Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors

Rosenthal, Eben L.; Chung, Tae Sub; Parker, William B.; Allan, Paula W.; Clemons, Lisa; Lowman, Deborah; Hong, Jeong S.; Hunt, F. R.; Richman, Joshua M.; Conry, Robert M.; Mannion, Kyle; Carroll, William R.; Nabell, Lisle; Sorscher, Eric J.

doi:10.1093/annonc/mdv196

Cited by 30 publications

(39 citation statements)

References 20 publications

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“…Eukaryotic PNP assembles as a homotrimer, whereas PNP from bacteria (such as Escherichia coli ) is homohexameric and includes an attack group within the active site that facilitates cleavage of adenine‐based nucleosides . Expression of E. coli PNP in a small number of tumor cells (eg, 2.5%) mediates pronounced tumor regressions in animal models, and similar effects have been demonstrated in phase I human clinical studies . Other prokaryotic PNPs, including the Trichomonas vaginalis enzyme, generate F‐Ade from fludarabine with Vmax/Km 20‐ to 25‐fold higher than E. coli PNP, and represent an important future means of improving the technology.…”

Section: Mechanisms For Purine‐based Generation Within a Tumor Mass Imentioning

confidence: 86%

“…In addition, F‐Ade is systemically inactivated by the ubiquitous mammalian enzyme, xanthine oxidase. In vivo studies to test clearance of F‐Ade released from tumor parenchyma have shown serum levels that are undetectable in animal models and human subjects following purine nucleoside phosphorylase (PNP)‐based treatment of HNSCC, despite substantial antitumor activity …”

Section: Generation Of Purine‐based Chemotherapy Within Tumor Parenchymamentioning

confidence: 99%

“…Subsequent to blood stream dephosphorylation of prodrug, fludarabine is cleaved intratumorally to generate F‐Ade (Figure ), leading to dose‐dependent tumor regressions in otherwise untreatable HNSCC. Malignant tissue in the same patients given only fludarabine phosphate (but not adenovirus encoding PNP) was used to establish specificity …”

Section: Clinical Evaluation Of the Pnp Technologymentioning

confidence: 99%

“…15 Expression of E. coli PNP in a small number of tumor cells (eg, 2.5%) mediates pronounced tumor regressions in animal models, and similar effects have been demonstrated in phase I human clinical studies. 13,16,17 Other prokaryotic PNPs, including the Trichomonas vaginalis enzyme, generate F-Ade from fludarabine with Vmax/Km 20-to 25-fold higher than E. coli PNP, and represent an important future means of improving the technology. Generation of anticancer compounds using these enzymes is most effective intracellularly.…”

Section: Mechanisms For Purine-based Generation Within a Tumor Massmentioning

confidence: 99%

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

Behbahani

Rosenthal

Parker³

et al. 2019

Head & Neck

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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.

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Section: Mechanisms For Purine‐based Generation Within a Tumor Mass Imentioning

confidence: 86%

Section: Generation Of Purine‐based Chemotherapy Within Tumor Parenchymamentioning

confidence: 99%

Section: Clinical Evaluation Of the Pnp Technologymentioning

confidence: 99%

Section: Mechanisms For Purine-based Generation Within a Tumor Massmentioning

confidence: 99%

See 2 more Smart Citations

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

Behbahani

Rosenthal

Parker³

et al. 2019

Head & Neck

View full text Add to dashboard Cite

show abstract

“…In this trial, the safety of E. coli PNP/fludarabine phosphate in patients with head and neck cancers has been studied. It was shown that localized production of fluoroadenine within tumor tissues, using fludarabine and E. coli PNP system is successful in eradicating tumors without causing any significant toxicity (Rosenthal et al 2015). …”

Section: Enzyme/prodrug Systemsmentioning

confidence: 99%

Enzyme/Prodrug Systems for Cancer Gene Therapy

et al. 2016

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The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings. These include slow prodrug-drug conversion rate, low transfection/transduction efficiency of the vectors and nonspecific toxicity/immunogenicity related to the delivery systems, plasmid DNA, enzymes and/or prodrugs. This mini review aims at providing an overview of the most widely used enzyme/prodrug systems with emphasis on reporting the results of the recent preclinical and clinical studies.

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

et al. 2022

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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.

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Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors

Cited by 30 publications

References 20 publications

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

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

Enzyme/Prodrug Systems for Cancer Gene Therapy

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

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