Targeted therapy in chronic lymphocytic leukemia: Past, present, and future

Clinical Therapeutics

Volumn 35, Issue 9, 2013, Pages 1258-1270

  Danilov, Alexey V ^a  

^a DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

Author keywords

B cell receptor; Chronic lymphocytic leukemia; Ibrutinib; NF B

Indexed keywords

ALEMTUZUMAB; ANTILEUKEMIC AGENT; B LYMPHOCYTE RECEPTOR; BENDAMUSTINE; BRUTON TYROSINE KINASE; DASATINIB; DINACICLIB; FOSTAMATINIB; IBRUTINIB; IDELALISIB; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LYMPHOCYTE MEMBRANE IMMUNOGLOBULIN; OFATUMUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE DELTA; PHOSPHOLIPASE C GAMMA2; RITUXIMAB; UNCLASSIFIED DRUG;

ARTHRALGIA; CALCIUM CELL LEVEL; CANCER CHEMOTHERAPY; CANCER GROWTH; CHRONIC LYMPHATIC LEUKEMIA; CROSS LINKING; DRUG ERUPTION; ENZYME PHOSPHORYLATION; FATIGUE; FOLLICULAR LYMPHOMA; FOLLOW UP; HUMAN; IMMUNOBLOTTING; LARGE CELL LYMPHOMA; LIGAND BINDING; LYMPHADENOPATHY; LYMPHOCYTOSIS; MANTLE CELL LYMPHOMA; MEDICAL RECORD REVIEW; MEDLINE; MOLECULE; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; NONHODGKIN LYMPHOMA; PROGRESSION FREE SURVIVAL; PUBLICATION; REVIEW; SIGNAL TRANSDUCTION; UNITED STATES; UPPER RESPIRATORY TRACT INFECTION;

B-CELL RECEPTOR; CHRONIC LYMPHOCYTIC LEUKEMIA; IBRUTINIB; NF-ΚB;

AGED; ANTINEOPLASTIC AGENTS; B-LYMPHOCYTES; CLINICAL TRIALS AS TOPIC; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MOLECULAR TARGETED THERAPY; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; PURINES; PYRAZOLES; PYRIMIDINES; QUINAZOLINONES; RECEPTORS, ANTIGEN, B-CELL; SIGNAL TRANSDUCTION;

EID: 84884339766     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2013.08.004     Document Type: Review

References (91)

