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Clinical Cancer Drugs

Editor-in-Chief

ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

Novel Pharmacodynamic Approach to Assess Obatoclax (GX15-070) and Bortezomib (BTZ) Synergism in Non-Hodgkin’s Lymphoma

Author(s): Karen E. Thudium, Lance Wollenberg, Cory Mavis, Jenny Gu, Gerald J. Fetterly, Myron S. Czuczman and Francisco J. Hernandez-Ilizaliturri

Volume 2, Issue 1, 2015

Page: [44 - 53] Pages: 10

DOI: 10.2174/2212697X02666150128003659

Price: $65

Abstract

Obatoclax (GX15-070) is a small molecule that binds to Bcl-2 family proteins (Bcl-2, Bcl- XL, and MCL-2) and has demonstrated efficacy in reinitiating programmed cell death. We previously demonstrated the synergistic effects of GX15-070 in combination with cytotoxic agents in rituximab sensitive and rituximab resistant models. Our aim was therefore to develop a pharmacodynamic model to characterize the degree of interaction between GX15-070 and Bortezomib (BTZ) on cells isolated from Non-Hodgkin’s Lymphoma (NHL) patients to understand the role of combination therapy. Cells were exposed to escalating concentrations of GX15-070 and BTZ for 48 hours; data were fit to pharmacodynamic model. Patient demographics, BCL-2 status, Ki67%, CD20, lifetime-rituximab dose and response to therapy were obtained for all patients and correlated with observed pharmacodynamic endpoints. The greatest degree of synergy was seen in the MCL, MZL, and untreated DLBCL-GCB. Previously un-treated B-cell lymphoma (DLBCL-ABC, DLBCL-GCB/transformed, FL) and relapsed refractory B-cell lymphoma (DLBCL-ABC, FL) demonstrate a combination shift towards a possible additive effect. The majority of the patients had DLBCL or FL, and 29% had relapsed/refractory disease. These results demonstrate synergism in NHL and may support the use of this combination in a future clinical trial.

Keywords: Bortezomib, NHL, obatoclax, pharmacodynamic modeling, synergy.

Graphical Abstract

[1]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29.
[2]
Piro LD, White CA, Grillo-Lopez AJ, Janakiraman N, Saven A, Beck TM. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1999; 10(6): 655-61.
[3]
McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16(8): 2825-33.
[4]
Leget GA, Czuczman MS. Use of rituximab, the new FDA-approved antibody. Curr Opin Oncol 1998; 10(6): 548-51.
[5]
Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, Gordon L, LoBuglio AF. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999; 17(1): 268-76.
[6]
Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106(12): 3725-32.
[7]
Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105(4): 1417-23.
[8]
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346(4): 235-42.
[9]
Forstpointner R, Unterhalt M, Dreyling M, Bock HP, Repp R, Wandt H. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006; 108(13): 4003-8.
[10]
Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7(5): 379-91.
[11]
Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 2005; 23(33): 8447-52.
[12]
Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2006; 24(10): 1582-9.
[13]
Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000; 18(17): 3135-43.
[14]
Davis TA, Czerwinski DK, Levy R. Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. Clin Cancer Res 1999; 5(3): 611-5.
[15]
Czuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H. Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res 2008; 14(5): 1561-70.
[16]
Olejniczak SH, Hernandez-Ilizaliturri FJ, Clements JL, Czuczman MS. Acquired resistance to rituximab is associated with chemotherapy resistance resulting from decreased Bax and Bak expression. Clin Cancer Res 2008; 14(5): 1550-60.
[17]
Ramanarayanan J, Hernandez-Ilizaliturri FJ, Chanan-Khan A, Czuczman MS. Pro-apoptotic therapy with the oligonucleotide Genasense (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab. Br J Haematol 2004; 127(5): 519-30.
[18]
O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007; 25(9): 1114-20.
[19]
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435(7042): 677-81.
[20]
Goldsmith KC, Liu X, Dam V, Morgan BT, Shabbout M, Cnaan A. BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma. Oncogene 2006; 25(33): 4525-33.
[21]
Brem EA, Thudium K, Khubchandani S, Tsai PC, Olejniczak SH, Bhat S. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol 2011; 153(5): 599-611.
[22]
Promega. Technical Bulletin CellTiter-Glo Luminescent Cell Viability Assay. In: Promega, editor.
[23]
Ariens EJ. [Molecular Basis of Drug Action] Med Arh 1964; 18: 21-38.
[24]
Chakraborty A, Jusko WJ. Pharmacodynamic interaction of recombinant human interleukin-10 and prednisolone using in vitro whole blood lymphocyte proliferation. J Pharm Sci 2002; 91(5): 1334-42.
[25]
D’Argenio D, Schumitzky A, Wang X. ADAPT 5 User’s Guide: Pharmacokinetic/Pharmacodynamic System Analysis Software. Los Angeles: Biomedical Simulations Resource 2009.
[26]
Cases A, Esforzado N, Mas M, Ricart MJ, Cruzado JM. Pure red blood cell aplasia associated with neutralizing antibodies against erythropoietin induced by epoetin alfa:a new form of acquired erythroblastopenia in auremic patients. Nefrologia 2003; 23(3): 266-70.
[27]
Szczuraszek K, Mazur G, Jelen M, Dziegiel P, Surowiak P, Zabel M. Prognostic significance of Ki-67 antigen expression in non-Hodgkin’s lymphomas. Anticancer Res 2008; 28(2A): 1113-8.
[28]
Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003; 22(47): 7359-68.
[29]
Rezvani AR, Maloney DG. Rituximab resistance. Best Pract Res Clin Haematol 2011; 24(2): 203-16.
[30]
Admetlla J, Leal C, Ricart A. Management of diabetes at high altitude. Br J Sports Med 2001; 35(4): 282-3.
[31]
O’Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 2009; 113(2): 299-305.
[32]
Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E. Human Metabolism Of The Proteasome Inhibitor Bortezomib: Identification Of Circulating Metabolites. Drug Metab Dispos 2005; 33(6): 771-7.

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