Abstract 2463: Enhanced anti-tumor activity of an Auristatin-based antibody-drug conjugate in combination with PI3K/mTOR inhibitors or taxanes: Translational implications and mechanistic insights

Abstract

Abstract Targeted treatment with antibody-drug conjugates (ADCs) can lead to dramatic regressions of solid tumors; combination therapies with the ADCs that could potentially help achieve long-term disease control remain largely unexplored. The aim of the study is to investigate most promising combination regimens of auristatin-based conjugates in preclinical models of cancer. A tool ADC, an auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and permeable auristatin analogs were combined with dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of common cancer cell lines of breast, lung or ovarian origin. Drug combinations were tested for their effects in vitro on cell viability, apoptosis, cell cycle or modulation of PI3K/mTOR pathway markers. Anti-tumor efficacy of selected combinations was also evaluated in a 5T4-positive human breast or lung tumor xenografts in vivo. Remarkably, ADC and auristatin analogs resulted in synergistic or additive effects on cell cytotoxicity when combined with PF-384 or with taxanes in vitro. ADC/PF-384, auristatin/PF-384 and ADC/Paclitaxel (PTX), auristatin/PTX combinations showed enhanced induction of apoptosis and selective attenuation of the downstream phospho-markers of the PI3K/mTOR pathway. Quantitative proteomic analysis of cells treated with auristatin-based agents and PF-384 alone or in combination revealed novel and unique effects on key components of mRNA translation, including translation initiation or elongation factors. In human lung or breast cancer xenograft models, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/PTX produced substantially greater antitumor effects with longer average survival as compared to monotherapy treatments. Our results provide strong rationale for combining 5T4-ADC with PI3K/mTOR pathway inhibitors or taxanes. New biological insights into molecular mechanisms underlying synergistic effects of ADC - drug combinations suggest/reveal that synergies are mediated by payload's mode of action. These findings can be applicable to several ADCs employing microtubule inhibitors that are undergoing clinical evaluation. Citation Format: Puja Sapra, Boris Shor, Maureen Dougher, Jennifer Kahler, Michelle Mack, Jane Xu, Shuyan Lu, Eugene Melamud, Fang Wang, Edward Rosfjord. Enhanced anti-tumor activity of an Auristatin-based antibody-drug conjugate in combination with PI3K/mTOR inhibitors or taxanes: Translational implications and mechanistic insights. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2463. doi:10.1158/1538-7445.AM2015-2463