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Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. Winter 2017 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib; lymphoma; proteasome; proteasome inhibitor; Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine IDENTIFYING THERAPEUTIC AGENTS FOR THE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib, lymphoma, proteasome, proteasome inhibitor, Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Marissa Cann Creator Department of Pharmacology School of Medicine Diffuse large B-cell lymphoma (DLBCL) can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. Signaling through the B-cell receptor is heavily dependent on the Src family kinases (SFKs), and NF-κB signaling is dependent on the proteasome. In Chapters 2 and 3, we examined the effects of the SFK inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, with a focus on changes in the kinome (Chapter 2) or the proteasome (Chapter 3). In Chapter 2, we found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, both subtypes display inhibition of the SFKs in response to dasatinib treatment. Subsequent analyses revealed several cell cycle kinases to be inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. In Chapter 3, we found that treatment with dasatinib results in a decrease in the proteasome’s chymotrypsin-like (ChL), trypsin-like (TL), and caspase-like (CaL) activities in the ABC but not GCB DLBCL cell lines. Furthermore, it appears that association between the proteasome 20S core particle and 19S regulatory particle is disrupted in the ABC DLBCL cell lines after dasatinib treatment. In Chapter 4, we explored the utility of site-specific inhibitors of the proteasome’s TL and CaL activities in a variety of cancer cell lines. We found that the TL/ChL and CaL/ChL ratios of proteasome activity correlate with sensitivity to TL and CaL inhibitors, respectively. In addition, the two hematological malignancy cell lines studied are most sensitive to the site-specific inhibitors. Furthermore, the combination of the TL or CaL site-specific inhibitors with bortezomib or carfilzomib is synergistic in all cell lines examined. The studies presented in this thesis have important implications for the clinical use of dasatinib and site-specific proteasome inhibitors for the treatment of DLBCL, either alone or in combination with other agents. These inhibitors show promise and warrant further exploration. 2017-12 2017 Pharmacology dasatinib; lymphoma; proteasome; proteasome inhibitor; Src family kinases eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution David Lawrence Thesis advisor Lee Graves Thesis advisor Kristy Richards Thesis advisor Gary Johnson Thesis advisor John Sondek Thesis advisor text Cann_unc_0153D_17456.pdf uuid:4d0629fd-dfd6-430b-ba7e-5067d5e859f7 2019-12-31T00:00:00 2017-11-28T02:52:50Z proquest application/pdf 7217792