STUDIES OF TARGETED THERAPIES AGAINST HUMAN T LYMPHOTROPIC VIRUS TYPE-1 ADULT T-CELL LYMPHOMA IN PRECLINICAL ANIMAL MODELS DISSERTATION Presented in Partial Fulfillment of the Requirement for the Doctor of Philosophy Degree in the Graduate School of The Ohio State University By Bevin Zimmerman, B.A., D.V.M. ***** The Ohio State University 2009 Dissertation Committee: Dr. Michael D. Lairmore, Advisor Approved by: Dr. Stefan Niewiesk ______ Dr. Lawrence Mathes Advisor Dr. Paul Stromberg Veterinary Biosciences Graduate Program
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Studies of Targeted Therapies Against Htlv in Preclinical Animal Models
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8/10/2019 Studies of Targeted Therapies Against Htlv in Preclinical Animal Models
1. Parrula C., Zimmerman B., Nadella P., Shu S., Rosol T., Fernandez S.,Lairmore M., Niewiesk S. Differential Expression of tumor invasion factors affectsystemic engraftment and induction of humoral hypercalcemia in mice by ATLcells. Veterinary Pathology, 2009 May 9 epub ahead of print
2. Arnold J, Zimmerman B., Li M., Lairmore M., Green P. HTLV-1 HBZ
Promotes Proliferation in Cell Culture and Tumor Growth in NOD/SCID
γchain-/-
(NOG) Mice, Blood 2008 Nov 1; 112(9): 3788-97
3. Knostman K., Venkateswaran A., Zimmerman B., Capen CC., Jhiang SM.Creation and Characterization of Doxycycline-Inducible Mouse Model of Thyroid
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4. Ratner L., Grant C., Zimmerman B., Fritz J., Weil G., Denes A., Rama S.,Campbell N., Jacobsen S., Lairmore M. Adult T-Cell Leukemia and StrongyloidesInfection, American Journal of Hematology 2007 Oct; 82(10):929-31
5. Zimmerman B., Yamaguchi M., Rush L. Immunoglobulin Crystals in ReactivePlasma Cells in a Dog, Veterinary Pathology. 2007 May; 44(3): 389-91
6. Zimmerman B., Rotstein D., Jones S. A Case of Large Granular Lymphoma
in a Mule, Vet Record 2004 Oct 9; 155(15):462-3
FIELD OF STUDY
Major Field: Veterinary Biosciences
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1.4 Animals Models of HTLV-1 Infection.............................................. 111.4.1 The Rabbit Model of HTLV-1 ............................................11
1.4.2 The Nonhuman Primate Model of HTLV-1........................131.4.3 The Rat Model of HTLV-1 Infection and Disease..............141.4.4 The Mouse Model of HTLV-1 Infection and Disease......... 15
1.4.4.1 Xenograft Mouse Models of ATL.............................. 161.4.4.2 Transgenic Mouse Models of HTLV-1...................... 20
1.5 Treatment of Adult T-cell Leukemia............................................... 24
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2. Combination Therapy of Bortezomib (PS-341) and 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) Decreases Tumor Burden in a MouseModel of Adult T-Cell Leukemia/Lymphoma………………………………………………………………...…….58
5. Synopsis and Future Directions ............................................................. 1435.1 Animal Models of HTLV-1............................................... 1435.2 Targeted Therapies Against ATL.................................... 1455.3 The Need for Prolonged Dosing to Achieve Efficacy in
ATL.................................................................................1465.4 Evaluation of Combinational Therapy Against ATL ........ 1475.5 HDACi in ATL Therapy………………………..................... 1495.6 Control of Proviral Load in HTLV-1 Infection .................1525.7 Summary and Impact of Work........................................ 1555.8 References...................................................................... 156
3.2 Western blot of whole cell lysates after 24 hours .................... ..109
3.3 Linear schematic of dosing regimen.......................................... 110
3.4 Engraftment of MET-1 cells in multiple organs.......................... 111
3.5 Oral gavage of OSU HDAC42 in the NOD/SCID ATLmouse model serum IL-2Rα levels of mice andsurvival curves ..........................................................................112
3.6 Mice fed formulated diets ad lib did not differ in intake.............. 113
3.7 In feed trial OSU-HDAC42 in the NOD/SCID ATLmouse model serum IL-2Rα levels of mice andsurvival curves. ......................................................................... 114
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Figure 1.1 The HTLV-1 genome including all transcripts and theirprotein products. HTLV-1 full length provirus followed by all viral transcripts
and their corresponding proteins. This includes the HBZ protein which isencoded by the antisense RNA. Open reading frames are indicated byroman numerals and colored boxes indicate the protein coding region.
54
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Table 1.1 Engraftment of ATL cell lines in immunodeficient miceEngraftment is defined as having evidence of growth within the mouse line,using either serum biomarkers or histopathology.
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Table 1.3 Preclinical efficacy studies utilizing mouse models of ATLEndpoints for studies included tumor burden (measured histologically,volumetrically or biochemically) or survival.
