Pre-Clinical Antitumor activity of MLN4924, An Inhibitor of NEDD8-Activating Enzyme (NAE), in a Novel Primary Human DLBCL Xenograft Model.

Abstract 927

MLN4924 is a novel, small molecule inhibitor of Nedd8-activating enzyme (NAE) currently in Phase I clinical trials. The classical response to NAE inhibition in cells is the induction of DNA re-replication, a DNA-damage response and cell death. In NF-kB dependent lymphomas we have shown an alternative mechanism resulting from an inhibition of NF-kB signaling and cell death following treatment with MLN4924.

To confirm and extend our observations we have developed a pre-clinical model of Diffuse Large B-cell lymphoma (PHTX-22L) that was established following direct transplantation of tumor tissue from patient to SCID.NOD mouse. The tumor tissue originated from a 71 year old male patient that had been diagnosed with CD20+ve Diffuse Large B-cell lymphoma. Our analysis indicate that PHTX-22L is a DLBCL that shares molecular features with those described for ABC-like DLBCL including an up-regulation of NF-kB target genes.

In pharmacokinetic analysis following a single SC dose of 10, 30, or 60 mg/kg MLN4924 to PHTX-22L xenograft bearing SCID.NOD mice a dose-proportional increase in plasma exposures was detected. A dose-dependent inhibition of NEDD8-Cullin levels in PHTX22L xenografts was demonstrated resulting in a robust elevation of pIkBa (Ser32), consistent with this model possessing an activated NF-kB pathway. A single 60 mg/kg dose of MLN4924 was also able to induce apoptosis as evidenced by the detection of cleaved caspase-3. Importantly, we were also able to demonstrate a robust downregulation of the transcription of several NF-kB target genes (e.g. Bcl-2, BIRC3, CCL1, ID2, IRF4) following a single dose of MLN4924 indicating that the NF-kB pathway had been effectively inhibited in vivo.

To assess the antitumor activity of MLN4924 in the PHTX-22L model, xenograft bearing SCID.NOD mice were administered twice-daily with 10, 30 and 60 mg/kg MLN4924 for 3 cycles of 2 days of treatment with 5 days rest. This schedule closely resembles one of the clinical dosing schedules currently under evaluation for MLN4924. A dose-dependent inhibition of tumor growth was observed with tumor regressions occurring at the 60 mg/kg dose level. The antitumor activity of MLN4924 in combination with Rituxmiab was also evaluated with significantly increased activity being observed in the combination group compared to the single agent groups. These data demonstrate the potent activity of MLN4924 in a primary human xenograft model that shares molecular features with the ABC-like subtype of DLBCL thereby providing further rationale for the evaluation of MLN4924 in patients with DLBCL.