Implication of znf217 in accelerating tumor development and therapeutically targeting ZNF217-induced PI3K–AKT signaling for the treatment of metastatic osteosarcoma

Branden A. Smeester, Garrett M. Draper, Nicholas J. Slipek, Alex T. Larsson, Natalie Stratton, Emily J. Pomeroy, Kelsie L. Becklin, Kenta Yamamoto, Kyle B. Williams, Kanut Laoharawee, Joseph J. Peterson, Juan E. Abrahante, Sue Rathe, Lauren J. Mills, Margaret R. Crosby, Wendy A. Hudson, Eric P. Rahrmann, David A. Largaespada, Branden S. Moriarity

Research output: Contribution to journalArticlepeer-review

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 ZNF217þ 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 ZNF217þ 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, ZNF217þ osteosarcoma.

Original languageEnglish (US)
Pages (from-to)2528-2541
Number of pages14
JournalMolecular Cancer Therapeutics
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
The authors would like to thank the Clinical and Translational Science Institute Histology and Research Laboratory team member Colleen Forester for tissue preparation and histology services. The authors acknowledge the Minnesota Supercomputing Institute, the Institute for Therapeutics Discovery and Development, and the Mouse Genetics Laboratory at the University of Minnesota for providing resources that contributed to the research results reported within this article. The cytogenetic analyses were performed in the Cytogenomics Shared Resource at the University of Minnesota with support from the comprehensive Masonic Cancer Center NIH Grant no. P30 CA077598. B.A. Smeester. was previously supported by an NIH NIAMS T32 AR050938 Musculoskeletal Training Grant and is currently supported by a Doctoral Dissertation Fellowship through the Graduate School at the University of Minnesota. G.M. Draper is supported by an NIH NIGMS T32 GM113846-09 Stem Cell Biology Training Grant. E.J. Pomeroy is supported by an NIH NIAID T32 AI997313 Immunology Training Grant. K.B. Williams is supported by a Children’s Tumor Foundation Young Investigator Award from the NF Research Initiative at Boston Children’s Hospital, made possible by an anonymous gift. This work was made possible through funding from the Zach Sobiech Osteosarcoma Fund Award, Randy Shaver Cancer and Community Fund, Aflac-AACR Career Development Award, and the Children’s Cancer Research Fund to B.S. Moriarity and the American Cancer Society Professor award to D.A. Largaespada.

Funding Information:
G.M. Draper reports grants from NIH during the conduct of the study. D.A. Largaespada reports grants from the American Cancer Society during the conduct of the study; grants from Genentech; personal fees and other from BmoGen Biotechnologies, Inc. (salary and equity); and other from NeoClone Biotechnologies, Inc. (equity), Recombinetics, Inc. (equity options), Luminary Therapeutics, Inc. (equity), and ImmuSoft Inc. (equity) outside the submitted work. No disclosures were reported by the other authors.

Publisher Copyright:
© 2020 American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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