57
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(37) Cavo M. Proteasome inhibitor bortezomib for the treatment of multiplemyeloma. Leukemia 2006 Jun 29;20(8):1341-52.
(38) Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, deVos S, et al. Multicenter Phase II Study of Bortezomib in Patients WithRelapsed or Refractory Mantle Cell Lymphoma. J Clin Oncol 2006 Oct20;24(30):4867-74.
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(39) Mimnaugh EG, Xu W, Vos M, Yuan X, Isaacs JS, Bisht KS, et al.Simultaneous inhibition of hsp 90 and the proteasome promotesprotein ubiquitination, causes endoplasmic reticulum-derived cytosolicvacuolization, and enhances antitumor activity. Mol Cancer Ther 2004May;3(5):551-66.
(40) Satou Y, Nosaka K, Koya Y, Yasunaga J, Toyokuni S, Matsuoka M.Proteasome inhibitor, bortezomib, potently inhibits the growth of adultT-cell leukemia cells both in vivo and in vitro. Leukemia 2004 Jun10;18(8):1357-63.
(41) Satou Y, Nosaka K, Koya Y, Yasunaga J, Toyokuni S, Matsuoka M.Proteasome inhibitor, bortezomib, potently inhibits the growth of adultT-cell leukemia cells both in vivo and in vitro. Leukemia 2004 Jun10;18(8):1357-63.
(42) Nasr R, El-Sabban ME, Karam JA, Dbaibo G, Kfoury Y, Arnulf B, et al.
Efficacy and mechanism of action of the proteasome inhibitor PS-341in T-cell lymphomas and HTLV-I associated adult T-cellleukemia/lymphoma. Oncogene 2005 Jan 13;24(3):419-30.
(43) Satou Y, Nosaka K, Koya Y, Yasunaga J, Toyokuni S, Matsuoka M.Proteasome inhibitor, bortezomib, potently inhibits the growth of adultT-cell leukemia cells both in vivo and in vitro. Leukemia 2004 Jun10;18(8):1357-63.
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Figure 2.1 The addition of 17-AAG significantly inhibits growth in both theMT-2 and Jurkat cell lines. MT-2, C8166, and Jurkat T-cells were grown inmedia only, 1, 2.5, or 5nM PS-341 with or without the addition of 1000nM 17-
AAG. At 24, 48, and 72 hours, growth was measured by the addition of MTS
reagent and absorbance at 490 nM
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Figure 2.2 Western blot of MT-2 cell whole cell lysate after 48 hours. Cellswere treated with media only, 5nM PS-341 or 1000 nM 17-AAG or thecombination of PS-341 and 17-AAG. Cells show decreased PARP, Akt and pAktwith increased ubiquitination.
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Figure 2.3 Histologic representation of mouse tissues from phase I. Panels A and B are sections of lung stained with routine H&E. Histologic findingsinclude fewer neoplastic round cells in the PS-341 and 17-AAG group whencompared to the no treatment group. Panels C and D are Ki67 stained sectionsof lung from Phase I. Numbers of positive nuclei (brown staining) were countedin ten randomly selected high powered fields (400X magnification) for eachtissue.
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BFigure 2.4 Serum IL-2Rα levels and survival curves of mice. A. Serum IL-2Rα levels of mice at the end of Phase I study. There is a statistically significantdecrease in serum IL-2Rα levels in both the PS-341 and combination therapygroups while there is a trend toward a significant decrease in the 17-AAG
treatment group. B. Kaplan Meier curve for Phase II in vivo experiments. Whiletreatment with either PS-341 or combination therapy proved better than vehicleonly treatment, treating with combination therapy did not improve survival overPS-341 alone.
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(1) Mahieux R, Gessain A. HTLV-1 and associated adult T-cellleukemia/lymphoma. Rev Clin Exp Hematol 2003 Dec;7(4):336-61.
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Effect of human T-lymphotropic virus type I infection on non- Hodgkin'slymphoma incidence. J Nat Cancer Inst 1995;87:1009-14.
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(21) Eadie MJ, Hooper WD, Dickinson RG. Valproate-associated hepatotoxicityand its biochemical mechanisms. Med Toxicol Adverse Drug Exp 1988Mar;3(2):85-106.
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compounds. Int J Biochem Cell Biol 2009 Jan;41(1):21-5.
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novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42,in prostate cancer. Clin Cancer Res 2006 Sep 1;12(17):5199-206.
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(41) Kaiser M, Zavrski I, Sterz J, Jakob C, Fleissner C, Kloetzel PM, et al. Theeffects of the histone deacetylase inhibitor valproic acid on cell cycle,growth suppression and apoptosis in multiple myeloma. Haematologica2006 Feb;91(2):248-51.
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Figure 3.1. Histone deacetylase inhibitors significantly inhibit growth inATL cell lines. A. MT-2, C8166, and Jurkat T-cells were grown in media only, 1,2.5, 5 mM valproic acid. At 24, 48, and 72 hours, growth was measured by theaddition of MTS reagent and absorbance at 490 nM. B. MT-2, C8166, andJurkat T-cells were grown in media only, 0.5, 1, 2.5 μM OSU-HDAC42. At 24,48, and 72 hours, growth was measured by the addition of MTS reagent andabsorbance at 490 nm.
