An evidence-based review of obatoclax mesylate in the treatment of hematological malignancies

References

• Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permea-bilization in cell death. Physiol Rev. 2007;87(1):99–163.
   PubMed Web of Science ®Google Scholar
• Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19(1):107–120.
   PubMed Web of Science ®Google Scholar
• Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11(9):621–632.
   PubMed Web of Science ®Google Scholar
• Happo L, Strasser A, Cory S. BH3-only proteins in apoptosis at a glance. J Cell Sci. 2012;125(Pt 5):1081–1087.
   PubMed Web of Science ®Google Scholar
• Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985;228(4706):1440–1443.
   PubMed Web of Science ®Google Scholar
• Pegoraro L, Palumbo A, Erikson J, et al. A 14;18 and an 8;14 chromosome translocation in a cell line derived from an acute B-cell leukemia. Proc Natl Acad Sci U SA. 1984;81(22):7166–7170.
   PubMedGoogle Scholar
• McDonnell TJ, Deane N, Platt FM, et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989;57(1):79–88.
   PubMed Web of Science ®Google Scholar
• Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440–442.
   PubMed Web of Science ®Google Scholar
• Korsmeyer SJ. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood. 1992;80(4):879–886.
   PubMed Web of Science ®Google Scholar
• Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9(1):47–59.
   PubMed Web of Science ®Google Scholar
• Kitada S, Pedersen IM, Schimmer AD, Reed JC. Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene. 2002;21(21):3459–3474.
   PubMed Web of Science ®Google Scholar
• Soltani-Arabshahi R, Leboeuf C, Rivet J, et al. Bcl-xL gene expression correlated with lower apoptotic cell numbers and shorter progressionfree survival in PCFCL. J Invest Dermatol. 2009;129(7):1703–1709.
   PubMed Web of Science ®Google Scholar
• Ni Chonghaile T, Sarosiek KA, Vo TT, et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334(6059):1129–1133.
   PubMed Web of Science ®Google Scholar
• Kornblau SM, Vu HT, Ruvolo P, et al. BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia. Clin Cancer Res. 2000;6(4):1401–1409.
   PubMed Web of Science ®Google Scholar
• Del Poeta G, Venditti A, Del Principe MI, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2003;101(6):2125–2131.
   PubMed Web of Science ®Google Scholar
• Tôthôva E, Fricova M, Stecova N, Kafkova A, Elbertova A. High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Neoplasma. 2002;49(3):141–144.
   PubMed Web of Science ®Google Scholar
• Kitada S, Andersen J, Akar S, et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood. 1998;91(9):3379–3389.
   PubMed Web of Science ®Google Scholar
• Wuillème-Toumi S, Robillard N, Gomez P, et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia. 2005;19(7):1248–1252.
   PubMed Web of Science ®Google Scholar
• Walensky LD, Kung AL, Escher I, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 2004;305(5689):1466–1470.
   PubMed Web of Science ®Google Scholar
• Raynaud FI, Orr RM, Goddard PM, et al. Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice. J Pharmacol Exp Ther. 1997;281(1):420–427.
   PubMed Web of Science ®Google Scholar
• Advani PP, Paulus A, Masood A, Sher T, Chanan-Khan A. Pharmacokinetic evaluation of oblimersen sodium for the treatment of chronic lymphocytic leukemia. Expert Opin Drug Metab Toxicol. 2011;7(6):765–774.
   PubMed Web of Science ®Google Scholar
• O’Brien S, Moore JO, Boyd TE, et al. 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):1114–1120.
   PubMed Web of Science ®Google Scholar
• O’Brien S, Moore JO, Boyd TE, et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009;27(31):5208–5212.
   PubMed Web of Science ®Google Scholar
• Limited AI. Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide - Genta, G 3139, GC 3139, oblimersen sodium. Drugs R D. 2007;8(5):321–334.
   PubMedGoogle Scholar
• Chanan-Khan AA, Niesvizky R, Hohl RJ, et al. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma. 2009;50(4):559–565.
   PubMed Web of Science ®Google Scholar
• Zhai D, Jin C, Satterthwait AC, Reed JC. Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ. 2006;13(8):1419–1421.
   PubMed Web of Science ®Google Scholar
• Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–3428.
   PubMed Web of Science ®Google Scholar
• Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M. Discovery. characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem. 2003;46(20):4259–4264.
   PubMed Web of Science ®Google Scholar
• Shore GC, Viallet J. Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. Hematology Am Soc Hematol Educ Program. 2005:226–230.
   PubMedGoogle Scholar
• Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677–681.
   PubMed Web of Science ®Google Scholar
• Rudin CM, Hann CL, Garon EB, et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012;18(11):3163–3169.
