Intratumoral generation of 2‐fluoroadenine to treat solid malignancies of the head and neck

Abstract

This report describes treatment of locoregional head and neck squamous cell carcinoma (HNSCC) by an innovative, experimental strategy involving generation of a robust anti‐cancer agent (2‐fluoroadenine [F‐Ade]) following transduction by Escherichia coli purine nucleoside phosphorylase (PNP) in a small number of tumor cells. F‐Ade works by a unique mechanism of action (ablation of RNA and protein synthesis) and confers tumor regressions of otherwise refractory HNSCC in human subjects. Clinical studies have now advanced to a pivotal (registration‐directed) trial involving locoregional HNSCC, with plans to begin subject enrollment late in 2018. The present review is the first to summarize use of PNP in the context of HNSCC, and provides background regarding this emerging anti‐cancer approach.

Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy

“…Considering that the transfection efficiency of the HeLa cells was probably not too high, which limited Ld NDT expression to a small percentage of the cells in the culture, we hypothesize that a high bystander effect might occur. This will be in accordance with results from the Ec PNP/prodrug system [ 6 , 33 , 36 , 37 , 38 , 39 ]. Similarly to what these authors observed, fludarabine and 6-methylpurine might also be good prodrug compounds for the Ld NDT/prodrug GDEPT ( Figure 6 A).…”

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

“…A clinical trial currently in progress employs intratumoral adenovirus encoding a C‐terminal modified E. coli PNP to treat needle accessible HNSCC 20 . As described above, bystander killing by PNP differs fundamentally from first generation systems using enzymes such as thymidine kinase or cytosine deaminase 1–5 . Due to lack of well‐standardized HNSCC tumor models obtained from human subjects, earlier preclinical evidence in support of the PNP strategy has largely depended on glioma and other non‐HNSCC neoplasms.…”

“…Therapeutic gene transfer comprises an important experimental approach to treatment of refractory solid tumors. Such strategies have been tested clinically with encouraging results against head and neck squamous cell carcinoma (HNSCC) using a modified Escherichia coli purine nucleoside phosphorylase (PNP) gene and replication deficient adenovirus 1–5 . PNP converts specific nucleosides to highly active purine base molecules that inhibit refractory tumors.…”

“…Moreover, PNP is active even when a very small fraction of cancer cells (e.g., <2.5% of a tumor mass) express the transgene 3,4,7,8 . This level of bystander cell killing is unprecedented, and the approach is fundamentally distinct from earlier interventions using transgenes such as thymidine kinase or cytosine deaminase 1–5 …”

“…F‐araAMP is rapidly converted in blood to fludarabine (F‐ araA), which is cleaved by E. coli PNP to 2‐fluoroadenine (F‐Ade), a purine base capable of abolishing large solid tumors. The PNP/F‐araAMP combination has been shown safe in both animal models and human subjects 2,3,5 . F‐Ade that escapes cancer parenchyma is markedly diluted in the host and metabolized by a ubiquitous enzyme (xanthine oxidase) to levels non‐toxic (and undetectable) in vivo 1–5,20 .…”