Proteasome inhibitors (Pis) such as Bortezomib (Btzmb), induce apoptosis in neoplastic cells throughmultiple mechanisms, including NF-KB activation, oxidative injury induction, an ER stress promotion, amongothers. Btzmb displays marked activity in multiple myeloma, and several types of non-Hodgkin's lymphoma(NHL), prompting the development of second generation proteasome inhibitors (e.g., PR-171) which mayhave superior PK/PD characteristics compared to Btzmb. However, the need to improve PI activity in NHLpersists. Recent evidence from our laboratory suggests that combining Pis with other clinically relevanttargeted agents, including HDAC or small molecule Bcl-2 inhibitors results in synergistic induction ofapoptosis in NHL cell lines. The goal of this project is to elucidate, using a diffuse large B-cell lymphoma(DLBCL) model, mechanisms of synergism between PR-171 and these other targeted agents, extend thesefindings to an in vivo model system, identify laboratory-based response determinants, and use thisinformation to initiate novel combination Phase I trials in patients with refractory NHL.
In Specific Aim #1, wewill determine whether synergism between Pis and HDAC inhibitors (vorinostat) in NHL cells reflects NF-KBdisruption, induction of oxidative injury, ER stress, or a combination of these factors.
In Specific Aim #2, wewill determine whether synergism between Pis and small molecule Bcl-2 inhibitors (e.g. GX15-070) stemsfrom oxidative injury, activation of stress-related signaling pathways, and/or Bak and Bax activation. We willalso establish a) whether these approaches are effective in Btzmb-resistant DLBCL cells; and b) which ofthese individual strategies might be most appropriate for specific DLBCL sub-types i.e., germinal center (GC)versus activated B-cell (ABC).
In Specific Aim #3, we will extend these findings to a xenograft DLBCL modelsystem, and determine whether in vitro determinants of synergism are operative in vivo .
In Specific Aim #4, we will select the most promising of regimens emanating from Aims #1-3 to pursue as one or more Phase Itrials combining Pis with HDAC or small molecule Bcl-2 inhibitors in patients with refractory NHL. We willalso conduct correlative laboratory studies to validate mechanisms of in vivo synergism, and identifysurrogate markers of disease responsiveness. It is anticipated that these studies will lay the foundation fornovel and potentially more effective Pi-based strategies in patients with refractory NHL.
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