ORCID

0009-0007-4086-0151

Keywords

Pancreatic Cancer, Colorectal Cancer, fibroblast growth factor receptor 4 (FGFR4), fibroblast growth factor 19 (FGF19), combination therapy, polyamine, tumor immune microenvironment

Subject Categories

Cancer Biology | Molecular Biology | Oncology

Abstract

Gastrointestinal (GI) cancers remain among the leading causes of cancer-related mortality worldwide, with therapeutic resistance continuing to limit the effectiveness of current treatments. Three complementary studies were conducted to identify therapeutic vulnerabilities and evaluate novel combination strategies in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).  First, dual inhibition of fibroblast growth factor receptor 4 (FGFR4) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling was investigated in PDAC models. A combination of targeted drug treatments reduced viability, clonogenic survival, migration, and suppressed signaling pathways involved in translational control. This supported a functional interaction between FGFR4 and PI3K-mTOR co-activation in clinical tumor datasets.  Second, we found using CRC models that inhibition of FGFR4 in combination with the chemotherapeutic 5-fluorouracil was antagonistic. Extracellular signal-regulated kinase (ERK) was identified as a compensatory signaling node. To overcome adaptive resistance mechanisms, dual inhibition of FGFR4 and ERK suppressed tumor-associated phenotypes, promoted apoptotic cell death, disrupted compensatory signaling, and reduced tumor growth in vitro and in vivo.  Finally, polyamine blockade therapy in combination with programmed cell death protein-1 (PD-1) inhibition was evaluated in PDAC and significantly suppressed tumor growth while remodeling the tumor immune microenvironment. Furthermore, this therapeutic strategy promoted systemic reprogramming of myeloid and lymphoid cell populations in the blood and spleen, reducing immunosuppressive phenotypes and enhancing anti-tumor immune responses. Collectively, these studies identify multiple therapeutic vulnerabilities in GI cancers and demonstrate that rational combination strategies can enhance antitumor efficacy by simultaneously targeting tumor-intrinsic signaling pathways and the tumor microenvironment. These findings advance our understanding of treatment resistance and support the development of more effective combination therapies for GI malignancies

Completion Date

2026

Semester

Summer

Committee Chair

Deborah A Altomare

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Document Type

Dissertation

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