Imbalanced nucleotide metabolism sensitises triple negative breast cancer cell lines to standard of care chemotherapies

  • Craig Davison

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Background. Triple negative breast cancer (TNBC) is diagnosed by the absence of ER, PR and the lack of HER2 overexpression and makes up 14-24% of breast cancers. TNBC treatment remains hampered by early visceral metastasis and lymph node involvement at the time of diagnosis and limited effective therapeutic options. Advances in treatment that translate to significant improvements in outcome have been painstakingly incremental, despite advances in research technologies and resulting TNBC subtyping. This has contributed to TNBC patients having the poorest prognosis of all BC subtypes demonstrated by a lower 5-year OS for early disease (73.8-83.2%) and very short median survival for metastatic disease (15-20 months).

Cancer cells rely on increased de novo nucleotide metabolism to deal with their increased requirement for DNA synthesis compared to normal cells. Deoxythymidylate triphosphate (TTP) is produced by the thymidylate biosynthesis pathway. Thymidylate biosynthesis is unique compared to the pathways which produce the other canonical nucleotides for DNA synthesis (dCTP, dGTP and dATP); requiring additional enzymatic reactions and also having the potential to produce the unwanted intermediate deoxyuridine triphosphate (dUTP) which can be misincorporated into DNA as DNA polymerase cannot distinguish between dUTP and TTP. Thymidylate metabolism is a demonstrably targetable pathway, with multiple chemotherapies currently used in the clinic targeting the enzyme thymidylate synthase (TS), such as fluoropyrimidines (e.g. 5-FU, FUdR, Capecitabine) and antifolates (Pemetrexed, Raltitrexed, Methotrexate).

We have identified novel therapeutic opportunities to target the enzymes thymidylate kinase (TMPK) and deoxyuridine 5’-triphosphate nucleotidohydrolase (dUTPase). TMPK is the subsequent enzyme following TS in the thymidylate biosynthesis pathway and catalyses the phosphorylation of TMP to TDP as part of TTP production. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP). Therefore, dUTPase is a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during DNA synthesis/repair. Clinical trials are underway, with more planned, evaluating dUTPase inhibitors alongside TS targeting therapies (Capecitabine and S-1).

We hypothesise that targeting dUTPase or TMPK will cause an imbalanced dUTP to TTP ratio and enhance the effects of standard of care chemotherapies in TNBC.
Date of AwardDec 2019
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SupervisorRobert Ladner (Supervisor), Richard Wilson (Supervisor) & Melissa LaBonte Wilson (Supervisor)

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