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Preclinical Development of a Non-Immunosuppressive FTY720 Derivative OSU-2S for Chronic Lymphocytic Leukemia and Other B-Cell Malignancies

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Preclinical development of a non-immunosuppressive FTY720 derivative OSU-2S for chronic lymphocytic leukemia and other B-cell malignancies DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Rajeswaran Mani, BVSc & AH Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2014 Dissertation Committee: Natarajan Muthusamy, Advisor John C. Byrd Ching-Shih Chen Cheryl A. London Copyrighted by Rajeswaran Mani 2014 Abstract Chemotherapeutics remains a choice of treatment for several malignant diseases. However, selective cytotoxicity against cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Current therapies for chronic lymphocytic leukemia (CLL), the most prevalent adulthood leukemia in the western world are not curative rendering drug adverse effects and immunosuppression. Here we developed a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A, phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in CLL. Moreover, with relevant to CLL disease TCL1A expression that was identified to be down regulated in response to OSU-2S in the gene expression profile was independently confirmed to be significantly down regulated both at the mRNA and protein levels. Exposure of OSU-2S to unintended cells is expected to adversely affect physiological functions of these ubiquitous phosphatases. To selectively deliver OSU-2S to leukemic cells, we developed tumor antigen targeted delivery of immunonanoparticle carrying a OSU-2S (2A2-OSU-2S-ILP). 2A2-OSU-2S-ILP immunonanoparticles mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 in all ii leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2- OSU-2S-ILP in-vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL specific surface antigen ROR1 directed immunonanoparticles and the novel transgenic mouse model of CLL that expresses human ROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma (MCL) and B-lineage acute lymphoblastic leukemia (ALL). Further, treatment of MCL with OSU-2S induced PARP cleavage and increased the cell surface expression of CD74 a therapeutic target. OSU-2S in combination with anti-CD74 antibody milatuzumab had additive cytotoxicity in MCL cells. Moreover, ROR1 targeted 2A2-OSU-2S-ILP mediated selective cytotoxicity of MCL. Treatment with 2A2-OSU- 2S-ILP significantly reduced the tumor weight in MCL xenografted mice. Thus OSU-2S and its delivery using tumor antigen ROR1 directed immunonanoparticles could increase the width of existing armamentarium for MCL. iii Dedicated to my parents and my brother iv Acknowledgments I am grateful to my advisor and my advisory committee members for their professional mentorship and Veterinary Biosciences department for supporting my studentship. I wholeheartedly thank Drs. Muthusamy and Byrd lab members for their kind assistance and their continuous support while I carried out my research. I thank Mr. Frank W. Frissora in particular for his support and in laboratory assistance all through the years since I joined the graduate program. I appreciate Dr.Yicheng Mao and Mr. Chi-Ling Chiang who supported the research by synthesizing targeted liposomal nanoparticles and for help with the experiments. Special thanks to Drs.Ching-Shih Chen and Ribai Yan for synthesizing and providing us the OSU-2S drug for conducting preclinical studies. I am also thankful to the patients and healthy donors who supported the research by providing their blood without which the preclinical investigation of OSU- 2S could not have been possible. I would like to extend my gratefulness to Dr. Byrd for providing translational insights to the experimental designs and Dr. London for her invaluable comments and providing me the opportunity for evaluation of OSU-2S in the spontaneous canine lymphoma samples. v Vita April 2002 ......................................................Carmel Matriculation Higher Secondary School, Erode, India 2007................................................................BVSc & AH (Veterinary Medicine) Tamilnadu Veterinary and Animal Sciences University (TANUVAS), Chennai, India 2009 to present ..............................................Graduate Research Associate, Department of Veterinary Biosciences & Comprehensive Cancer Center, The Ohio State University Publications 1. Mani, R., Y. Mao, F.W. Frissora, C.L. Chiang, J. Wang, Y. Zhao, Y. Wu, B. Yu, R. Yan, X. Mo, L. Yu, J. Flynn, J. Jones, L. Andritsos, S. Baskar, C. Rader, M.A. Phelps, C.S. Chen, R.J. Lee, J.C. Byrd, L.J. Lee, and N. Muthusamy, Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B cell cytotoxicity in chronic lymphocytic leukemia. Leukemia, 2014. doi: 10.1038/leu.2014.199. 