Gastrointestinal (GI) cancers represent one of the most widespread cancer malignancies that affect populations across the globe and two well-known subtypes of GI cancers, colorectal (CRC) and pancreatic ductal (PDAC) adenocarcinomas, account for the second and third leading causes of cancer related deaths in the U.S., respectively. Both cancer types rely heavily on fluoropyrimidines (FPs) for treatment, as these agents have been well established in terms of their effectiveness and tolerability through decades of use. Capecitabine and 5-fluoruracil (5-FU) are the two most widely used FPs in CRC and PDAC chemotherapies and both work through conversion to fluorodeoxyuridylate (FdUMP), which directly inhibits the function of thymidylate synthase (TS), a key enzyme involved in the synthesis of thymidine, a crucial molecule needed for DNA replication and thus high rates of cancer cell division. However, there is an unmet need to improve on the tolerability and efficacy of FPs, as conversion to FdUMP is not efficient and metabolism of 5-FU yields toxic metabolites. This work focuses on studying a novel polymeric FP, AraC-FduMP (CF10), a second-generation molecule of FdUMP (F10), which has been shown to be more efficacious and better tolerated than 5-FU in multiple solid and liquid tumor types, for treatment of CRC and PDAC. We present preclinical data with CF10 in both CRC and PDAC models that shows CF10 to be more efficacious than F10 and 5-FU in vitro and demonstrates CF10 in vivo efficacy with murine xenograft and orthotopic models. We also present mechanistic studies that reveal CF10 to be more stable than F10, validate CF10 as a potent inhibitor of TS and poison of topoisomerase 1, and further show that CF10 induces replication stress and DNA damage. Lastly, we describe findings from a focused drug screen that identified a novel synergistic relationship between CF10 and inhibition of a DNA repair factor called poly (ADP) glycohydrolase (PARG) and provide mechanistic data that suggests the synergy observed between CF10 and PARG inhibition generates substantial levels of DNA strand breaks and damage that trigger apoptosis. Overall, our studies detail important steps towards bringing CF10 to clinical trials for CRC and PDAC treatment.
|Advisor:||Brody, Jonathan R., Gmeiner, William H.|
|Commitee:||Languino, Lucia, Merry, Diane E., Bussard, Karen M.|
|School:||Thomas Jefferson University|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 82/9(E), Dissertation Abstracts International|
|Subjects:||Oncology, Molecular biology|
|Keywords:||Colorectal Cancer, Fluoropyrimidine therapy, Novel drug combinations, Pancreatic cancer, Topoisomerase poisons, Gastrointestinal cancers, DNA repair|
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