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  • Review Article
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Beyond chemotherapy: new agents for targeted treatment of lymphoma

Nature Reviews Clinical Oncology volume 8, pages 85–96 (2011)Cite this article

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A Correction to this article was published on 02 March 2011

Abstract

An improved understanding of the molecular biology of cancer cell growth and survival and the role of the microenvironment in supporting the survival of cancer cells, including lymphoma cells, has led to the identification of a number of potential therapeutic targets. Despite these advances, drug development for lymphoma remains slow, inefficient, and frequently unfocused. Future work should focus on identifying 'driver' molecular defects of oncogenic pathways that can be targeted therapeutically, discovering predictive biomarkers for treatment response, and prioritizing promising drugs to accelerate their approval. This Review summarizes the current development status of novel agents for lymphoma and discusses strategies to move the field forward.

Key Points

  • Lymphomas are heterogeneous group of malignancies with an estimated 74,000 new cases in 2009 in the USA

  • Several agents have been approved by the FDA for the treatment of relapsed non-Hodgkin lymphoma, but no drug has been approved for Hodgkin lymphoma in the past 30 years

  • Antibody–drug conjugates and small-molecule inhibitors that target well-defined oncogenic pathways are being evaluated for the treatment of lymphoma and have shown promising results

  • In the future, biomarker-driven clinical trials will be important for the development of personalized treatment strategies

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Figure 1: Targeted therapy for lymphoma treatment.
Figure 2: Targeting the PI3K/Akt/mTOR pathway to treat lymphoma.
Figure 3: Summary of single agents with activity in patients with relapsed diffuse large B-cell lymphoma.

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References

  1. Jemal, A., Center, M. M., Ward, E. & Thun, M. J. Cancer occurrence. Methods Mol. Biol. 471, 3–29 (2009).

    Article  PubMed  Google Scholar 

  2. Zelenetz, A. D. et al. NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's Lymphomas. J. Natl Compr. Canc. Netw. 8, 288–334 (2010).

    Article  PubMed  Google Scholar 

  3. Sridhara, R. et al. Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007. J. Natl Cancer Inst. 102, 230–243 (2010).

    Article  PubMed  Google Scholar 

  4. Cheson, B. D. & Leonard, J. P. Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N. Engl. J. Med. 359, 613–626 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Coiffier, B. et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood 111, 1094–1100 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Hagenbeek, A. et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 111, 5486–5495 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Hagenbeek, A. et al. Evaluation of ofatumumab, a novel human CD20 monoclonal antibody, as single agent therapy in rituximab-refractory follicular lymphoma. Blood (ASH Annual Meeting Abstracts) 114, 935 (2009).

    Google Scholar 

  9. McLaughlin, P. 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. 16, 2825–2833 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Maloney, D. G. Rituximab for follicular lymphoma. Curr. Hematol. Rep. 2, 13–22 (2003).

    PubMed  Google Scholar 

  11. Leonard, J. P. et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma. J. Clin. Oncol. 21, 3051–3059 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Byrd, J. C. et al. Phase 1 study of lumiliximab with detailed pharmacokinetic and pharmacodynamic measurements in patients with relapsed or refractory chronic lymphocytic leukemia. Clin. Cancer Res. 13, 4448–4455 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Baeuerle, P. A. & Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 69, 4941–4944 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Nagorsen, D. et al. Confirmation of safety, efficacy and response duration in non-Hodgkin lymphoma patients treated with 60 μg/m2/d of BiTE(R) antibody blinatumomab. Blood (ASH Annual Meeting Abstracts) 114, 2723 (2009).

    Google Scholar 

  16. Topp, M. S. et al. Report of a phase ii trial of single-agent BiTE(R) antibody blinatumomab in patients with minimal residual disease (MRD) positive B-precursor acute lymphoblastic leukemia (ALL). Blood (ASH Annual Meeting Abstracts) 114, 840 (2009).

    Google Scholar 

  17. Strauss, S. J. et al. Multicenter phase II trial of immunotherapy with the humanized anti-CD22 antibody, epratuzumab, in combination with rituximab, in refractory or recurrent non-Hodgkin's lymphoma. J. Clin. Oncol. 24, 3880–3886 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Micallef, I. N. et al. Final results of NCCTG N0489: Epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (ER-CHOP) in patients with previously untreated diffuse large B-cell lymphoma. J. Clin. Oncol. ASCO Meeting Abstracts 27 (Suppl.), 8508 (2009).