2. Lapalombella, R., Q. Sun, K. Williams, L. Tangeman, S. Jha, Y. Zhong, V. Goettl, E. Mahoney, C. Berglund, S. Gupta, A. Farmer, R. Mani, A.J. Johnson, D. Lucas, vi X. Mo, D. Daelemans, V. Sandanayaka, S. Shechter, D. McCauley, S. Shacham, M. Kauffman, Y.M. Chook, and J.C. Byrd, Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood, 2012. 120(23): p. 4621- 34. 3. Alinari, L., C.J. Prince, R.B. Edwards, W.H. Towns, R. Mani, A. Lehman, X. Zhang, D. Jarjoura, L. Pan, A.D. Kinghorn, M.R. Grever, R.A. Baiocchi, and D.M. Lucas, Dual Targeting of the Cyclin/Rb/E2F and Mitochondrial Pathways in Mantle Cell Lymphoma with the Translation Inhibitor Silvestrol. Clin Cancer Res, 2012. 4. Lapalombella, R., Y.Y. Yeh, L. Wang, A. Ramanunni, S. Rafiq, S. Jha, J. Staubli, D.M. Lucas, R. Mani, S.E. Herman, A.J. Johnson, A. Lozanski, L. Andritsos, J. Jones, J.M. Flynn, B. Lannutti, P. Thompson, P. Algate, S. Stromatt, D. Jarjoura, X. Mo, D. Wang, C.S. Chen, G. Lozanski, N.A. Heerema, S. Tridandapani, M.A. Freitas, N. Muthusamy, and J.C. Byrd, Tetraspanin CD37 Directly Mediates Transduction of Survival and Apoptotic Signals. Cancer Cell, 2012. 21(5): p. 694-708. 5. Alinari, L., E. Mahoney, J. Patton, X. Zhang, L. Huynh, C.T. Earl, R. Mani, Y. Mao, B. Yu, C. Quinion, W.H. Towns, C.S. Chen, D.M. Goldenberg, K.A. Blum, J.C. Byrd, N. Muthusamy, M. Praetorius-Ibba, and R.A. Baiocchi, FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death. Blood, 2011. 118(26): p. 6893-903. vii 6. Bai, L.Y., Y. Ma, S.K. Kulp, S.H. Wang, C.F. Chiu, F. Frissora, R. Mani, X. Mo, D. Jarjoura, J.C. Byrd, C.S. Chen, and N. Muthusamy, OSU-DY7, a novel D-tyrosinol derivative, mediates cytotoxicity in chronic lymphocytic leukaemia and Burkitt lymphoma through p38 mitogen-activated protein kinase pathway. Br J Haematol, 2011. 153(5): p. 623-33. 7. Liu, Q., L. Alinari, C.S. Chen, F. Yan, J.T. Dalton, R. Lapalombella, X. Zhang, R. Mani, T. Lin, J.C. Byrd, R.A. Baiocchi, and N. Muthusamy, FTY720 shows promising in vitro and in vivo preclinical activity by downmodulating Cyclin D1 and phospho-Akt in mantle cell lymphoma. Clin Cancer Res, 2010. 16(12): p. 3182-92. Fields of Study Major Field: Comparative and Veterinary Medicine Experimental Therapeutics Molecular Pharmacology viii Table of Contents Abstract ............................................................................................................................... ii Acknowledgments............................................................................................................... v Vita ..................................................................................................................................... vi Table of Contents ............................................................................................................... ix List of Tables .................................................................................................................... xii List of Figures .................................................................................................................. xiii List of Abbreviations ..................................................................................................... xviii Introduction ......................................................................................................................... 1 Chronic Lymphocytic Leukemia ............................................................................ 1 Role of Kinases in leukemia ................................................................................... 3 Role of Phosphatases in leukemia........................................................................... 7 FTY720 ................................................................................................................. 10 FTY720 in solid tumors ............................................................................. 10 FTY720 in hematologic malignancies ...................................................... 11 OSU-2S a non-immunosuppressive FTY720 analogue ........................................ 13 Materials and Methods .....................................................................................................
