All ETDs from UAB

Advisory Committee Chair

Karina J Yoon

Advisory Committee Members

Susan Bellis

Douglas Hurst

Rajeev Samant

Ralph Sanderson

Robert Van Waardenburg

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive neoplasm which arises from the epithelial layer of the biliary tract. It is the second most common primary hepatic malignancy. As CCA is typically diagnosed at late disease stage, the current standard of care, resection followed by gemcitabine with cisplatin, is not effective. Further, up to 90% of CCA patients are ineligible for resection. Of those eligible for resection, postoperative chemotherapy does not prolong overall survival leading to a 5-year survival of ~30%. Previously, mutations have been identified in KRAS (17% of CCA cases), TP53 (44%) and SMAD4 (17%) but none have been recognized as critical for CCA. This demonstrates an imperative need to identify novel molecular targets to improve CCA patient outcome. Proto oncogene and transcription factor, c-Myc, is highly expressed in up to 94% of CCA cases while undetectable in normal liver. This suggests c-Myc overexpression may contribute to CCA, however, this hypothesis has not been addressed. The bromodomain and extraterminal domain (BET) family of proteins are epigenetic adapter proteins which promote the transcription of genes including MYC. We previously reported that the BET inhibitor JQ1 lead to significant growth reduction and decreased c- Myc expression in a patient-derived xenograft (PDX) model of CCA. Further, downregulation of c-Myc transcriptional target, Chk1, was also observed. This dissertation details the use of in vitro and in vivo models of CCA to evaluate the mechanism through which JQ1 leads to reduced tumor growth and c-Myc expression. We report that treatment of CCA in vitro models with JQ1 corroborated our CCA PDX results. In addition, downregulation or therapeutic inhibition of DNA damage response (DDR) factor, Chk1, has been reported to sensitize cancer cells to PARP inhibition as well as to gemcitabine. Therefore, we assessed whether treatment with a BET inhibitor lead to enhanced efficacy of these therapeutics in CCA. We assessed whether JQ1 in combination with PARP inhibition or gemcitabine lead to enhanced therapeutic efficacy in our in vitro and in vivo CCA models. Our models suggest that these combinations are more effective than when administered as single agents. As our results were completed using chemotherapy-sensitive models, we developed clinically relevant models of gemcitabine resistance including one cell line model and two gemcitabine resistant PDX models. Our in vitro gemcitabine resistant model showed greater sensitivity to JQ1 which suggests BET inhibition may potentially overcome gemcitabine resistance. Taken together, these data demonstrate that inhibition of BET proteins in combination with PARP inhibition or gemcitabine are rational approaches for treatment of CCA.

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