kinases

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Evaluation of Therapeutic Response of Histiocytic Sarcoma Cell Lines to Novel Small Molecule Inhibitors of Receptor Tyrosine Kinases EVALUATION OF THERAPEUTIC RESPONSE OF HISTIOCYTIC SARCOMA CELL LINES TO NOVEL SMALL MOLECULE INHIBITORS OF RECEPTOR TYROSINE KINASES By Marilia Takada A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Small Animal Clinical Sciences – Master of Science 2013 ABSTRACT EVALUATION OF THERAPEUTIC RESPONSE OF HISTIOCYTIC SARCOMA CELL LINES TO NOVEL SMALL MOLECULE INHIBITORS OF RECEPTOR TYROSINE KINASES By Marilia Takada The current standard of care treatment for canine histiocytic sarcoma (HS) is based on the administration of conventional chemotherapeutic drugs, which results in low percentage of partial and short-term favorable responses. In order to identify novel drug candidates for the treatment of dogs with HS, we investigated the cytostatic activity of a panel of sixteen compounds over two canine HS cell lines. Our results demonstrated that dasatinib, a receptor tyrosine kinase pan-inhibitor, and other novel molecularly- targeted drugs JQ1, a BET bromodomain inhibitor, and bortezomib, a proteasome inhibitor, effectively inhibited the growth of HS cells in vitro. The antiproliferative response of dasatinib was augmented when combined to doxorubicin, a classical chemotherapeutic agent. For all these drugs, the effective inhibitory concentration in vitro was within a clinically achievable and tolerable plasma concentration in vivo, as described in the veterinary and human medicine literature. In this study we identified three molecularly targeted drugs that may represent a promising anticancer strategy for canine HS. Further in vivo studies and clinical trials are needed to fully evaluate therapeutic potential of these drugs in HS in dogs and in similar disorders in humans. DEDICATION Dedicated to my father Kinichi Takada. iii ACKNOWLEDGMENTS I would like to thank my committee members Dr. Matti Kiupel, Dr. Nik Dervisis, and Dr. Joe Hauptman for their support and guidance. A special thank you to Dr. Vilma Yuzbasiyan-Gurkan for giving the opportunity to join her laboratory and enrich me with a wonderful experience. Thank you Dr. Pat Venta, Emmy, Maciej, Tina, and Eilidh for helping me and for creating such a friendly and pleasant laboratory environment. Thank you Dr. Barbara Kitchell whose passion for teaching was incredibly inspirational. Paulo, you gave new colors to my winter in Michigan. Thank you for always being there for me. Thank you my family. Nala who brought so much joy. Leo and Emy, your my inspiration and my best friends. Mama, your sweetness and love give me strength to keep following my dreams. Papa, thank you for teaching me to be ambitious and to enjoy life as much as I can. iv TABLE OF CONTENTS LIST OF TABLES ........................................................................................................... vii LIST OF FIGURES ........................................................................................................ viii KEY TO SYMBOLS or ABBREVIATIONS ....................................................................... ix CHAPTER 1. Introduction ............................................................................................. 1 CHAPTER 2. Literature Review .................................................................................... 4 2.1. HISTIOCYTIC SARCOMA (HS) IN DOGS .................................................................. 4 2.1.a. Epidemiology of canine HS ................................................................. 4 2.1.b. Pathology of canine HS ...................................................................... 5 2.1.c. Clinical presentation of canine HS ...................................................... 7 2.1.d. Diagnosis and staging of canine HS ................................................... 7 2.1.e. Treatment and prognosis of canine HS .............................................. 9 2.2. PROTEIN TYROSINE KINASE RECEPTORS ............................................................. 10 2.2.a. Structure of receptor tyrosine kinases (RTKs) .................................. 10 2.2.b. Functions and mechanisms of activation of RTKs ............................ 14 2.2.c. Deregulation of RTKs in cancer ........................................................ 15 i. Overexpression of receptor by abnormal number of RTKs ......... 17 ii. Mutations in the RTK gene ......................................................... 17 iii. Autocrine signaling .................................................................... 17 iv. Deficiency on autoinhibitory mechanisms ................................. 18 2.2.d. RTKs as targets for cancer therapy .................................................. 