Abstract 2057: Evaluation of anti-tumor efficacy of EC1456 in low-passage and pre-treated patient-derived xenograft models of triple-negative breast cancer
Authors: Lu Yingjuan , Parker Nikki L. , Chu Haiyan , Pugh Michael R. , Rao Satish I. , Klein Patrick J. , Ritchie Michael F. , Myer Lonnie D. , Jaskowiak Jennifer , Leamon Christopher P. 
Published: July 2017

Triple negative breast cancer (TNBC) patients are insensitive to hormonal or anti-HER2 therapy and have a higher recurrence rate among all breast cancer subtypes. There is a lack of common therapeutic targets in TNBC due to its six distinct molecular characteristics. Recently, ~50% of TNBC cases were found to express the folate receptor alpha (FRα) on tumor cells. FRα is a GPI-anchored membrane glycoprotein capable of bringing folate-targeted small-molecule drug conjugates (SMDCs) inside the cell. EC1456 is a folic acid-tubulysin B hydrazide (TubBH) SMDC that specifically binds to the membrane FRα and is internalized by endocytosis. While encapsulated within the early endosome, EC1456 releases TubBH into the cytosol where it inhibits the polymerization of tubulin into microtubules, thus blocking spindle formation to arrest cells in metaphase which ultimately induces apoptosis. EC1456 is currently under Phase 1 clinical investigation in patients with common solid tumors [IND# 118,859]. The purpose of this study is to evaluate EC1456 activity in Champions TumorGraftTM TNBC patient-derived xenograft (PDX) models to help guide our drug development strategies. These PDX models were derived from patients who were treated with multiple lines of standard-of-care agents. A total of six low-passage, FR-positive TNBC models were tested against two different treatment regimens of EC1456 (once or twice a week for 2 weeks only). Plasma and tumor drug concentrations were quantified by LC-MS/MS using satellite study animals. The tumor-bearing animals were monitored for up to 60 days to assess both short-term (i.e. % TGI) and long-term (%PR, CR, TFS) anti-tumor responses. Using a stringent efficacy criteria (≥60% CR/TFS), 3 of the 6 TNBC models were found highly sensitive to EC1456 and 3 were found resistant. To identify potential gene signatures of EC1456 response, bioinformatics analysis was performed using existing RNA-seq data and compared across a broad panel of TumorGraftTM TNBC models, regardless of FR expression status. Specific biomarkers of interest were further analyzed by qRT-PCR using control tumors from the current study. Together, our analysis revealed potential resistance mechanisms associated with microtubule dynamics as well as a cancer cell’s ability to undergo apoptosis.

Citation Format: Yingjuan Lu, Nikki L. Parker, Haiyan Chu, Michael R. Pugh, Satish I. Rao, Patrick J. Klein, Michael F. Ritchie, Lonnie D. Myer, Jennifer Jaskowiak, Christopher P. Leamon. Evaluation of anti-tumor efficacy of EC1456 in low-passage and pre-treated patient-derived xenograft models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2057. doi:10.1158/1538-7445.AM2017-2057