All ETDs from UAB

Advisory Committee Chair

Robin G Lorenz

Advisory Committee Members

Elizabeth A Beierle

Smita Bhatia

A Joseph Tector

Christopher D Willey

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Hepatoblastoma is the most common primary liver malignancy in children. Despite increasing incidence, treatment has not changed significantly in the past 20 years, making the need for novel therapeutics imperative. Proviral Integration site for Moloney murine leukemia virus (PIM) kinases are a family of serine/threonine kinases that have been implicated in multiple other cancer types including the adult liver cancer, hepatocellular carcinoma. Emerging evidence has begun to elucidate a role for PIM kinases in stem-cell like cancer cells (SCLCCs). This subpopulation of cells is thought tobe responsible for tumor maintenance, recurrence, metastasis, and chemoresistance. Chemoresistance is a significant barrier to effective treatment of hepatoblastoma. We hypothesized that PIM kinases would play a role in hepatoblastoma tumorigenicity, SCLCC maintenance, and chemoresistance and that inhibition of PIM kinases could effectively target this pediatric cancer. Our work established PIM3 as the particular family member that plays a role in hepatoblastoma. Using knockdown, knockout, inhibition, overexpression, and rescue models, we demonstrated that PIM3 affected viability, proliferation, cell cycle, motility, attachment-independent growth, apoptosis, and tumor growth in a mouse model using a long-term passaged hepatoblastoma cell line and a patient-derived xenograft. We also defined CD133 as a marker for SCLCCs in hepatoblastoma and found that PIM inhibition targeted SCLCCs and decreased the SCLCC phenotype. In a mouse model, PIM inhibition led to tumor regression in a majority of mice bearing tumors from SCLCC-enriched hepatoblastoma cells. We developed a cisplatin-resistant hepatoblastoma model and found that resistant cells were enriched for SCLCCs and expressed higher levels of PIM3. PIM inhibition led to resensitization to cisplatin, indicating a role for PIM inhibition in patients with chemoresistance. Finally, we assessed the frequency of PIM3 expression in patient specimens and found that the majority of hepatoblastoma specimens express PIM3 and that PIM3 expression is correlated with decreased survival. This dissertation provides evidence regarding the role of PIM kinases in hepatoblastoma tumorigenicity, SCLCC maintenance, and chemoresistance. These findings provide evidence that PIM inhibition may be a useful targeted therapy in a majority of hepatoblastoma patients and a promising treatment for those who experience poor outcomes with current treatment regimens.

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