Abstract 2758: Pediatric preclinical testing program (PPTP) stage 1 evaluation of MLN0128, a potent TOR kinase inhibitor.
Authors: Houghton Peter , Kang Min H. , Reynolds Patrick , Lock Richard , Carol Hernan , Gorlick Richard , Kolb Anders , Maris John , Keir Stephen , Billups Catherine , Kurmasheva Raushan , Smith Malcolm 
Published: August 2014

Introduction: The PI3K-TORC1 pathway links extracellular (growth factors) and intracellular (nutrient sensing) to cell cycle progression and proliferation. This pathway is dysregulated in many adult cancers, but less is known regarding childhood malignancies. MLN0128 is a novel orally-available small molecule inhibitor of both the TORC1 and TORC2 complexes, key components of the PI3K/mTOR signaling pathway.

Methods: MLN0128 was evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure at concentrations from 0.1 nM to 1.0 μM. MLN0128 was tested against the PPTP solid tumor xenografts (SCID mice) and acute lymphoblastic leukemia (ALL; NOD-SCID mice) panels using a dose of 1 mg/kg administered by the P.O. route daily for 21 days.

Results: In vitro the median relative IC50 value for the PPTP cell lines was 19 nM, with a range from 2 nM to 102 nM. There was a trend for lower median rIC50 values for the rhabdomyosarcoma and Ewing sarcoma cell line panels (8 nM and 5 nM, respectively). The median rIC50 value for the ALL cell lines (68 nM) was significantly greater than that for the non-ALL cell lines.

In vivo MLN0128 was well tolerated, with only a 1.4% toxicity rate in the treated groups, compared to a 0.3% toxicity rate in control animals. All 38 tested xenograft models were considered evaluable for efficacy. MLN0128 induced significant differences in EFS distribution compared to control in 24 of 31 (77%) of the evaluable solid tumor xenografts, but did not induce significant differences in EFS distribution in any of the 7 evaluable ALL xenografts. MLN0128 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C &gt; 2) in 6 of 30 (20%) evaluable solid tumor xenografts. Intermediate activity for the EFS T/C metric occurred in the rhabdoid tumor panel (2 of 3) and in single xenografts in four other panels. Objective responses were not observed for the solid tumor or for the ALL xenograft panels. Pharmacodynamic studies to determine TOR inhibition are planned.

Conclusions: The activity observed for MLN0128 against the PPTP preclinical models is similar to that previously reported by the PPTP for another TOR kinase inhibitor (Houghton PJ, et al. Pediatr Blood Cancer. 58:191-9, 2012). When combined with PPTP results reported for PI3K and AKT inhibitors (Reynolds CP, et al. Pediatr Blood Cancer. 2012. Epub 2012/09/25 and Gorlick R, et al. Pediatr Blood Cancer. 59:518-24, 2012), the available data suggest that kinase inhibitors targeting the PI3K pathway produce limited single agent activity for the tumor types represented by the PPTP models. (Supported by award NO1-CM-42216 from the NCI).

Citation Format: Peter Houghton, Min H. Kang, Patrick Reynolds, Richard Lock, Hernan Carol, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Catherine Billups, Raushan Kurmasheva, Malcolm Smith. Pediatric preclinical testing program (PPTP) stage 1 evaluation of MLN0128, a potent TOR kinase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2758. doi:10.1158/1538-7445.AM2013-2758