    Google Scholar 

  19. Younes, A. & Kadin, M. E. Emerging applications of the tumor necrosis factor family of ligands and receptors in cancer therapy. J. Clin. Oncol. 21, 3526–3534 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Advani, R. et al. A phase 2 clinical trial of SGN-40 monotherapy in relapsed diffuse large B-cell lymphoma. Blood (ASH Annual Meeting Abstracts) 112, 1000 (2008).

    Google Scholar 

  21. Advani, R. et al. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin's lymphoma. J. Clin. Oncol. 27, 4371–4377 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Younes, A. et al. Results of a phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory non-Hodgkin's lymphoma (NHL) (ETR1-01). Blood (ASH Annual Meeting Abstracts) 106, 489 (2005).

    Google Scholar 

  23. Wang, S. The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway. Oncogene 27, 6207–6215 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Bartlett, N. L. et al. A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies. Blood 111, 1848–1854 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Ansell, S. M. et al. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma. J. Clin. Oncol. 25, 2764–2769 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Blum, K. A. et al. Phase I study of an anti-CD30 Fc engineered humanized monoclonal antibody in Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) patients: Safety, pharmacokinetics (PK), immunogenicity, and efficacy. J. Clin. Oncol. ASCO Meeting Abstracts 27 (Suppl.), 8531 (2009).

    Google Scholar 

  27. Kreitman, R. J. et al. Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies. J. Clin. Oncol. 23, 6719–6729 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Advani, A. et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study. J. Clin. Oncol. 28, 2085–2093 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Dang, N. H. et al. Anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) + rituximab: clinical activity including survival in patients with recurrent/refractory follicular or 'aggressive' lymphoma. Blood (ASH Annual Meeting Abstracts) 114, 584 (2009).

    Google Scholar 

  30. Younes, A. et al. Phase I multi-dose escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous (IV) infusion every 3 weeks to patients with relapsed/ refractory B-cell non-hodgkin's lymphoma (NHL). Blood (ASH Annual Meeting Abstracts) 114, 585 (2009).

    Google Scholar 

  31. Aboukameel, A. et al. Superior anti-tumor activity of the CD19-directed immunotoxin, SAR3419 to rituximab in non-Hodgkin's xenograft animal models: preclinical evaluation. Blood (ASH Annual Meeting Abstracts) 110, 2339 (2007).

    Google Scholar 

  32. Oflazoglu, E., Kissler, K. M., Sievers, E. L., Grewal, I. S. & Gerber, H. P. Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma. Br. J. Haematol. 142, 69–73 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Younes, A. et al. Multiple complete responses in a phase 1 dose-escalation study of the antibody-drug conjugate SGN-35 in patients with relapsed or refractory CD30-positive lymphomas. Blood (ASH Annual Meeting Abstracts) 112, 1006 (2008).

    Google Scholar 

  34. Fanale, M. et al. The antibody-drug conjugate brentuximab vedotin (SGN-35) induced multiple objective responses in patients with relapsed or refractory CD30-positive lymphomas in a phase 1 weekly dosing study. Blood (ASH Annual Meeting Abstracts) 114, 2731 (2009).

    Google Scholar 

  35. Ihle, N. T. & Powis, G. Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol. Cancer Ther. 8, 1–9 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Franke, T. F. PI3K/Akt: getting it right matters. Oncogene 27, 6473–6488 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550–562 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Jaiswal, B. S. et al. Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463–474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Berenjeno, I. M. & Vanhaesebroeck, B. PI3K regulatory subunits lose control in cancer. Cancer Cell 16, 449–450 (2009).

    Article  PubMed  CAS  Google Scholar 

  40. Georgakis, G. V., Yazbeck, V. Y., Li, Y. & Younes, A. Preclinical rationale for therapeutic targeting of mTOR by CC-I779 and rapamycin in Hodgkin lymphoma. J. Clin. Oncol. ASCO Meeting Abstracts 24 (Suppl.), 10070 (2006).

    Google Scholar 

  41. Jücker, M. et al. Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia 16, 894–901 (2002).

    Article  PubMed  Google Scholar 

  42. Morrison, J. A., Gulley, M. L., Pathmanathan, R. & Raab-Traub, N. Differential signaling pathways are activated in the Epstein-Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma. Cancer Res. 64, 5251–5260 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Nagel, S. et al. HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3. Leukemia 19, 841–846 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Renné, C. et al. High expression of several tyrosine kinases and activation of the PI3K/AKT pathway in mediastinal large B cell lymphoma reveals further similarities to Hodgkin lymphoma. Leukemia 21, 780–787 (2007).

