Designing novel therapeutic strategies against tumor stroma and fibrosis

Fibrosis is a pathological outcome of most chronic inflammatory diseases and characterized with the accumulation of abundant extracellular matrix component produced by myofibroblasts. These prominent cells are found both in fibrosis and fibrotic tumor such as pancreatic cancer. In normal condition, fibroblasts maintain structural integrity of healthy tissue. However, in fibrotic diseases and in cancers, fibroblasts play a vital role in the development of the diseases. During tumor progression, malignant cells recruit surrounding cells including fibroblasts and together create tumor microenvironment (TME). The TME presents a complex network that contribute in the tumor progression, invasion, metastasis, and resistance. With the increasing understanding of the TME and its key players, novel therapeutic strategies have been investigated with focus on the modulation of the TME.

This thesis describes the development of specific targeting to achieve better outcome of the treatment. In detail, the first chapter of this thesis describes fibrosis in organs and cancers and their current treatment strategies. In the context of cancer, we specifically targeted human pancreatic stellate cells (hPSCs), the key cells in the pancreatic cancer progression. Relaxin (RLX), a biological that is able to reverse fibroblast activation was investigated in pancreatic cancer (chapter 2). In addition, RLX was also examined in a different fibrotic disease, liver cirrhosis (chapter 3). Another biomolecule, fibroblast growth factor 2 (FGF2) was also investigated in a 3D heterospheroid models of pancreatic cancer in vitro (chapter 4). Next to endogenous biologicals, novel peptides were designed to target integrin α5 (ITGA5), a potential therapeutic target in pancreatic cancer. The properties of peptides, including secondary structures, binding affinity, stability in plasma, and their inhibitory effect against ITGA5 were elucidated (chapter 5). The most promising peptide (cyAV3.3) were then further trailed in more relevant models (chapter 6). In vitro data collectively indicate that cyAV3.3 is able to induce the therapeutic effects of gemcitabine by inhibiting hPSCs. Furthermore, cyAV3.3 reduced the tumor growth in co-injection tumor models in vivo in mice.

There is an unmet clinical need for novel therapeutic strategies to treat pancreatic cancer since the common treatments such as radiotherapies and chemotherapies are failing to cure patients. This thesis explores several strategies to actively target and modulate the stroma in pancreatic cancer and shows the benefits of stroma targeting.