18 2.2.e. Tyrosine kinase inhibitors (TKIs) in cancer therapy .......................... 21 2.2.f. Tyrosine kinase inhibitors in veterinary oncology .............................. 21 CHAPTER 3. Therapeutic Response of HS Cell Lines to RTK Inhibitors .................... 23 3.1. INTRODUCTION ................................................................................................. 23 3.2. MATERIAL AND METHODS ................................................................................... 23 3.2.a. Canine HS-derived cell lines............................................................. 23 3.2.b. Cell culture conditions ...................................................................... 23 3.2.c. Chemotherapeutic drugs................................................................... 24 3.2.d. Proliferation assay and data analysis ............................................... 26 3.3. RESULTS ......................................................................................................... 27 3.3.a. Inhibitory effects of drugs on HS cells proliferation ........................... 27 3.3.b. Assessing feasibility of a panel of TKIs using maximum achievable plasma concentrations ................................................. 33 3.3.c. Exploring synergistic combinations ................................................... 35 3.4. DISCUSSION ..................................................................................................... 37 v CHAPTER 4. Conclusions and Future Directions ....................................................... 45 REFERENCES .............................................................................................................. 47 vi LIST OF TABLES Table 2.1. Immunohistochemical expression patterns for HS in dogs ............................. 8 Table 2.2. Immunohistochemical markers for specific cellular antigens .......................... 8 Table 2.3. Tyrosine kinase receptors associated with cancer ....................................... 16 Table 2.4. U.S. FDA approved tyrosine kinase inhibitors for treatment of cancer in humans ..................................................................................................................... 20 Table 2.5. U.S. FDA approved tyrosine kinase inhibitors for treatment of cancer in dogs .......................................................................................................................... 22 Table 3.1. List of the drugs used for the proliferation assays on HS cell lines ............... 25 Table 3.2. Results of IC50 values (nM) from drugs used on two HS cell lines .............. 28 Table 3.3. List of achievable plasma concentration of drugs described in the veterinary and human medicine literature, and the corresponding cell proliferation rate ........... 34 vii LIST OF FIGURES Figure 2.1. Families of receptor protein-tyrosine kinases .............................................. 13 Figure 3.1. Results of dose-response curves of both cell lines, BD () and DH82 (), generated from the drug-screening assay using the following 16 drugs: (A) dasatinib, (B) erlotinib, (C) gefitinib, (D) imatinib, (E) masitinib, (F) nilotinib, (G) toceranib, (H) sorafenib, (I) sunitinib, (J) tozasertib, (K) lomustine, (L) cladribine, (M) doxorubicin, (N) JQ1, (O) src inhibitor, (P) bortezomib .................................................................. 29 Figure 3.2. Effect of drugs on the proliferation rate of HS cells at the maximum achievable plasma concentration .............................................................................. 35 Figure 3.3. The inhibitory effect on cell proliferation of dasatinib and doxorubicin administered alone and in combination against BD (A) and DH82 (B) cell lines ....... 36 viii KEY TO SYMBOLS or ABBREVIATIONS ALK = anaplastic lymphoma kinase ALL = acute lymphocytic leukemia AML = acute myeloid leukemia ATP = adenosine triphosphate BMD = bernese mountain dog CCNU = N-(2-chloroethyl)-N’-cyclohexyl-N-nitrosourea CML = chronic myelogenous leukemia CMML = chronic myelomonocytic leukemia CNA = copy number aberration DC = dendritic cell DMSO = dimethyl sulfoxide DNA = deoxyribonucleic acid EGFR = epithelial growth factor receptor EPHR = ephrin receptor FDA = food and drug administration FGFR = fibroblast growth factor receptor GIST = gastrointestinal stromal tumor GM-CSF = granulocyte-macrophage colony-stimulating factor GTPase = guanosine triphosphate HS = histiocytic sarcoma IL-1α = interleukin 1 alfa ix IL-1β = interleukin 1 beta IMHA = immune mediated hemolytic anemia M-CSF = macrophage colony-stimulating factor MCT = mast cell tumor NGFR = nerve growth factor receptor NOAEL = no-observed-adverse-effect level PAHS = peri-articular histiocytic sarcoma PBMC = peripheral blood mononuclear cells PDGF = platelet growth factor PDGFR = platelet growth
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