   PubMed Web of Science ®Google Scholar
• Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11(12):1149–1159.
   PubMed Web of Science ®Google Scholar
• Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127–3135.
   PubMed Web of Science ®Google Scholar
• Leber B, Geng F, Kale J, Andrews DW. Drugs targeting Bcl-2 family members as an emerging strategy in cancer. Expert Rev Mol Med. 2010;12:e28.
   PubMed Web of Science ®Google Scholar
• Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013.
   Google Scholar
• ClinicalTrials.gov, A Service of the US National Institutes of Health [web site on the Internet]. Available from: http://clinicaltrials.gov, Accessed December 12, 2012.
   Google Scholar
• Heist RS, Fain J, Chinnasami B, et al. Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol. 2010;5(10):1637–1643.
   PubMed Web of Science ®Google Scholar
• Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res. 2009;15(9):3172–3176.
   PubMed Web of Science ®Google Scholar
• Ready N, Karaseva NA, Orlov SV et al. Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer. J Thorac Oncol. 2011;6(4):781–785.
   PubMed Web of Science ®Google Scholar
• Baggstrom MQ, Qi Y, Koczywas M, et al. A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol. 2011;6(10):1757–1760.
   PubMed Web of Science ®Google Scholar
• Sonpavde G, Matveev V Burke JM, et al. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol. 2012;23(7):1803–1808.
   PubMed Web of Science ®Google Scholar
• Joudeh J, Claxton D. Obatoclax mesylate: pharmacology and potential for therapy of hematological neoplasms. Expert Opin Investig Drugs. 2012;21(3):363–373.
   PubMed Web of Science ®Google Scholar
• Nguyen M, Marcellus RC, Roulston A, et al. Small molecule obatoclax (GX15–070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104(49):19512–19517.
   PubMed Web of Science ®Google Scholar
• Hussain SR, Cheney CM, Johnson AJ, et al. Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity. Clin Cancer Res. 2007;13(7):2144–2150.
   PubMed Web of Science ®Google Scholar
• Derenne S, Monia B, Dean NM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 2002;100(1):194–199.
   PubMed Web of Science ®Google Scholar
• Wenzel SS, Grau M, Mavis C, et al. MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma. Leukemia. 2012.
   PubMedGoogle Scholar
• Konopleva M, Watt J, Contractor R, et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15–070 (obatoclax). Cancer Res. 2008;68(9):3413–3420.
   PubMed Web of Science ®Google Scholar
• Buet D, Gallais I, Lauret E, et al. Cotargeting signaling pathways driving survival and cell cycle circumvents resistance to Kit inhibitors in leukemia. Blood. 2012;119(18):4228–4241.
   PubMed Web of Science ®Google Scholar
• Aichberger KJ, Gleixner KV, Mirkina I, et al. Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs. Blood. 2009;114(26):5342–5351.
   PubMed Web of Science ®Google Scholar
• Bonapace L, Bornhauser BC, Schmitz M, et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest. 2010;120(4):1310–1323.
   PubMed Web of Science ®Google Scholar
• Heidari N, Hicks MA, Harada H. GX15–070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death Dis. 2010;1:e76.
   PubMed Web of Science ®Google Scholar
• Herishanu Y, Gibellini F, Njuguna N, et al. Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1. LeukLymphoma. 2011;52(9):1758–1769.
   PubMed Web of Science ®Google Scholar
• Vogler M, Weber K, Dinsdale D, et al. Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ. 2009;16(7):1030–1039.
   PubMed Web of Science ®Google Scholar
• Pérez-Galan P, Roué G, Lôpez-Guerra M, et al. BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15–070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia. 2008;22(9):1712–1720.
   PubMed Web of Science ®Google Scholar
• Campàs C, Cosialls AM, Barragan M, et al. Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol. 2006;34(12):1663–1669.
   PubMed Web of Science ®Google Scholar
• Brem EA, Thudium K, Khubchandani S, et al. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol. 2011;153(5):599–611.
   PubMed Web of Science ®Google Scholar
• Pérez-Galan P, Roué G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15–070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109(10):4441–4449.
   PubMed Web of Science ®Google Scholar
• Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015–070) in multiple myeloma. Blood. 2007;109(12):5430–5438.
   PubMed Web of Science ®Google Scholar
• Albershardt TC, Salerni BL, Soderquist RS, et al. Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem. 2011;286(28):24882–24895.
   PubMed Web of Science ®Google Scholar
• Dasmahapatra G, Lembersky D, Son MP, et al. Obatoclax interacts synergistically with the irreversible proteasome inhibitor carfilzomib in GC- and ABC-DLBCL cells in vitro and in vivo. Mol Cancer Ther. 2012;11(5):1122–1132.