    Article  PubMed  CAS  Google Scholar 

  45. Dutton, A., Reynolds, G. M., Dawson, C. W., Young, L. S. & Murray, P. G. Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR. J. Pathol. 205, 498–506 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Gough, N. R. Focus Issue: demystifying mTOR signaling. Sci. Signal. 2, eg5 (2009).

    PubMed  Google Scholar 

  47. Dancey, J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7, 209–219 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307–318 (2009).

    Article  PubMed  CAS  Google Scholar 

  50. Younes, A. Therapeutic activity of mTOR inhibitors in mantle cell lymphoma: clues but no clear answers. Autophagy 4, 707–709 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Zheng, Y. et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J. Immunol. 178, 2163–2170 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Del Bufalo, D. et al. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 66, 5549–5554 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Younes, A. Therapeutic activity of mTOR inhibitors in mantle cell lymphoma: clues but no clear answers. Autophagy 4, 707–709 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Smith, S. M. et al. Activity of single agent temsirolimus (CCI-779) in non-mantle cell non-Hodgkin lymphoma subtypes. J. Clin. Oncol. ASCO Meeting Abstracts 26 (Suppl.), 8514 (2008).

    Google Scholar 

  55. Witzig, T. E. et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol. 23, 5347–5356 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Hess, G. et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 27, 3822–3829 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Courtney, K. D., Corcoran, R. B. & Engelman, J. A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 28, 1075–1083 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao, L. & Vogt, P. K. Class I PI3K in oncogenic cellular transformation. Oncogene 27, 5486–5496 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lannutti, B. J. et al. CAL-101, an oral p110{delta} selective phosphatidylinositol-3-kinase (PI3K) inhibitor for the treatment of B cell malignancies inhibits PI3K signaling, cellular viability and protective signals of the microenvironment. Blood (ASH Annual Meeting Abstracts) 114, 286 (2009).

    Google Scholar 

  60. Flinn, I. W. et al. evidence of clinical activity in a phase 1 study of CAL-101, an oral P110{delta} isoform-selective inhibitor of phosphatidylinositol 3-kinase, in patients with relapsed or refractory B-cell malignancies. Blood (ASH Annual Meeting Abstracts) 114, 922 (2009).

    Google Scholar 

  61. Fisher, R. I. et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 24, 4867–4874 (2006).

    Article  PubMed  Google Scholar 

  62. Blum, K. A. et al. Single agent bortezomib in the treatment of relapsed and refractory Hodgkin lymphoma: cancer and leukemia Group B protocol 50206. Leuk. Lymphoma 48, 1313–1319 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Younes, A., Pro, B. & Fayad, L. Experience with bortezomib for the treatment of patients with relapsed classical Hodgkin lymphoma. Blood 107, 1731–1732 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Dunleavy, K. et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113, 6069–6076 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Xu, W. S., Parmigiani, R. B. & Marks, P. A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541–5552 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Duvic, M. et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109, 31–39 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Piekarz, R. L. et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J. Clin. Oncol. 27, 5410–5417 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Piekarz, R. et al. Final results of a phase 2 NCI multicenter study of romidepsin in patients with relapsed peripheral T-cell lymphoma (PTCL). Blood (ASH Annual Meeting Abstracts) 114, 1657 (2009).

    Google Scholar 

  69. Younes, A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology Am. Soc. Hematol. Educ. Program 507–519 (2009).

  70. Younes, A. et al. Isotype-selective HDAC inhibitor MGCD0103 decreases serum TARC concentrations and produces clinical responses in heavily pretreated patients with relapsed classical Hodgkin lymphoma (HL). Blood (ASH Annual Meeting Abstracts) 110, 2566 (2007).

    Google Scholar 

  71. Kirschbaum, M. H. et al. Vorinostat (suberoylanilide hydroxamic acid) in relapsed or refractory Hodgkin lymphoma: SWOG 0517. Blood (ASH Annual Meeting Abstracts) 110, 2574 (2007).

    Google Scholar 

  72. Spencer, A. et al. Oral panobinostat (LBH589), a novel deacetylase inhibitor (DACi) demonstrates clinical activity in relapsed/refractory Hodgkin lymphoma (HL) [abstract]. Ann. Oncol. 19, a136 (2008).

    Article  Google Scholar 

  73. Younes, A. et al. Efficacy of panobinostat in phase II study in patients with relapsed/refractory Hodgkin lymphoma (HL) after high-dose chemotherapy with autologous stem cell transplant. Blood (ASH Annual Meeting Abstracts) 114, 923 (2009).

