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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE026941-01A1
Application #
9311681
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Wang, Chiayeng
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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 :