Evaluation of TAK-264, an Antibody-Drug Conjugate in Pancreatic Cancer Cell Lines and Patient-Derived Xenograft Models

Author(s): Anna R. Schreiber, Anna Nguyen, Stacey M. Bagby, John J. Arcaroli, Betelehem W. Yacob, Kevin Quackenbush, Joe L. Guy, Thomas Crowell, Bradley Stringer, Hadi Danaee, Thea Kalebic, Wells A. Messersmith, Todd M. Pitts*.

Journal Name: Clinical Cancer Drugs

Volume 5 , Issue 1 , 2018

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Abstract:

Background: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload via a peptide linker.

Methods: The antiproliferative effects of TAK-264 assessed in a panel of eleven pancreatic cancer cell lines. Additionally, ten unique pancreatic ductal adenocarcinoma cancer patient-derived xenograft models were treated with TAK-264 and the efficacy was determined. Baseline levels of GCC were analyzed 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 both normal and tumor tissue; marked increase in GCC expression was observed in tumor tissue. The in vitro experiments demonstrated a range of responses to TAK-264. Eight of the ten PDAC PDX models treated with TAK-264 demonstrated a statistically significant tumor growth inhibition. Immunoblotting demonstrated an increase in phosphorylated-HistoneH3 in both responsive and less responsive cell lines and PDAC PDX models treated with TAK-264. There was no correlation between baseline levels of GCC and response in either PDX or cell line models.

Conclusion: TAK-264 has shown suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support further investigation of ADC targeting GCC.

Keywords: TAK-264, antibody-drug conjugate, pancreatic cancer, GCC, PDX models, p-histone H3.

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Article Details

VOLUME: 5
ISSUE: 1
Year: 2018
Page: [42 - 49]
Pages: 8
DOI: 10.2174/2212697X05666180516120907

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