Abstract 740: Pediatric Preclinical Testing Program (PPTP) evaluation of the NEDD8-activating enzyme (NAE) inhibitor MLN4924
Authors: Carol Hernan , Lock Richard B. , Maris John M. , Keir Stephen T. , Gorlick Richard , Kolb E. Anders , Kang Min H. , Reynolds C Patrick , Morton Christopher L. , Smith Peter G. , Thomas Michael , McDonald Alice , Houghton Peter J. , Smith Malcolm A. 
Published: June 2012

Background: MLN4924 is a potent and selective small molecule NAE inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. The activity of MLN4924 was evaluated against the PPTP's in vitro and in vivo panels.

Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). MLN4294 (provided by Millennium Pharmaceuticals) was tested in vitro at concentrations from 1.0 nM to 10.0 µM and was tested against the PPTP in vivo panel using a 100 mg/kg dose (66mg/kg for ALL panel) BID administered SQ daily × 5 for 3 weeks, with observation for 6 weeks. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft.

Results: The median relative IC50 for MLN4924 against the PPTP cell lines was 143 nM, with a range from 15 nM to 678 nM. The median relative IC50 value for the Ewing panel (31 nM) was significantly lower than that of the remaining PPTP cell lines. MLN4924 demonstrated an activity pattern consistent with cytotoxic activity. MLN4924 was well tolerated, with a toxicity rate of 4.6%. 42 of 45 xenograft models were considered evaluable for efficacy. MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) solid tumor xenografts. MLN4924 induced intermediate activity (EFS T/C values &gt; 2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilms tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T/C measure. The maximum shift in time to event for treated animals was 3.8-fold (ALL-3), and two other xenografts had shifts in time to event of 3.0-fold (ALL-2 and ALL-17). MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels, with the best response being stable disease for 1 ALL xenograft.

Conclusions: MLN4924 potently inhibits the cell lines of the PPTP in vitro panel and shows an interesting pattern of in vivo activity. Pharmacokinetic and pharmacodynamic studies are ongoing. (Supported by NCI NO1CM42216)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 740. doi:10.1158/1538-7445.AM2011-740