1. Howlader N NA, Krapcho M, Garshell J, eds. SEER Cancer Statistics Review, 1975-2010. Accessed September 9, 2013. http://seer.cancer.gov/csr/1975_2010/.
2. Zent C.S., Kyasa M.J., Evans R., et al. Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data. Cancer 2001, 92:1325-1330.
3. Kristinsson S.Y., Dickman P.W., Wilson W.H., et al. Improved survival in chronic lymphocytic leukemia in the past decade: a population-based study including 11,179 patients diagnosed between 1973-2003 in Sweden. Haematologica 2009, 94:1259-1265.
4. Brenner H., Gondos A., Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood 2008, 111:4916-4921.
5. Galton D.A., Israels L.G., Nabarro J.D., et al. Clinical trials of p-(di-2-chloroethylamino)-phenylbutyric acid (CB 1348) in malignant lymphoma. Br Med J 1955, 2:1172-1176.
6. Shaw RK, BDR, Silberman HR, Frei E III. A study of prednisone in chronic lymphocytic leukemia. Blood. 1961;17:182-195.
7. Keating M.J., O'Brien S., Albitar M., et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005, 23:4079-4088.
8. Byrd J.C., Rai K., Peterson B.L., et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005, 105:49-53.
9. Tam C.S., O'Brien S., Wierda W., et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008, 112:975-980.
10. Smolej L., Brychtova Y., Specek M., et al. Low-dose fludarabine and cyclophosphamide combined with rituximab is a safe and effective treatment option for elderly and comorbid patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: preliminary results of a Project Q-lite, by the Czech CLL Study Group, XIV International Workshop on CLL. Houston, TX. Clinical Lymphoma Myeloma & Leukemia 2011, S261.
11. Mulligan S.P., Gill D., Turner P., et al. Safety and tolerability of oral fludarabine, with or without oral cyclophosphamide and intravenous rituximab therapy, in previously untreated patients with chronic lymphocytic leukemia aged 65 years or older: second interim analysis from the Australian Leukemia and Lymphoma Group and CLL Australian Research Consortium CLL5 Study. XIV International Workshop on CLL. Houston, TX. Clinical Lymphoma, Myeloma & Leukemia 2011, S259-S260.
12. Thurmes P., Call T., Slager S., et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008, 49:49-56.
13. Rai K.R., Peterson B.L., Appelbaum F.R., et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000, 343:1750-1757.
14. Eichhorst B.F., Busch R., Hopfinger G., et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006, 107:885-891.
15. Catovsky D., Richards S., Matutes E., et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007, 370:230-239.
16. Flinn I.W., Neuberg D.S., Grever M.R., et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007, 25:793-798.
17. Landau D.A., Carter S.L., Stojanov P., et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013, 152:714-726.
18. Auphan N., DiDonato J.A., Rosette C., et al. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995, 270:286-290.
19. Bailey S., Hall A.G., Pearson A.D., et al. Glucocorticoid resistance and the AP-1 transcription factor in leukaemia. Adv Exp Med Biol 1999, 457:615-619.
20. McLaughlin P., Grillo-Lopez A.J., Link B.K., et al. 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, 16:2825-2833.
21. Byrd J.C., Murphy T., Howard R.S., et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001, 19:2153-2164.
22. Stephens D.M., Byrd J.C. Improving the treatment outcome of patients with chronic lymphocytic leukemia through targeted antibody therapy. Hematol Oncol Clin North Am 2013, 27:303-327.
23. Cang S., Mukhi N., Wang K., et al. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol 2012, 5:64.
24. Kurosaki T. Regulation of B-cell signal transduction by adaptor proteins. Nat Rev Immunol 2002, 2:354-363.
25. Messmer B.T., Albesiano E., Efremov D.G., et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med 2004, 200:519-525.
26. Tobin G., Thunberg U., Karlsson K., et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood 2004, 104:2879-2885.
27. Stevenson F.K., Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004, 103:4389-4395.
28. Lankester A.C., Schijndel G.M., Pakker N.G., et al. Antigen receptor function in chronic lymphocytic leukemia B cells. Leuk Lymphoma 1996, 24:27-33.
29. Lanham S., Hamblin T., Oscier D., et al. Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 2003, 101:1087-1093.
30. Allsup D.J., Kamiguti A.S., Lin K., et al. B-cell receptor translocation to lipid rafts and associated signaling differ between prognostically important subgroups of chronic lymphocytic leukemia. Cancer Res 2005, 65:7328-7337.
