Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Joyce Solheim

Abstract

Pancreatic cancer has a dismally low survival rate, due to inadequate understanding of the processes that are involved in disease development and progression. Despite the identification of oncogenic drivers such as KRAS and p53, there is a need for the identification of molecular targets to improve and develop novel therapeutic approaches for the treatment of pancreatic cancer. Studies from our laboratory have identified and evaluated targets and therapeutic approaches that can aid in our understanding of pancreatic cancer disease progression and improve patient outcomes. Through the use of epidermal growth factor receptor (EGFR) ligands (EGF and TGF-α) and small molecule inhibitor erlotinib, we evaluated the effects that EGFR activation and inhibition have on MHC class I expression. Activation of EGFR by EGF and TGF-α led to decreased expression of MHC class I at the cell surface. EGFR and MHC class I were also found to associate with one another. Inhibition of EGFR by erlotinib led to significant increases in MHC class I expression at the cell surface. We further investigated the ability of an histone deacetylase (HDAC) inhibitor (M344) to enhance MHC class I expression on pancreatic cancer cells, and found M344 increased it, while also inhibiting cell viability, proliferation, migration and having longer lasting anti-proliferative effects than the FDA-approved vorinostat. In combination with gemcitabine, M344 was found to significantly slow tumor growth in an orthotopic mouse model.

Utilizing our novel KPC mouse model with pancreas-specific loss of amyloid precursor-like protein 2 (APLP2) (KPCA), which has been shown to prolong survival and inhibit metastasis, we investigated the role APLP2 has on collagen deposition during tumor development and the ability of APLP2 to alter pancreatic cancer cells to sense the tumor microenvironment. Loss of APLP2 led to a biphasic shift in collagen deposition, decreased integrin expression, and increased actin expression. Overall, we have shown that APLP2 and its downstream targets provide novel therapeutic strategies, while the use of erlotinib and M344 could potentially improve efficacy for the treatment of pancreatic cancer when used in a combinatorial approach with immunotherapy.

Download

Share

COinS