1. Implication of ZNF217 in Accelerating Tumor Development and Therapeutically Targeting ZNF217-Induced PI3K-AKT Signaling for the Treatment of Metastatic Osteosarcoma.
- Author
-
Smeester BA, Draper GM, Slipek NJ, Larsson AT, Stratton N, Pomeroy EJ, Becklin KL, Yamamoto K, Williams KB, Laoharawee K, Peterson JJ, Abrahante JE, Rathe SK, Mills LJ, Crosby MR, Hudson WA, Rahrmann EP, Largaespada DA, and Moriarity BS
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Ectopic Gene Expression, Gene Amplification, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Models, Biological, Osteosarcoma drug therapy, Osteosarcoma etiology, Osteosarcoma metabolism, Osteosarcoma pathology, Trans-Activators metabolism, Xenograft Model Antitumor Assays, Biomarkers, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Trans-Activators genetics
- Abstract
We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas using the Sleeping Beauty ( SB ) transposon system. Here, we followed up by investigating the genetic role of ZNF217 in osteosarcoma initiation and progression through the establishment of a novel genetically engineered mouse model, in vitro assays, orthotopic mouse studies, and paired these findings with preclinical studies using a small-molecule inhibitor. Throughout, we demonstrate that ZNF217 is coupled to numerous facets of osteosarcoma transformation, including proliferation, cell motility, and anchorage independent growth, and ultimately promoting osteosarcoma growth, progression, and metastasis in part through positive modulation of PI3K-AKT survival signaling. Pharmacologic blockade of AKT signaling with nucleoside analogue triciribine in ZNF217
+ orthotopically injected osteosarcoma cell lines reduced tumor growth and metastasis. Our data demonstrate that triciribine treatment may be a relevant and efficacious therapeutic strategy for patients with osteosarcoma with ZNF217+ and p-AKT rich tumors. With the recent revitalization of triciribine for clinical studies in other solid cancers, our study provides a rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217+ osteosarcoma., (©2020 American Association for Cancer Research.)- Published
- 2020
- Full Text
- View/download PDF