A long-range goal of the proposed research is to identify novel and effective therapeutic approaches for the treatment of relapsed or refractory B cell non-Hodgkin's lymphoma (B-NHL). Despite recent advances (i.e. incorporation of rituximab) in the design of treatment for B-NHL, greater than half of previously treated patients subsequently demonstrate therapy-resistant disease at the time of relapse.
The specific aims of the proposed research seek to understand the mechanism(s)-of-action of bortezomib (Velcade""""""""), a proteasome inhibitor that has shown recent promise in the treatment of therapy-resistant B cell malignancies. The precise mechanism(s)-of-action of bortezomib remains largely undefined, but in many cases likely involves the induction of cell death via apoptosis. Preliminary data indicate that bortezomib is effective at killing several chemotherapy-resistant aggressive B-NHL cell lines, as well as in patient lymphoma specimens. Interestingly, bortezomib demonstrates the capacity to engage several molecular pathways to promote cell death. In the first specific aim, a role for apoptosis and the Bcl-2 family of proteins in regulating bortezomib-mediated cell death of therapy resistant B-NHL will be investigated. In the second aim, a potential role for two additional modes of cell death, autophagy and necrosis, will be explored. The results obtained from this aim are expected to be of particular interest, as targeting non-apoptotic mechanisms of cell death are just beginning to be considered therapeutically. Finally, in aim 3, we will apply the knowledge gained from the laboratory studies to further delineate bortezomib's therapeutic efficacy and validate its mechanism(s)-of-action in primary lymphoma samples. Each refractory/resistant lymphoma will be categorized by DNA microarray (Collaborator: L. Staudt, NIH) as having an activated B cell (ABC), a germinal center B cell (GCB), or other genotype. This will allow direct comparison of each unique proteasome's activity, both ex vivo and (with bortezomib) clinically, between DLBCLs with poor prognosis (ABC) versus those with generally better outcomes (GCB). Preliminary data from a recently completed Phase II NCI Velcade-EPOCH clinical trial (PI: W. Wilson, NCI;Co-investigator: M. Czuczman, RPCI) in patients with relapsed/refractory B-cell NHL indicates that bortezomib increased EPOCH's anti-tumor activity primarily in the """"""""poor prognosis"""""""" ABC subgroup secondary to its ability to down- modulate NF:B activity and lead to an increased pro-apoptotic potential in lymphoma cells. Collectively, the proposed studies are designed to reveal detailed mechanism(s)-of-action of bortezomib in the context of overcoming therapy-resistant B-NHL, and concurrently developing an effective, less toxic, novel immunochemotherapeutic salvage regimen (i.e. VDR) for patients with relapsed/refractory DLBCL. To strengthen our original submission, we have identified three next-generation proteasome inhibitors with unique mechanisms-of-action which we will include into our experimental design. Our research findings will be utilized in the development of future evidence-based proteasome inhibitor-associated therapies for B-cell lymphomas.
Despite remarkable advances in the treatment of cancer, therapy-refractory disease and development of therapy resistance remains a major clinical problem and cause of mortality. This is true for many types of cancer, including B-cell non-Hodgkin lymphoma (B-NHL). The proposed research is directly relevant to this problem, as the goals of the study are to identify novel ways to treat therapy-refractory B-cell lymphoma, and to precisely define how these agents kill B-NHL that are resistant to conventional therapies.
|Xue, Kai; Gu, Juan J; Zhang, Qunling et al. (2016) Vorinostat, a histone deacetylase (HDAC) inhibitor, promotes cell cycle arrest and re-sensitizes rituximab- and chemo-resistant lymphoma cells to chemotherapy agents. J Cancer Res Clin Oncol 142:379-87|
|Czuczman, Natalie M; Barth, Matthew J; Gu, Juan et al. (2016) Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo. Blood 127:1128-37|
|Frys, Sarah; Simons, Zachary; Hu, Qiang et al. (2015) Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents. Br J Haematol 169:506-19|
|Gu, Juan J; Hernandez-Ilizaliturri, Francisco J; Mavis, Cory et al. (2013) MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical mod Anticancer Drugs 24:1030-8|
|Gu, Juan J; Hernandez-Ilizaliturri, Francisco J; Kaufman, Gregory P et al. (2013) The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma. Br J Haematol 162:657-69|
|Tsai, Ping-Chiao; Hernandez-Ilizaliturri, Francisco J; Bangia, Naveen et al. (2012) Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. Clin Cancer Res 18:1039-50|
|Brem, Elizabeth A; Thudium, Karen; Khubchandani, Sapna et al. (2011) Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol 153:599-611|
|Olejniczak, Scott H; Blickwedehl, Jennifer; Belicha-Villanueva, Alan et al. (2010) Distinct molecular mechanisms responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells. Blood 116:5605-14|