All ETDs from UAB

Advisory Committee Chair

Karina Yoon

Advisory Committee Members

Donald Buchsbaum

Joanne Murphy-Ullrich

William Parker

Teresa Wilborn

Eddy Yang

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with a 5-year survival rate of 8%. Over 80% of patients are diagnosed with locally advanced or metastatic disease and undergo systemic chemotherapy with gemcitabine. Virtually all patients develop gemcitabine-resistant disease and median survival for these patients is ~6 months. Thus, identification of novel molecular targets and pre-clinical evaluation of therapeutics is essential to improving patient outcome. The bromodomain and extraterminal domain (BET) proteins are important regulators of transcription and have recently become a potentially effective target to treat PDAC. We have shown that the BET inhibitor JQ1 suppressed PDAC tumor growth in patient-derived xenograft (PDX) mouse models. This dissertation details the use of in vitro and in vivo models of PDAC to elucidate the mechanism by which JQ1 inhibited tumor growth as a single agent and the use of mechanism-based approaches to identify additional chemotherapeutic agents that may be combined with JQ1 to enhance tumor response. Expression profile analysis revealed JQ1’s anti-tumor effects at least in part involved inhibition of CDC25B a G2 cell cycle regulator and a protein important during the DNA damage response. We next expounded on these initial studies and showed that treatment with JQ1 increased DNA damage by inhibiting the expression of DNA repair proteins and further suppressed PDAC tumor growth in vivo when administered in combination with the PARP inhibitor olaparib. G2 cell cycle abrogators have been shown to sensitize cells to gemcitabine. Having shown JQ1 inhibited the expression of G2 cell cycle regulator CDC25B we investigated the efficacy of JQ1+gemcitabine. In vitro and in vivo results demonstrated that the combination was more effective than either single agent. Furthermore, we developed gemcitabine resistant cell lines and PDX models to generate a clinically relevant model of gemcitabine resistance. We showed that gemcitabine resistant PDAC cells may be more sensitive to BET inhibitors, suggesting that JQ1 may be an effective treatment to overcome gemcitabine resistance. Taken together these data support BET inhibition as a reasonable approach for the treatment of PDAC, and that combining BET inhibitors with currently available therapeutics may provide a more durable response.

Share

COinS