Abstract 4652: Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors

Abstract

Abstract Background: Non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancers, the leading cause of cancer-related deaths. Notch signaling has been shown to play an important role in lung cancer initiation and progression. Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. Demcizumab (OMP-21M18) is a humanized IgG2 anti-DLL4 antibody currently being tested in a Phase 2 trial in combination with pemetrexed and carboplatin for first-line treatment of patients with NSCLC. Previously, OMP-21M18 in combination with its mouse anti-DLL4 surrogate has been shown to inhibit tumor growth, decrease cancer stem cell frequency, and cause dysfunctional sprouting of new vessels resulting in an anti-angiogenic effect in patient-derived tumor xenograft (PDX) models in breast, colon, ovarian, and pancreatic cancers. Here we show results from NSCLC PDX models. Methods and Results: Anti-DLL4 treatment was tested in a series of NSCLC PDX models. Because DLL4 inhibition has been shown to have effects on the tumor as well as the vasculature, the combination of OMP-21M18 (targeting human DLL4) and 21R30 (antibody targeting mouse DLL4) treatment in the PDX models was used to model demcizumab treatment in humans. Treatment with anti-DLL4 in combination with chemotherapy inhibited tumor growth in a series of NSCLC PDX models. Additionally, a tumorigenicity assay showed a decrease in the frequency of tumor-initiating cells following treatment with anti-DLL4 and chemotherapy. Gene expression analysis of tumor samples provided insights into the mechanism of action. Conclusions: Anti-DLL4 treatment in a panel of NSCLC PDX tumor models in vivo showed inhibition of tumor growth and a decrease in the frequency of tumor-initiating cells. Mechanism of action and gene expression analysis of these models treated with anti-DLL4 will be presented. These findings provide additional evidence supporting demcizumab as an effective treatment for NSCLC patients. Citation Format: Alayne Brunner, Fiore Cattaruzza, Wan-Ching Yen, Pete Yeung, Marcus Fischer, Belinda Cancilla, Gilbert O’Young, Raymond Tam, Yu-Wang Liu, Austin Gurney, John Lewicki, Tim Hoey, Min Wang, Ann M. Kapoun. Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4652.