Evaluating antitumor activity of Escherichia coli purine nucleoside phosphorylase against head and neck patient-derived xenografts

• Type of Material: Article
• Authors: Regina Rab, Emory University; Annette Ehrhardt, Emory University; Bhagelu R Achyut, Emory University; Disha Joshi, Emory University; Melissa Gilbert-Ross, Emory University; Chunzi Huang, Emory University; Katharine Floyd, Emory University; Anton V Borovjagin, The University of Alabama at Birmingham; William B Parker, The University of Alabama at Birmingham; Eric Sorscher, Emory University; Jeong S Hong, Emory University
• Language: English
• Date: 2023-02-01
• Publisher: Wiley Periodicals LLC.
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.
• Final Published Version (URL): http://dx.doi.org/10.1002/cnr2.1708
• Title of Journal or Parent Work: Cancer Reports
• Volume: 6
• Issue: 2
• Start Page: e1708
• End Page: e1708
• Keywords: Adenoviridae; head and neck squamous cell carcinoma; patient-derived xenografts; Genetic Therapy; Genetic Vectors; Head and Neck Neoplasms; Humans; Purine-Nucleoside Phosphorylase; tropism modified adenovirus; Escherichia coli; Heterografts; purine nucleoside phosphorylase; gene transfer
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

Background: Purine nucleoside phosphorylase (PNP) gene transfer represents a promising approach to treatment of head and neck malignancies. We tested recombinant adenovirus already in phase I/II clinical testing and leading-edge patient-derived xenografts (PDX) as a means to optimize this therapeutic strategy. Methods: Our experiments investigated purine base cytotoxicity, PNP enzyme activity following treatment of malignant tissue, tumor mass regression, viral receptor studies, and transduction by tropism-modified adenovirus. Results: Replication deficient vector efficiently transduced PDX cells and mediated significant anticancer effect following treatment with fludarabine phosphate in vivo. Either 6-methylpurine or 2-fluoroadenine (toxic molecules generated by the PNP approach) ablated head and neck cancer cell proliferation. High levels of adenovirus-3 specific receptors were detected in human tumor models, and vector was evaluated that utilizes this pathway. Conclusions: Our studies provide the scientific foundation necessary to improve PNP prodrug cleavage and advance a new treatment for head and neck cancer.