Diffuse large B cell lymphoma. 40% of Non-Hodgkin lymphomas. ~23,000 new diagnoses/yr. ~40% cure rate. ~10,000 deaths/yr

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1 Diffuse large B cell lymphoma 40% of Non-Hodgkin lymphomas ~23,000 new diagnoses/yr ~40% cure rate ~10,000 deaths/yr

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3 Putative Cells of Origin for DLBCL Subgroups T B PB Plasma Cell ABC DLBCL PB BCL-6- Blimp-1+ IRF-4+ RIP B FDC + Antigen B B GCB DLBCL B BCL-6+ Blimp-1 IRF-4 B B B B B B B

4 PMBL GCB DLBCL ABC DLBCL 5-year survival 64% 59% 30%

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7 Activation of the NF-kB Signaling Pathway

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10 Constitutive Nuclear NF-kB in Activated B Cell-like DLBCL

11 Constitutive Activity of IkB Kinase in Activated B Cell-like DLBCL

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14 Primary Mediastinal B Cell Lymphoma

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16 Hodgkin Lymphoma

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20 Molecular Targets in Cancer by Gene-Expression Profiling 1. The NF-kB pathway is constitutively active and required for the survival of ABC DLBCL and PMBL. 2. The NF-kB pathway is a therapeutic target for certain molecularly defined subgroups of DLBCL. 3. Selective IKK inhibitors hold promise for the therapy of multiple lymphoma subtypes.

21 Unknown Signaling Mechanisms Upstream and Downstream of IkB Kinase in Activated B Cell-like DLBCL? Proliferation? Survival

22 Achilles Heel RNA Interference Screens to Identify New Molecular Targets in Cancer

23 Defining Molecular Targets in Cancer Hanahan and Weinberg, Cell 2000

24 Defining Molecular Targets in Cancer Hanahan and Weinberg, Cell 2000

25 Achilles Heel RNA Interference Screens for New Therapeutic Targets in Cancer

26 Achilles Heel RNA Interference Screens for New Therapeutic Targets in Cancer Goal: Identify shrnas that block the proliferation or survival of cancer cells.

27 Achilles Heel RNA Interference Screens for New Therapeutic Targets in Cancer Goal: Identify shrnas that block the proliferation or survival of cancer cells. Problem: Such shrnas will be difficult to study due to their toxic phenotype.

28 Achilles Heel RNA Interference Screens for New Therapeutic Targets in Cancer Goal: Identify shrnas that block the proliferation or survival of cancer cells. Problem: Such shrnas will be difficult to study due to their toxic phenotype. Solution: Create an inducible system for shrna expression.

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31 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro

32 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro

33 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro

34 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro

35 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro shrna that blocks cell proliferation or survival

36 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro

37 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 21 day growth in vitro

38 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2

39 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2

40 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2

41 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2

42 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2 2

43 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2 2

44 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2 2

45 shrna Library Screen for Genes Controlling Cancer Cell Proliferation and Survival 2 2 2

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47 3 Increasing bar code depletion log 2 (shrna uninduced/ shrna induced)

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50 Increasing bar code depletion log 2 (shrna uninduced/ shrna induced)

51 shrnas That Are Selectively Toxic for Different Subgroups of Diffuse Large B Cell Lymphoma Increasing bar code depletion log 2 (shrna uninduced/ shrna induced)

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53 Acknowledgements Center for Cancer Research, National Cancer Institute RNAi Vu Ngo Laurence Lamy Art Shaffeer Xin Yu Hong Zhao Liming Yang NF-kB Lloyd Lam Eric Davis Millenium Pharmaceuticals Lenny Dang Julian Adams