Abstract 2828: Antitumor activity of the investigational proteasome inhibitor MLN9708 in preclinical models of NSCLC
Authors: Chattopadhyay Nibedita , Bannerman Bret , Donelan Jill , Bano Kristen , Blakemore Steve , Yang Yu , Stringer Brad , Manfredi Mark , Berger Allison 
Published: June 2012

Abstract
The successful development of VELCADE® (bortezomib) for multiple myeloma and previously treated mantle cell lymphoma has validated the proteasome as a therapeutic target for hematological malignancies. The investigational drug MLN9708 is a modified dipeptidyl boronic acid and a potent, reversible and specific inhibitor of the proteasome. MLN9708 is currently being evaluated in Phase I trials for hematologic malignancies as well as solid tumors. In preclinical models, MLN9708 showed better antitumor activity and PD response compared to bortezomib.Upon exposure to aqueous solutions or plasma, MLN9708 immediately hydrolyzes to MLN2238, the biologically active form. MLN2238 was used for all preclinical studies described in this report.
We evaluated the antitumor activity of MLN2238 in several non small cell lung cancer (NSCLC) xenografts. More than 70% tumor growth inhibition was observed in the HCC-827 xenograft model with 13 mg/kg, IV, twice weekly (BIW) dosing. In the H1650 NSCLC xenograft model, 40-50% tumor growth inhibition was found at 8 and 11 mg/kg, IV, BIW dosing. However, a synergistic effect on H1650 tumor growth inhibition was found when MLN2238 was combined with chemotherapeutic agents including doxorubicin 8 mg/kg IV, weekly (QW) dosing (90% tumor growth inhibition) and taxotere 5 and 10 mg/kg, IV, QW (80-100% tumor growth inhibition). Furthermore, the combination of MLN2238 (8 and 11 mg/kg, IV, BIW) and taxotere (10 mg/kg, IV, QW) resulted in tumor regression in the H1650 xenograft model, whereas no regressions were observed with either drug as a single agent. Similar single agent activity and combination effect with taxotere was observed We also evaluated single agent activity and combination with taxotere in an early-passage primary human tumor xenograft model, PHTX-132Lu.
In an effort to understand the factors that may determinecontributing sensitivity vs resistance to proteasome inhibitors, we tested the ability of MLN2238 to inhibit anchorage independent growth and colony formation of NSCLC tumor cells in semi-solid medium. For these studies, tumor cells are derived from primary human tumor explants which have been maintained by serial passage in immunocompromised mice. Initial experiments show a range of sensitivity to MLN2238 among the primary tumors, Comparisons of genomic data, including gene expression profiles, copy number variation, and sequencing of commonly mutated genes, may illuminate factors contributing to sensitivity and resistance. In addition, in vivo studies will be performed on selected models to examine the value of this in vitro colony formation assay in predicting in vivo sensitivity.
Data suggest that MLN2238 has antitumor activity alone and in combination with cytotoxic agents in preclinical models of NSCLC, and these results support the ongoing Phase I clinical investigation of MLN9708 in solid tumor types including NSCLC.
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 2828. doi:10.1158/1538-7445.AM2011-2828