    Google Scholar 

  74. Witzig, T. E. et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's lymphoma. J. Clin. Oncol. 27, 5404–5409 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Witzig, T. E. et al. Durable responses after lenalidomide oral monotherapy in patients with relapsed or refractory (R/R) aggressive non-Hodgkin's lymphoma (a-NHL): results from an international phase 2 study (CC-5013-NHL-003). Blood (ASH Annual Meeting Abstracts) 114, 1676 (2009).

    Google Scholar 

  76. Fehniger, T. A. et al. A phase II multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts) 114, 3693 (2009).

    Google Scholar 

  77. Kuruvilla, J. et al. Phase II trial of lenalidomide in patients with relapsed or refractory Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts) 112, 3052 (2008).

    Google Scholar 

  78. Fowler, N. et al. A biologic combination of lenalidomide and rituximab for front-line therapy of indolent B-cell non-Hodgkin's lymphoma. Blood (ASH Annual Meeting Abstracts) 114, 1714 (2009).

    Google Scholar 

  79. Wang, L. et al. A phase I/II study of lenalidomide in combination with rituximab in relapsed/refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts) 114, 2719 (2009).

    Google Scholar 

  80. Chen, L. et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 111, 2230–2237 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Friedberg, J. W. et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115, 2578–2585 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pollyea, D. A. et al. A phase I dose escalation study of the Btk inhibitor PCI-32765 in relapsed and refractory B cell non-Hodgkin lymphoma and use of a novel fluorescent probe pharmacodynamic assay. Blood (ASH Annual Meeting Abstracts) 114, 3713 (2009).

    Google Scholar 

  83. Cheson, B. D. et al. Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL). J. Clin. Oncol. ASCO Meeting Abstracts 27 (Suppl.), 8502 (2009).

    Google Scholar 

  84. Tolcher, A. W. et al. Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J. Clin. Oncol. 26, 5198–5203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wilson, W. et al. ABT-263 activity and safety in patients with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). J. Clin. Oncol. ASCO Meeting Abstracts 27 (Suppl.), 8574 (2009).

    Google Scholar 

  86. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Wiezorek, J., Holland, P. & Graves, J. Death receptor agonists as a targeted therapy for cancer. Clin. Cancer Res. 16, 1701–1708 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Wu, D. et al. No evidence for the JAK2 (V617F) or JAK2 exon 12 mutations in primary mediastinal large B-cell lymphoma. Diagn. Mol. Pathol. 18, 144–149 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Melzner, I., Weniger, M. A., Menz, C. K. & Möller, P. Absence of the JAK2 V617F activating mutation in classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Leukemia 20, 157–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Weniger, M. A. et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 25, 2679–2684 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Melzner, I. et al. Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein. Int. J. Cancer 118, 1941–1944 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Joliot, V., Cormier, F., Medyouf, H., Alcalde, H. & Ghysdael, J. Constitutive STAT5 activation specifically cooperates with the loss of p53 function in B-cell lymphomagenesis. Oncogene 25, 4573–4584 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Nagy, Z. S. et al. STAT5 regulation of BCL10 parallels constitutive NFkappaB activation in lymphoid tumor cells. Mol. Cancer 8, 67 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Scheeren, F. A. et al. IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111, 4706–4715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kube, D. et al. STAT3 is constitutively activated in Hodgkin cell lines. Blood 98, 762–770 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Alas, S. & Bonavida, B. Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin. Cancer Res. 9, 316–326 (2003).

    CAS  PubMed  Google Scholar 

  97. Amin, H. M. et al. Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23, 5426–5434 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Holtick, U. et al. STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis. Leukemia 19, 936–944 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Yared, M. A., Khoury, J. D., Medeiros, L. J., Rassidakis, G. Z. & Lai, R. Activation status of the JAK/STAT3 pathway in mantle cell lymphoma. Arch. Pathol. Lab. Med. 129, 990–996 (2005).

    CAS  PubMed  Google Scholar 

  100. Ding, B. B. et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 111, 1515–1523 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Younes, A. et al. Phase-I study of the novel oral JAK-2 inhibitor SB1518 in patients with relapsed lymphoma: evidence of clinical and biologic activity. Blood (ASH Annual Meeting Abstracts) 114, 588 (2009).

