Abstract B050: Evaluation of TAK-264, a novel antibody-drug conjugate in pancreatic cancer cell lines and patient-derived xenograft models
Authors: Schreiber Anna R. , Nguyen Anna , Bagby Stacey M. , Yacob Betelehem , Quackenbush Kevin , Guy Joe L. , Crowell Thomas , Stringer Bradley , Danaee Hadi , Kalebic Thea , Messersmith Wells A. , Arcaroli John J. , Pitts Todd M. 
Published: August 2018

Abstract
Background: Antibody-drug conjugates (ADCs) are an emerging technology consisting of antibody, linker, and toxic agent, which have the potential to offer a more targeted therapeutic approach than standard chemotherapy regimens. ADCs selectively bind to antigens expressed in tumor environments. An emerging target for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). GCC is a transmembrane G protein receptor found on the apical surface of intestinal enterocytes. It plays an important role in GI homeostasis. GCC is highly expressed in various colorectal carcinomas as well as adenocarcinomas of the upper GI tract. The objective of this study was to determine the antitumorigenic activity of TAK-264, an investigational ADC that targets GCC. Experimental Procedures: The antiproliferative effects of TAK-264 were assessed in a panel of eleven pancreatic cancer cell lines with various molecular backgrounds. Additionally, ten unique pancreatic ductal adenocarcinoma (PDAC) cancer patient-derived xenograft (PDX) models were treated with TAK-264 and the efficacy was determined. Tumor size was evaluated twice per week by caliper measurements. Sensitivity to TAK-264 was defined based on tumor growth inhibition that was statistically significant when compared to the vehicle control. Baseline levels of GCC were analyzed by IHC/immunoblotting and RT-PCR on PDX models and cell lines. Immunoblotting was performed to evaluate the effects of TAK-264 on downstream effectors. Results: GCC protein expression was analyzed by immunoblotting in normal versus tumor tissue; a marked increase in GCC expression was observed in tumor tissue when compared to matching normal tissue. The in vitro experiments demonstrated a range of responses to TAK-264 in an SRB assay. Eight of the ten PDAC PDX models demonstrated a statistically significant tumor growth inhibition when compared to the vehicle control. Immunoblotting demonstrated an increase in phosphorylated-Histone-H3 in two cell lines and in the PDAC PDX models treated with TAK-264, indicating a DNA damage response. The analysis of GCC protein expression in normal versus tumor tissue has shown a marked increase in GCC expression in tumor tissue when compared to matching normal tissue. There was no correlation between baseline levels of GCC and response to TAK-264 in either PDX or cell line models. Conclusions: TAK-264, an ADC targeting GCC, has good growth suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support a hypothesis that further investigation of ADC targeting GCC may lead to novel therapeutic modalities for pancreatic cancer.
Citation Format: Anna R. Schreiber, Anna Nguyen, Stacey M. Bagby, Betelehem Yacob, Kevin Quackenbush, Joe L. Guy, Thomas Crowell, Bradley Stringer, Hadi Danaee, Thea Kalebic, Wells A. Messersmith, John J. Arcaroli, Todd M. Pitts. Evaluation of TAK-264, a novel antibody-drug conjugate in pancreatic cancer cell lines and patient-derived xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B050.