31. Cutrona G., Colombo M., Matis S., et al. Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells. Haematologica 2008, 93:413-422.
32. Mockridge C.I., Potter K.N., Wheatley I., et al. Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood 2007, 109:4424-4431.
33. Hoellenriegel J., Meadows S.A., Sivina M., et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011, 118:3603-3612.
34. Hallek M., Cheson B.D., Catovsky D., et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008, 111:5446-5456.
35. Wyndham H., Wilson J.F., Goy A., et al. The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, Phase 2 study. Blood 2012, 120:686.
36. Burger J.A., Keating M.J., Wierda W.G., et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Blood 2012, 120:187.
37. Fowler N.H., Advani R.H., Sharman J., et al. The Bruton's tyrosine kinase inhibitor ibrutinib (PCI-32765) is active and tolerated in relapsed follicular lymphoma. Blood 2012, 156.
38. Wang M., Rule S.A., Martin P., et al. Interim results of an international, multicenter, Phase 2 study of Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. Blood 2012, 120:904.
39. Byrd J.C., Furman R.R., Coutre S., et al. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in a Phase Ib/II study. Blood 2012, 120:189.
40. Pettitt A.R., Jackson R., Carruthers S., et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol 2012, 30:1647-1655.
41. Castro J.E., James D.F., Sandoval-Sus J.D., et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia 2009, 23:1779-1789.
42. Brown JR. Ibrutinib in chronic lymphocytic leukemia and B cell malignancies. Leuk Lymphoma. 2013 June 24 [E-pub ahead of print].
43. Herman S.E., Gordon A.L., Wagner A.J., et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010, 116:2078-2088.
44. Furman R.R., Byrd J.C., Brown J.R., et al. CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. ASH Annual Meeting. Blood 2010, 116:55.
45. Fowler NH, dVS, Schreder MT, et al. Combinations of the phosphatidylinositol 3-kinase-delta (PI3Kδ) inhibitor Gs-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent non-Hodgkin lymphoma: results from a Phase I study, ASH Annual Meeting. Atlanta, GA. Blood. 2012;120:3645.
46. Coutre S.E., Leonard J.P., Furman R.R., et al. Combinations of the selective phosphatidylinositol 3-kinase-delta (PI3Kdelta) inhibitor GS-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): results from a Phase I study, ASH Annual Meeting. Atlanta, GA. Blood 2012, 120:191.
47. Herko A., Mavis C., Czuczman M.S., Hernandez F. AMG 319, a novel inhibitor of phosphoinositide-3 kinase delta (PI3Kd), demonstrates activity in lymphoma pre-clinical models. Blood 2012, 120:3718.
48. Flinn I.W., Horwitz S.M., Patel M., et al. Clinical safety and activity in a Phase 1 trial of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-gamma/delta in patients with advanced hematologic malignancies. Blood 2012, 120:3663.
49. Iyengar S., Clear A., Bodor C., et al. P110alpha-mediated constitutive PI3K signaling limits the efficacy of p110delta-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood 2013, 121:2274-2284.
50. Braselmann S., Taylor V., Zhao H., et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006, 319:998-1008.
51. Friedberg J.W., Sharman J., Sweetenham J., et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010, 115:2578-2585.
52. Hoellenriegel J., Coffey G.P., Sinha U., et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia 2012, 26:1576-1583.
53. Chen R., Wierda W.G., Chubb S., et al. Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood 2009, 113:4637-4645.
54. Chen R., Keating M.J., Gandhi V., et al. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood 2005, 106:2513-2519.
55. Cosimo E., McCaig A.M., Carter-Brzezinski L.J., et al. Inhibition of NF-κB-mediated signaling by the CDK inhibitor CR8 overcomes prosurvival stimuli to induce apoptosis in chronic lymphocytic leukemia cells. Clin Cancer Res 2013, 19:2393-2405.
56. Parry D., Guzi T., Shanahan F., et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther 2010, 9:2344-2353.
57. Johnson A.J., Yeh Y.Y., Smith L.L., et al. The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. Leukemia 2012, 26:2554-2557.
58. Flinn JM, JJA, Andritsos L, et al. Phase I study of the CDK inhibitor dinaciclib (SCH727965) in patients with relapsed/refractory CLL. J Clin Oncol. 2011; pp 6623.
59. Baiocchi R.A., Flynn J.M., Jones J.A., et al. Early evidence of anti-lymphoma activity of the cyclin dependent kinase inhibitor dinaciclib (SCH 727965) in heavily pre-treated low grade lymphoma and diffuse large cell lymphoma patients. Blood 2010, 3966.