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    BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Immunother Cancer Supplementary Table S5. Differentially expressed gene lists of PD-1high CD39+ CD8 TILs according to 4-1BB expression compared to PD-1+ CD39- CD8 TILs Up- or down- regulated genes in Up- or down- regulated genes Up- or down- regulated genes only PD-1high CD39+ CD8 TILs only in 4-1BBneg PD-1high CD39+ in 4-1BBpos PD-1high CD39+ CD8 compared to PD-1+ CD39- CD8 CD8 TILs compared to PD-1+ TILs compared to PD-1+ CD39- TILs CD39- CD8 TILs CD8 TILs IL7R KLRG1 TNFSF4 ENTPD1 DHRS3 LEF1 ITGA5 MKI67 PZP KLF3 RYR2 SIK1B ANK3 LYST PPP1R3B ETV1 ADAM28 H2AC13 CCR7 GFOD1 RASGRP2 ITGAX MAST4 RAD51AP1 MYO1E CLCF1 NEBL S1PR5 VCL MPP7 MS4A6A PHLDB1 GFPT2 TNF RPL3 SPRY4 VCAM1 B4GALT5 TIPARP TNS3 PDCD1 POLQ AKAP5 IL6ST LY9 PLXND1 PLEKHA1 NEU1 DGKH SPRY2 PLEKHG3 IKZF4 MTX3 PARK7 ATP8B4 SYT11 PTGER4 SORL1 RAB11FIP5 BRCA1 MAP4K3 NCR1 CCR4 S1PR1 PDE8A IFIT2 EPHA4 ARHGEF12 PAICS PELI2 LAT2 GPRASP1 TTN RPLP0 IL4I1 AUTS2 RPS3 CDCA3 NHS LONRF2 CDC42EP3 SLCO3A1 RRM2 ADAMTSL4 INPP5F ARHGAP31 ESCO2 ADRB2 CSF1 WDHD1 GOLIM4 CDK5RAP1 CD69 GLUL HJURP SHC4 GNLY TTC9 HELLS DPP4 IL23A PITPNC1 TOX ARHGEF9 EXO1 SLC4A4 CKAP4 CARMIL3 NHSL2 DZIP3 GINS1 FUT8 UBASH3B CDCA5 PDE7B SOGA1 CDC45 NR3C2 TRIB1 KIF14 TRAF5 LIMS1 PPP1R2C TNFRSF9 KLRC2 POLA1 CD80 ATP10D CDCA8 SETD7 IER2 PATL2 CCDC141 CD84 HSPA6 CYB561 MPHOSPH9 CLSPN KLRC1 PTMS SCML4 ZBTB10 CCL3 CA5B PIP5K1B WNT9A CCNH GEM IL18RAP GGH SARDH B3GNT7 C13orf46 SBF2 IKZF3 ZMAT1 TCF7 NECTIN1 H3C7 FOS PAG1 HECA SLC4A10 SLC35G2 PER1 P2RY1 NFKBIA WDR76 PLAUR KDM1A H1-5 TSHZ2 FAM102B HMMR GPR132 CCRL2 PARP8 A2M ST8SIA1 NUF2 IL5RA RBPMS UBE2T USP53 EEF1A1 PLAC8 LGR6 TMEM123 NEK2 SNAP47 PTGIS SH2B3 P2RY8 S100PBP PLEKHA7 CLNK CRIM1 MGAT5 YBX3 TP53INP1 DTL CFH FEZ1 MYB FRMD4B TSPAN5 STIL ITGA2 GOLGA6L10 MYBL2 AHI1 CAND2 GZMB RBPJ PELI1 HSPA1B KCNK5 GOLGA6L9 TICRR TPRG1 UBE2C AURKA Leem G, et al.
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