All ETDs from UAB

Advisory Committee Chair

Karina J Yoon

Advisory Committee Members

Mary-Ann Bjornsti

Chris A Klug

Charlesa N Landen

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Pancreatic cancer (PC) and cholangiocarcinoma (CCA) are the most common malignancies of the pancreaticobiliary system and represent a serious health concern worldwide. These cancers present late in the course of disease limiting treatment options, with the majority of patients receiving chemotherapy. However, currently available chemotherapy has not impacted overall patient survival, and new therapies are urgently needed. Preclinical drug testing is essential to identifying chemotherapeutic agents that have potential clinical utility and it is essential that we utilize models that can best predict clinical efficacy. One model, the patient derived xenograft (tumorgraft) model has been shown to retain tumor heterogeneity, recapitulate tumor architecture, and be a better predictor of clinical utility, than established cell lines. Thus, we proposed that tumorgraft models would be critical to better understanding these malignancies and to evaluate chemotherapeutic compounds. The first goal of this dissertation was to establish a panel of tumorgraft models of PC and CCA by subcutaneous implantation human tumor specimens into immunocompromised mice. We investigated and showed that tumorgraft models of PDAC and CCA retain key histological, genetic, and molecular features of the primary tumor after serial propagation in mice. The second goal of this dissertation was to utilize these tumorgraft models as a platform for in vivo drug evaluation. First, we validated our tumorgraft model system by testing the standard of care gemcitabine. As expected, gemcitabine strongly suppressed tumor growth. Next, we evaluated the novel bromodomain inhibitor JQ1, which has been shown to induce its antitumor activity through an inhibition of the oncogene c-Myc. A subset of PC and CCA tumors have been shown to express c-Myc, but the effects of c-Myc inhibition has not been explored. Interestingly, JQ1 administration resulted in a suppression of tumor growth in all (5 PC and 1 CCA) tumorgraft models tested. Work presented in this dissertation further clarifies the potential mechanisms of JQ1 inhibition in pancreaticobiliary malignancies. We conclude that tumorgrafts can faithfully recapitulate key features of the primary tumor and be used as a platform for in vivo drug evaluation. Also, bromodomain inhibition warrants further investigation as a potential treatment strategy for pancreaticobiliary malignancies

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