Oncotarget

Research Papers:

TRAIL stabilization and cancer cell sensitization to its pro-apoptotic activity achieved through genetic fusion with arginine deiminase

Elena Brin _, Katherine Wu, Eleanor Dagostino, Mario Meng-Chiang Kuo, Yudou He, Wei-Jong Shia, Li-Chang Chen, Mariusz Stempniak, Richard Hickey, Robert Almassy, Richard Showalter and James Thomson

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Oncotarget. 2018; 9:36914-36928. https://doi.org/10.18632/oncotarget.26398

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Abstract

Elena Brin1, Katherine Wu1, Eleanor Dagostino1, Mario Meng-Chiang Kuo1, Yudou He1, Wei-Jong Shia1, Li-Chang Chen1, Mariusz Stempniak1, Richard Hickey1, Robert Almassy1, Richard Showalter1 and James Thomson1

1Polaris Pharmaceuticals, San Diego, CA, USA

Correspondence to:

Elena Brin, email: [email protected]

Keywords: TRAIL; arginine deiminase; apoptosis; fusion protein; anti-cancer biologic

Received: September 20, 2018     Accepted: November 16, 2018     Published: December 11, 2018

ABSTRACT

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) binds to death receptors and induces apoptosis in various cancer cell lines while sparing normal cells. Recombinant TRAIL has shown good safety and efficacy profiles in preclinical cancer models. However, clinical success has been limited due to poor PK and development of resistance to death receptor-induced apoptosis. We have addressed these issues by creating a fusion protein of TRAIL and arginine deiminase (ADI). The fusion protein benefits from structural and functional synergies between its two components and has an extended half-life in vivo. ADI downregulates survivin, upregulates DR5 receptor and sensitizes cancer cells to TRAIL induced apoptosis. ADI-TRAIL fusion protein was efficacious in a number of cell lines and synergized with some standard of care drugs. In an HCT116 xenograft model ADI-TRAIL localized to the tumor and induced dose-dependent tumor regression, the fusion protein was superior to rhTRAIL administered at the same molar amounts.


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