Pancreatic cancer (PanCa) treatment is exceptionally difficult due to the extremely poor response to available therapeutic options. This poor response is mainly due to dysregulation of ribosome biogenesis and desmoplastic pancreatic tumor microenvironment. The main objective of this SC1 proposal is to establish a rationale based novel therapeutic regimen for the treatment of advanced stage pancreatic cancer (PanCa). This novel therapy will provide therapeutic benefit and circumvent chemoresistance via simultaneous targeting of ribosome biogenesis by RNA polymerase I inhibitor (BMH-21) and desmoplastic tumor microenvironment with hyaluronan inhibitor (4-Methylumbelliferone). The ribosome biogenesis is the complex and highly coordinated cellular process leading to the production of ribosomes. This process is aberrantly operated during the development of cancer, including PanCa and also involved in chemoresistance to therapeutic drugs, such as including gemcitabine. Hyaluronan (Hyaluronic acid) is one of the major components of the extracellular matrix secreted by fibroblasts and pancreatic stellate cells which is involved in the formation of desmoplasia in pancreatic tumors that prevent drug accessibility in the tumors. Thus, strategically targeting of both ribosome biogenesis and hyaluronan synthesis will effectively suppress the growth and metastasis of pancreatic tumors. BMH-21 was recently developed as a potent selective inhibitor of RNA polymerase that has shown potent anti-cancer effect in pre-clinical studies. Our preliminary results have shown promising anti-cancer and chemosensitization effects of BMH-21 in PanCa models. 4-Methylumbelliferone (4-MU) is a non-toxic hyaluronic acid synthesis inhibitor with an anti-cancer property that has never been tested in combination with BMH-21 for PanCa treatment. BMH- 21 demonstrated remarkable tumor growth inhibition in the orthotopic tumor xenograft mouse model when combined with 4-MU. Based on these compelling evidences, we hypothesize that the combination of BMH-21 and 4-MU proffers a pronounced anti-cancer efficacy due to improved drug uptake into tumors via repression of desmoplasia and ribosome biogenesis processes. Three specific aims are proposed. In Aim 1, we plan to investigate underlying molecular mechanisms and functional impact of BMH-21 and 4-MU to inhibit the growth, metastatic phenotypes, and overcome chemoresistance. In Aim 2, we will investigate whether and how BMH-21 and 4-MU combination inhibits pancreatic tumor growth and metastasis in an orthotopic xenograft mouse model. Under Aim 3, we will elucidate the therapeutic and chemosensitization efficacy of BMH-21 and 4-MU combination in a transgenic mouse model (KPC) of PanCa. We will also determine how this combination influences pancreatic tumor immune surveillance. This study has a high significant translational impact on the clinic as it will establish a new rationale-based therapy for the treatment of advanced metastatic PanCa i...