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Figure 3.2 Western blot of whole cell lysate after 24 hours. MT-2 cells weretreated with media only, 1, 2.5, 5 mM valproic acid or 0.5, 1, 2.5 μM OSU-HDAC42. Cells showed a dose dependent increase in cleaved PARP,cytochrome C, and acetylated histone H3. C8166 cells were treated with mediaonly, 1, 2.5, 5 mM valproic acid or 0.5, 1, 2.5 μM OSU-HDAC42. Cells showed adose dependent increase in cleaved PARP, cytochrome C, and acetylatedhistone H3.
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Figure 3.3 Linear schematic of dosing regimen. In phase I, mice weretreated by gavage with 50mg/kg OSU-HDAC42 of vehicle three times per weekfor two weeks, rested one week and treated in a similar manner for two weeks.In phase II, the mice were started on OSU-HDAC42 or vehicle in diet at day 21.In both instances, the mice were allowed to survive until removal criteria weremet.
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Figure 3.4 Engraftment of MET-1 cells in multiple organs. Examples ofNOD/SCID mice inoculated intraperitoneally with 2x107 MET-1 cells. Neoplasticround cells are present in the brain (meninges),stomach, heart, lung, kidney, andliver. All tissues magnified 200X, bar denotes 50 µm.
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Figure 3.5 Oral gavage of OSU-HDAC42 in the NOD/SCID ATL mousemodel. A. Serum IL-2Rα levels of mice during the Phase I study. Solid squaresindicate values for mice administered vehicle only. Open circles indicate valuesfor mice administered OSU-HDAC42. Serum levels of this biomarker do not
differ significantly between the groups at any time. B. Kaplan Meier curve forPhase I in vivo experiments. The solid line represents control mice. Dotted linerepresents the OSU-HDAC42 treated. Treatment of OSU-HDAC42 by oralgavage did not significantly improve survival in mice.
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Figure 3.7 In feed OSU-HDAC42 in the NOD/SCID ATL mouse model. A.Serum IL-2Rα levels of mice during the Phase II study. Solid squares indicatevalues for mice administered vehicle only. Open circles indicate values for miceadministered OSU-HDAC42. Serum levels of this biomarker do not differsignificantly between the groups at any time. B. Kaplan Meier curve for Phase IIin vivo experiments. The solid line represents control mice. Dotted linerepresents the OSU-HDAC42 treated. There is a trend toward prolongedsurvival in the treatment group.
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(1) Lairmore M, Franchini G. Human T-cell Leukemia Virus Types 1 and 2. In:David M.KNIPE, editor. Fields Virology. Fifth ed. Wolters Kluwer/lippincottWilliams & Wilkins; 2007. p. 2071-105.
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effects of the histone deacetylase inhibitor valproic acid on cell cycle,growth suppression and apoptosis in multiple myeloma. Haematologica2006 Feb;91(2):248-51.
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(29) Shimoyama M. Diagnostic criteria and classification of clinical subtypes ofadult T- cell leukaemia-lymphoma. A report from the Lymphoma StudyGroup (1984- 87) Br J Haematol 1991 Nov;79(3):428-37.
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Figure 4.1 Experimental design for rabbit inoculation and treatment withVPA. Twenty New Zealand white rabbits were inoculated with either R49 orJurkat cells. At 0,1,2,4,6,8 weeks, whole blood was collected from the centralauricular artery and processed for hematology, VPA levels, humoral response,viral load, and viral production.
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Figure 4.2 Linear timeline of valproic acid administration. All rabbits wereinoculated with R49 or control cells at week 0. Group 1 received VPA starting at
week zero, three times per week ending at week four. Group 2 received VPAbeginning at week four of infection through week eight. Group 3 received salinebeginning at week zero through week four.
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Figure 4.3 Morphology of atypical lymphocytes. Atypical lymphocytes arelarger than normal and had at least two nuclear indentations that were greaterthan 1/3 of the nuclear diameter. Panel A is a normal small lymphocyte. Panel B
represents a reactive lymphocyte. Panel C is a representative atypicallymphocyte
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BFigure 4.4 Hematologic values by differential cell count. A: Percent of whiteblood cells that are lymphocytes. There is a marked variation in the percentlymphocytes in group 1. This fluctuation is not observed in group 2 or group3.
Grey bars denote duration of VPA treatment. B. Percent Atypical lymphocytes. Atypical lymphocyte percentages increase at week 1 in both group 2 and group3. This is not observed in group 1.
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Figure 4.5 Rabbit serum response to HTLV-1. The antibody response to
HTLV-1 infection in the rabbits at eight weeks is similar among the groups.Rabbits 4 and 8 were inoculated with Jurkats and remained uninfectedthroughout the study.
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Figure 4.6 Grading of western blot strip intensity. Four serum antibody
responses were measured at each timepoint in each infected rabbit. Responseswere rated 0-3 based on intensity. Solid lines represent group 1. Dotted linesrepresent group 2. Dashed lines represent group 3.
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