This study will address a novel tumor cell killing approach designed to ablate solid tumors with a low proliferative index and the attendant neoplastic progenitor cells. Our laboratory has pursued 2-Fluoroadenine (F-Ade), a purine base that disrupts DNA, RNA, and protein synthesis, as an anticancer compound. Here, we utilize F-araAMP, a clinically approved drug that otherwise has negligible activity against solid tumors, as an F- Ade precursor. F-Ade is generated from fludarabine by intratumoral expression of the E. coli purine nucleoside phosphorylase (PNP) gene. The strategy has demonstrated significant efficacy in comprehensive nonclinical studies and a recently completed, first-in-human trial of head and neck squamous cell carcinoma (HNSCC). The scientific objectives of the current proposal are to establish strong and safe tumor regressions based on activity across multiple HNSCC tumor types in vitro and in vivo, and to augment delivery and safety of the PNP gene (Specific Aims 1 and 2). The experiments will evaluate mechanism of action (nucleoside cleavage, PNP transgene activity, disruption of the noncycling tumor cell compartment) (Specific Aim 3). Our experimental plan is multidisciplinary (biomedical engineering, nanoparticle chemistry, DNA/RNA delivery technology, nucleoside metabolism and enzymology), mutually reinforcing, and directed by a senior investigator trained in oncology (Sorscher) and a biomedical engineering scientist beginning his research career (Dahlman). Translational potential is high, as indicated by a successful Phase 1 trial of the technology, formal orphan drug designation, and a Phase 2 study approved by FDA.
In this project, we describe a tumor cell-killing strategy that has proven safe and robust against non- proliferating cancer cells. The approach is directed towards solid tumors refractory to conventional therapy, with supportive data in both animal models and human subjects. Unlike personalized cancer interventions, the strategy is active against tumors from a large number of subcategories irrespective of underlying driver-type mutations.
|Sago, Cory D; Kalathoor, Sujay; Fitzgerald, Jordan P et al. (2018) Barcoding chemical modifications into nucleic acids improves drug stability in vivo. J Mater Chem B 6:7197-7203|
|Parker, William B; Sorscher, Eric J (2017) Use of E. coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors. Curr Pharm Des :|