60. Karaman M.W., Herrgard S., Treiber D.K., et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008, 26:127-132.
61. Meade J., Fernandez C., Turner M. The tyrosine kinase Lyn is required for B cell development beyond the T1 stage in the spleen: rescue by over-expression of Bcl-2. Eur J Immunol 2002, 32:1029-1034.
62. Contri A., Brunati A.M., Trentin L., et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest 2005, 115:369-378.
63. McCaig A.M., Cosimo E., Leach M.T., et al. Dasatinib inhibits B cell receptor signalling in chronic lymphocytic leukaemia but novel combination approaches are required to overcome additional pro-survival microenvironmental signals. Br J Haematol 2011, 153:199-211.
64. Amrein P.C., Attar E.C., Takvorian T., et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 2011, 17:2977-2986.
65. Weiss A., Littman D.R. Signal transduction by lymphocyte antigen receptors. Cell 1994, 76:263-274.
66. Paterson J.C., Tedoldi S., Craxton A., et al. The differential expression of LCK and BAFF-receptor and their role in apoptosis in human lymphomas. Haematologica 2006, 91:772-780.
67. Talab F., Allen J.C., Thompson V., et al. LCK is an important mediator of B cell receptor signaling in chronic lymphocytic leukaemia cells. Mol Cancer Res 2013.
68. Rosenwald A., Alizadeh A.A., Widhopf G., et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001, 194:1639-1647.
69. Castro J.E., Prada C.E., Loria O., et al. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 2005, 106:2506-2512.
70. Chen L., Apgar J., Huynh L., et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 2005, 105:2036-2041.
71. Gobessi S., Laurenti L., Longo P.G., et al. ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Blood 2007, 109:2032-2039.
72. Chen L., Widhopf G., Huynh L., et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2002, 100:4609-4614.
73. Chen L., Huynh L., Apgar J., et al. ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia. Blood 2008, 111:2685-2692.
74. Soderquist R., Bates D.J., Danilov A.V., et al. Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo. Leukemia 2013.
75. Rickert R.C., Jellusova J., Miletic A.V. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011, 244:115-133.
76. Tromp J.M., Tonino S.H., Elias J.A., et al. Dichotomy in NF-kappaB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering. Oncogene 2010, 29:5071-5082.
77. Vogler M., Butterworth M., Majid A., et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009, 113:4403-4413.
78. Hewamana S., Alghazal S., Lin T.T., et al. The NF-kappaB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target. Blood 2008, 111:4681-4689.
79. Pickering B.M., de Mel S., Lee M., et al. Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells. Oncogene 2007, 26:1166-1177.
80. Dunleavy K., Pittaluga S., Czuczman M.S., et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 2009, 113:6069-6076.
81. Pham L.V., Tamayo A.T., Yoshimura L.C., et al. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 2003, 171:88-95.
82. Pahler J.C., Ruiz S., Niemer I., et al. Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. Clin Cancer Res 2003, 9:4570-4577.
83. Faderl S., Rai K., Gribben J., et al. Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer 2006, 107:916-924.
84. Liu F.T., Agrawal S.G., Movasaghi Z., et al. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood 2008, 112:3835-3846.
85. Zhang L., Qian J., Ou Z., et al. Carfilzomib, an irreversible proteasome inhibitor, induces long-term growth inhibition of mantle cell lymphoma in vivo. ASH Annual Meeting. Blood 2011, 3740.
86. Gupta S.V., Hertlein E., Lu Y., et al. The proteasome inhibitor carfilzomib functions independently of p53 to induce cytotoxicity and an atypical NF-kappaB response in chronic lymphocytic leukemia cells. Clin Cancer Res 2013, 19:2406-2419.
87. Herishanu Y., Perez-Galan P., Liu D., et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011, 117:563-574.
88. Alsina M., Trudel S., Furman R.R., et al. A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res 2012, 18:4830-4840.
89. Swords R.T., Kelly K.R., Smith P.G., et al. Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 2010, 115:3796-3800.
90. Milhollen M.A., Traore T., Adams-Duffy J., et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood 2010, 116:1515-1523.
91. Soucy T.A., Smith P.G., Rolfe M. Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer. Clin Cancer Res 2009, 15:3912-3916.