    Google Scholar 

  102. LoRusso, P. M., Boerner, S. A. & Seymour, L. An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics. Clin. Cancer Res. 16, 1710–1718 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Hunsberger, S., Rubinstein, L. V., Dancey, J. & Korn, E. L. Dose escalation trial designs based on a molecularly targeted endpoint. Stat. Med. 24, 2171–2181 (2005).

    Article  PubMed  Google Scholar 

  104. Korn, E. L. Nontoxicity endpoints in phase I trial designs for targeted, non-cytotoxic agents. J. Natl Cancer Inst. 96, 977–978 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Barker, A. D. et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin. Pharmacol. Ther. 86, 97–100 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Younes, A. et al. Safety and tolerability of conatumumab in combination with bortezomib or vorinostat in patients with relapsed or refractory lymphoma. Blood (ASH Annual Meeting Abstracts) 114, 1708 (2009).

    Google Scholar 

  107. Satoh, T. et al. Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors. Clin. Cancer Res. 15, 3872–3880 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Linardou, H., Dahabreh, I. J., Bafaloukos, D. & Murray, S. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat. Rev. Clin. Oncol. 6, 352–366 (2000).

    Article  CAS  Google Scholar 

  109. Dhomen, N. & Marais, R. BRAF signaling and targeted therapies in melanoma. Hematol. Oncol. Clin. North Am. 23, 529–545 (2009).

    Article  PubMed  Google Scholar 

  110. Lieberman, R. Personalized medicine enters the US marketplace: KRAS, anti-EGFR monoclonal antibodies, and colon cancer. Am. J. Ther. 16, 477–479 (2009).

    Article  PubMed  Google Scholar 

  111. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Cheson, B. D. et al. Revised response criteria for malignant lymphoma. J. Clin. Oncol. 25, 579–586 (2007).

    Article  PubMed  Google Scholar 

  113. Flaherty, K. et al. Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J. Clin. Oncol. ASCO Meeting Abstracts 27 (Suppl.), 9000 (2009).

    Google Scholar 

  114. Coiffier, B. et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92, 1927–1932 (1998).

    CAS  PubMed  Google Scholar 

  115. Leonard, J. P. et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin's lymphoma: phase I/II clinical trial results. Clin. Cancer Res. 10, 5327–5334 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. O'Mahony, D. et al. Yttrium-90 radiolabeled humanized monoclonal antibody to CD25 in refractory and relapsed Hodgkin's lymphoma. Blood (ASH Annual Meeting Abstracts) 112, 231 (2008).

    Google Scholar 

  117. Viviani, S., Bonfante, V., Fasola, C., Valagussa, P. & Gianni, A. M. Phase II study of the histone-deacetylase inhibitor ITF2357 in relapsed/refractory Hodgkin's lymphoma patients. J. Clin. Oncol. ASCO Meeting Abstracts 26 (Suppl.), 8532 (2008).

    Google Scholar 

  118. Fehniger, T. A. et al. A phase II multicenter study of lenalidomide in patients with relapsed or refractory classical Hodgkin lymphoma (cHL): preliminary results. Blood (ASH Annual Meeting Abstracts) 112, 2595 (2008).

    Google Scholar 

  119. Johnston, P. B. et al. mTOR inhibition for relapsed or refractory Hodgkin lymphoma: promising single agent activity with everolimus (RAD001). Blood (ASH Annual Meeting Abstracts) 110, 2555 (2007).

    Google Scholar 

  120. Reeder, C. B. et al. A phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed aggressive non-Hodgkin lymphoma (NHL). Blood (ASH Annual Meeting Abstracts) 110, 121 (2007).

    Google Scholar 

  121. Ansell, S. M. et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 113, 508–514 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Goy, A. et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 23, 667–675 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Crump, M. et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann. Oncol. 19, 964–969 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Younes, A. et al. Treatment of relapsed or refractory lymphoma with the oral isotype-selective histone deacetylase inhibitor MGCD0103: interim results from a phase II study. Blood (ASH Annual Meeting Abstracts) 110, 2571 (2007).

    Google Scholar 

  125. Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol. 25, 1741–1746 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work is partially supported by lymphoma SPORE grant 1P50CA136411-01A1, Clay Chiles Lymphoma Fund, Jack L. Stotsky Memorial Fund, and the Living Legend Fund.

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  1. Department of Lymphoma and Myeloma, Unit 429, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, TX, USA

    Anas Younes

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Supplementary Figure 1

Rationale for targeting histone deacetylases (HDACs) in cancer. (DOC 99 kb)

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Younes, A. Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev Clin Oncol 8, 85–96 (2011). https://doi.org/10.1038/nrclinonc.2010.189

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