Antitumor Activity of MLN9708, a Second-Generation Proteasome Inhibitor, in Preclinical Models of Lymphoma.

Abstract

3724 Poster Board III-660 Lymphomas account for about 5% of all cases of cancer in the US. In 2009, it is estimated that 74490 Americans will be diagnosed with lymphoma, which includes approximately 8510 new cases of Hodgkin's lymphoma and 65980 new cases of non-Hodgkin's lymphoma (NHL). An estimated 20790 men and women will die from lymphoma in 2009, the majority (93.8%) of which from NHL. Standard treatment includes chemotherapy and radiation to destroy the malignant lymphoma cells; however, newer therapies are currently being explored. Bortezomib is approved for multiple myeloma and relapsed mantle cell lymphoma, and is under clinical investigation in other types of NHL and other B-cell malignancies. Similar to bortezomib, MLN9708 is a modified dipeptidyl boronic acid that is a potent, reversible and specific inhibitor of the proteasome. MLN9708 preferentially binds to and inhibits b5 enzymatic activity of the 20S catalytic core. It is currently in Phase I trials for the treatment of solid and hematologic malignancies. MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, on exposure to aqueous solutions or plasma. MLN2238 was used for all preclinical studies described below. We evaluated the ability of MLN2238 to inhibit tumor growth in two preclinical models of diffuse large B-cell lymphoma (DLBCL), an aggressive lymphoma that accounts for ∼40% of lymphomas in adults. OCI-LY10 and PHTX-22L are two examples of ABC-subtype of DLBCL. The antitumor activity of MLN2238 was evaluated in CB-17 Scid female mice bearing OCI-LY10 lymphoma xenografts. Tumor inhibition was determined by calculating the treatment over control (T/C) ratio of the mean tumor volume and the percentage of tumor growth inhibition (TGI) on the last day of the study. MLN2238 administered intravenous (IV) at 18 mg/kg once weekly (QW) resulted in tumor regression in 6 of 7 animals (T/C = 0.12; TGI = 88%) and a partial response in the remaining animal (43% reduction in tumor volume). MLN2238 administered at 8 mg/kg or 4 mg/kg IV QW resulted in a T/C of 0.42 and 0.36. Proteasome activity in the tumor was inhibited 49 and 44% 1 hour after a single IV dose of MLN2238 at 14 or 7 mg/kg, respectively. The other tumor model, PHTX-22L, is a primary tumor xenograft that was derived from a tumor surgically removed from the right lymph node of a 71-year-old Caucasian male. SCID NOD female mice implanted with PHTX-22L tumor fragments were treated twice weekly (BIW) with IV doses of vehicle, MLN2238 at 4 mg/kg SC once daily (QD), MLN2238 at 14 mg/kg IV BIW or bortezomib at 0.8 mg/kg IV BIW. The strongest antitumor activity was seen in PHTX-22L tumor bearing mice treated with IV MLN2238 14 mg/kg BIW (T/C = 0.14; TGI = 86%, p < 0.001) or SC MLN2238 4 mg/kg QD (T/C = 0.15; TGI = 85%, p < 0.01). These dosing regimens significantly inhibited tumor growth compared with vehicle treatment. In the same study, bortezomib treatment IV at 0.8 mg/kg on a BIW schedule had no antitumor effect (T/C = 0.88; TGI = 12%, p = 0.86) and was not statistically different from the vehicle treated group. Proteasome activity was significantly inhibited in both blood and tumor following a single dose of MLN2238 administered IV at 14 mg/kg or SC at 4 mg/kg. Proteasome activity was inhibited greater than 50% for up to 8 hrs following the IV dose in both blood and tumor, whereas proteasome activity recovered more quickly following the SC dose. In a separate preclinical study, the antitumor activity of MLN2238 administered at lower doses and on alternate schedules was examined. SCID NOD mice bearing PHTX-22L xenografts were administered MLN2238 IV at 11 mg/kg BIW, 7 mg/kg BIW, 11 mg/kg QW or 5 mg/kg QDx2/week resulted in significant antitumor activity (T/C = 0.04, 0.08, 0.15, 0.16; TGI = 96, 92, 85, 84%, respectively). More importantly, drug treatment caused tumor regression (tumor volume at the end of the study was less than 50% of the starting tumor volume) in 8 of 10 mice in the 11 mg/kg BIW, 5/10 in the 7 mg/kg BIW, 2/8 in the 11 mg/kg QW and 1/10 in the 5 mg/kg QDx2/week treatment groups. The efficacy of MLN2238 dosed IV either at 7 mg/kg QW or 3.5 mg/kg BIW in this model was less efficacious (T/C = 0.61 and 0.64). In addition to PHTX-22L, we have access to several other primary lymphoma tumor xenograft models that we plan to evaluate for sensitivity to MLN2238 treatment. These studies demonstrate that MLN2238 is active in preclinical models of lymphoma, and that MLN2238 has antitumor activity in a model of lymphoma that is refractory to bortezomib treatment. Disclosures: Donelan: Milllennium: Employment. Bannerman:Milllennium: Employment. Bano:Milllennium: Employment. Babcock:Milllennium: Employment. Hales:Millennium Pharmaceuticals: Employment. Stringer:Milllennium: Employment. Burke:Milllennium: Employment. Danaee:Milllennium: Employment, Equity Ownership. Faron-Yowe:Milllennium: Employment. Koenig:Milllennium: Employment. Lichter:Milllennium: Employment. Kupperman:Milllennium: Employment.

Novel Therapies for Aggressive B-Cell Lymphoma

“…In a phase I study, NPI-0052 produced dose-dependent pharmacologic effects, with less peripheral neuropathy, neutropenia, and thrombocytopenia than was typically noted with other proteasome inhibitors. MLN9708 has shown activity in preclinical models of lymphoma [ 141 , 142 ]. Further, the novel proteasome inhibitor carfilzomib has been shown to interact synergistically with histone deacetylase inhibitors (HDACIs) [ 143 ].…”