Author ORCID Identifier
Date Available
4-30-2023
Year of Publication
2023
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Clinical and Translational Science
Advisor
Dr. B Mark Evers
Co-Director of Graduate Studies
Dr. Tom Kelly
Abstract
Despite clinical advances, pancreatic neuroendocrine neoplasms (pNEN) remain a difficult clinical entity to treat and can carry a poor prognosis. Systemic therapy is used to treat pNENs which are not amenable to surgical resection. Peptide receptor radionuclide therapy, a form of radiation therapy (RT) and cisplatin are two different forms of DNA-damaging therapy in current use to treat pNENs. However, their efficacy remains poor as single agents. This study aimed to increase the sensitivity of pNENs to the DNA-damaging agents, RT and cisplatin, by inhibiting deoxynucleotide triphosphate (dNTP) synthesis. Triapine, a ribonucleotide reductase inhibitor (RNRi), and ataxia telangiectasia and Rad3-related protein inhibitors (ATRi) were used to block the de novo and salvage pathways for dNTP synthesis, respectively. Of the three orally bioavailable ATRi tested (VX-970, AZD-6738, and BAY1895344), BAY1895344 was the most cytotoxic with and without RT. BAY1895344 and triapine show synergistic potential with increased DNA damage, cell cycle arrest, and apoptosis compared to singular treatment, which is amplified when combined with either RT or cisplatin. Additionally, we identified synergism between cisplatin and BAY1895344 which further amplified their therapeutic effects on the pNEN cells. With triapine treatment alone, we identified strong activation of the ATR pathway which may represent a mechanism of resistance to this treatment which is subsequently blocked by the addition of BAY1895344. With direct quantification, we identified levels of phosphorylated deoxynucleotides increased with triapine treatment alone but were decreased with combination therapy of triapine and BAY1895344, supporting our hypothesis that this combination therapy blocks dNTP synthesis. A similar trend was observed when combined with radiation therapy. Our findings show inhibition of the de novo and salvage pathways for dNTP synthesis markedly sensitize pNENs to subsequent radiation therapy and cisplatin therapy. By capitalizing on the synergy of this combination, clinical efficacy may be achieved at lower doses and represents two potentially novel pNEN treatments.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.108
Funding Information
This research was supported by the National Institutes of Health Training Grant T32CA160003 (2021-2023)
Recommended Citation
Castle, Jennifer MD, "ENHANCING DNA-DAMAGING THERAPY THROUGH THE INHIBITION OF DNTP SYNTHESIS USING A SYNERGISTIC DRUG COMBINATION TO TREAT PANCREATIC NEUROENDOCRINE NEOPLASMS" (2023). Theses and Dissertations--Clinical and Translational Science. 20.
https://uknowledge.uky.edu/cts_etds/20
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