Abstract

This thesis is divided into three chapters. In each case, the goal is to achieve inhibition of a growth kinase (PIM or AXL) and subsequent arrest of cell growth and induction of apoptosis (in vitro cell culture models) or decrease in tumor volume (in vivo xenograft studies). Chapter one and chapter two discuss inhibition of proviral integration site for Moloneymurine leukemia virus (PIM) kinases. The three PIM kinases, PIM-1, PIM-2, and PIM-3, are a subfamily of serine/threonine kinases that are known to be involved in signaling pathways as downstream effectors of signal transducer and activator of transcription-5 (STAT5) signaling and inhibitors of apoptosis. PIM kinases are implicated in a large percentage of hematological malignancies and solid tumors. Because they have been shown to correlate with disease progression and poor prognosis in many of these conditions, PIM kinase inhibitors are being developed and investigated for therapeutic use. The aim of this study in chapter one was to evaluate the role of PIM 1, 2 and 3 in urothelial carcinomas, using second generation Pan-PIM kinase inhibitor TP-3654. Retrospective immunohistochemical analysis of bladder cancer specimens found that PIM 1, 2, and 3 was expressed in a significant number of cases. PIM-1 was expressed in 4 bladder cancer cell lines and TP-3654 treatment was able to inhibit BAD phosphorylation to induce apoptosis. The second aim of this study was to investigate the effects of TP-3654 on the interaction of c-MYC with PIM kinase family members. The data indicate that PIM-1 only interacts with c-MYC in the acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines studied, and that PIM-1 siRNA knockdown or treatment with TP-3654 is able to decrease this interaction. The third chapter discusses inhibition of the receptor tyrosine kinase Axl. Pancreatic cancer is a highly lethal disease characterized by malignant cells that rapidly disseminate from the primary tumor to form local and distant metastases. Axl is overexpressed in over 50% of pancreatic cancers and expression of Axl in these cancers is highly associated with a poor prognostic outcome for patients. Small molecule inhibitors of AXL are currently under investigation, as AXL is associated with cell migration mediated by epithelial-mesenchymal transition (EMT). The aim of this study was to investigate the effects of a small molecule inhibitor of AXL, TP-0903, on pancreatic cancer cell lines. Consistent with the known function of Axl, TP-0903 inhibited Gas6-induced migration and invasion of pancreatic cancer cells invitro and potently induced apoptosis. Additionally, we found that inhibition of AXL decreased expression of EMT marker genes and induced mesenchymal pancreatic cancer cell lines to take on an epithelial phenotype. TP-0903 also significantly inhibited the growth of pancreatic cancer cell lines grown in xenograft tumor mouse model and taken together, the results suggest Axl is a potential therapeutic target in pancreatic cancer and TP-0903 as a potential therapeutic agent.

Degree

MS

College and Department

Life Sciences; Physiology and Developmental Biology

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2014-02-24

Document Type

Thesis

Handle

http://hdl.lib.byu.edu/1877/etd6749

Keywords

STAT5 signaling, Bcl-2, BAD, apoptosis, carcinoma, oncogene, migration, metastasis, EMT, xenograft

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