Abstract B189: MLN0128, an investigational mTORC1/2 inhibitor, demonstrates potent antitumor activity alone and in combination with paclitaxel in preclinical models of endometrial cancer.
Authors: Kannan Karuppiah , Fabrey Robyn , Cooper Jodi , Huck Jessica , Gangolli Esha , Westin Eric , Brake Rachael 
Published: August 2014

Endometrial cancers are the most common gynecologic cancers in the US, and are a heterogeneous group of malignancies with distinct molecular characteristics. The phosphatidylinositol-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway is frequently dysregulated, being activated in 70-80% of hormone-dependent endometrioid carcinomas (Type I) and 40% of non-endometrioid carcinomas (Type II). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT and up-regulation of mTOR. We evaluated MLN0128, an investigational catalytic mTORC1/2 inhibitor, in preclinical models of endometrial cancer to assess its activity as a single agent and in combination with paclitaxel across various dose schedules and sequences. In vitro MLN0128 showed antiproliferative activity with IC50 values of 5-100 nM across cell line models (n=9) with various genetic aberrations including complex combinations of PTEN loss and mutations in PIK3CA, KRAS and/or FGFR. This antiproliferative activity was associated with inhibition of pathway markers, including phosphorylated AKT, S6, and 4EBP1. In vivo MLN0128 demonstrated tumor growth inhibition (TGI) in a PIK3CA/KRAS model (HEC-1A) and a PTEN/FGFR model (AN3CA) with TGI values of 62% and 73%, respectively. Similar TGI values were achieved regardless of dosing schedule (once daily [QD], 3 days a week [QDx3D], or once weekly [QW]). TGI could be improved by using a combination approach. In the AN3CA model, the in vitro combination of MLN0128 and paclitaxel suppressed the PI3K pathway activation (phosphorylation of AKT, S6, and 4EBP1) that occurred when paclitaxel was administered alone; the combination also suppressed S6 phosphorylation at 24 hours. This finding correlated with an increase in the induction of cleaved PARP, a marker of apoptosis, and accumulation of cells in the sub-G1 phase of the cell cycle. The combination was also observed to add benefit in vivo, most prominently when tumor regrowth was assessed. In the HEC-1A model, TGI only increased by 10% with concomitant administration of MLN0128 and paclitaxel daily vs MLN0128 alone. However, when monitoring re-growth 18 days after administration, this difference in TGI (combination vs MLN0128 alone) increased to 44%. Furthermore pretreatment with paclitaxel before MLN0128 was also associated with significant enhancement of antitumor activity relative to the concomitant administration of both agents; this effect was observed with the QDx3D and QW MLN0128 schedules. Results from these preclinical studies support further investigation of MLN0128 in endometrial cancer, either as a single agent or in combination with current standards of care. Phase 1 studies are ongoing to investigate single-agent MLN0128 (NCT01058707) and MLN0128 plus paclitaxel (NCT01351350) in advanced solid tumors.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B189.

Citation Format: Karuppiah Kannan, Robyn Fabrey, Jodi Cooper, Jessica Huck, Esha Gangolli, Eric Westin, Rachael Brake. MLN0128, an investigational mTORC1/2 inhibitor, demonstrates potent antitumor activity alone and in combination with paclitaxel in preclinical models of endometrial cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B189.