   PubMed Web of Science ®Google Scholar
• Lôpez-Guerra M, Roué G, Pérez-Galan P, et al. p65 activity and ZAP- 70 status predict the sensitivity of chronic lymphocytic leukemia cells to the selective IkappaB kinase inhibitor BMS-345541. Clin Cancer Res. 2009;15(8):2767–2776.
   PubMed Web of Science ®Google Scholar
• Rahmani M, Aust MM, Attkisson E, Williams DC Jr, FerreiraGonzalez A, Grant S. Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process. Blood. 2012;119(25):6089–6098.
   PubMed Web of Science ®Google Scholar
• Chen S, Dai Y, Pei XY, et al. CDK inhibitors upregulate BH3-only proteins to sensitize human myeloma cells to BH3 mimetic therapies. Cancer Res. 2012;72(16):4225–4237.
   PubMed Web of Science ®Google Scholar
• Martinez-Paniagua MA, Baritaki S, Huerta-Yepez S, et al. Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15–070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis. Cell Cycle. 2011;10(16):2792–2805.
   PubMed Web of Science ®Google Scholar
• Jôna A, Khaskhely N, Buglio D, et al. The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors. Exp Hematol. 2011;39(10):1007–1017. e1.
   PubMed Web of Science ®Google Scholar
• Wei Y, Kadia T, Tong W, et al. The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15–070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Autophagy. 2010;6(7):976–978.
   PubMed Web of Science ®Google Scholar
• Wei Y, Kadia T, Tong W, et al. The combination of a histone deacetylase inhibitor with the Bcl-2 homology domain-3 mimetic GX15–070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Clin Cancer Res. 2010;16(15):3923–3932.
   PubMed Web of Science ®Google Scholar
• Samuel S, Tumilasci VF, Oliere S, et al. VSV oncolysis in combination with the BCL-2 inhibitor obatoclax overcomes apoptosis resistance in chronic lymphocytic leukemia. Mol Ther. 2010;18(12):2094–2103.
   PubMed Web of Science ®Google Scholar
• Campbell CJ, Lee JB, Levadoux-Martin M, et al. The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for selfrenewal capacity. Blood. 2010;116(9):1433–1442.
   PubMed Web of Science ®Google Scholar
• O’Brien SM, Claxton DF, Crump M, et al. 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.
   PubMed Web of Science ®Google Scholar
• Schimmer AD, O’Brien S, Kantarjian H, et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(24):8295–8301.
   PubMed Web of Science ®Google Scholar
• Hwang JJ, Kuruvilla J, Mendelson D, et al. Phase I dose finding studies of obatoclax (GX15–070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010;16(15):4038–4045.
   PubMed Web of Science ®Google Scholar
• Oki Y, Copeland A, Hagemeister F, et al. Experience with obatoclax mesylate (GX15–070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. Blood. 2012;119(9):2171–2172.
   PubMed Web of Science ®Google Scholar
• Parikh SA, Kantarjian H, Schimmer A, et al. Phase II study of obatoclax mesylate (GX15–070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leuk. 2010;10(4):285–289.
   PubMed Web of Science ®Google Scholar
• Stewart AK, Trudel S, Zonder JA, et al. Phase I trial of obatoclax mesylate in combination with bortezomib for treatment of relapsed multiple myeloma. J Clin Oncol. 2012;30(Suppl 15):Abstract 8013.
   Web of Science ®Google Scholar
• Jiang N, Reich CF 3rd, Pisetsky DS. Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells. Blood. 2003;102(6):2243–2250.
   PubMed Web of Science ®Google Scholar
• Brown JR, Tesar B, Werner L, et al. Obatoclax in combination with fludarabine and rituximab (FR) is well-tolerated and shows promising clinical activity in relapsed CLL/SLL. Blood (ASH Annual Meeting Abstracts). 2011;118(21):Abstract 2865.
   Google Scholar
• Certo M, Del Gaizo Moore V Nishino M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9(5):351–365.
   PubMed Web of Science ®Google Scholar
• Del Gaizo Moore V Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007;117(1):112–121.
   PubMed Web of Science ®Google Scholar
• Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007;12(2):171–185.
   PubMed Web of Science ®Google Scholar
• Vo TT, Ryan J, Carrasco R, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 2012;151(2):344–355.
   PubMed Web of Science ®Google Scholar
• Goy AG, Ford P, Feldman T, et al. A phase I trial of the pan Bcl-2 family inhibitor obatoclax mesylate (GX15–070) in combination with bortezomib in patients with relapsed/refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2007;110(11):Abstract 2569.
   Google Scholar