Implication of ZNF217 in accelerating tumor development and therapeutically targeting ZNF217-induced PI3K-AKT signaling for the treatment of metastatic osteosarcoma.

We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas (OSAs) using the Sleeping Beauty (SB) transposon system. Here, we followed up investigating the genetic role of ZNF217 in OSA initiation and progression through establishment of a novel genetically engineered mouse model (GEMM), 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 OSA transformation including proliferation, cell motility, anchorage independent growth, and ultimately promoting OSA growth, progression, and metastasis in part through positive modulation of PI3K-AKT survival signaling. Pharmacological blockade of AKT signaling with nucleoside analogue triciribine (TCN) in ZNF217+ orthotopically-injected OSA cell lines reduced tumor growth and metastasis. Our data demonstrate that TCN treatment may be a relevant and efficacious therapeutic strategy for OSA patients with ZNF217+ and p-AKT rich tumors. With the recent revitalization of TCN for clinical studies in other solid cancers (PTX-200, Prescient Therapeutics), our study provides rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217+ OSA.