Presentation Type
Oral Presentation
Discipline Track
Translational Science
Abstract Type
Research/Clinical
Abstract
Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine (GEM), a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis (RiBi), which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting RiBi process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A (RPA194) overexpression and how its targeting along with p53 status impacts RNA polymerase I inhibitor therapy against PanCa. The expression level of RPA194 was significantly elevated in pancreatic tumor tissues when compared with adjacent normal pancreatic tissues. BMH-21 is a potent pharmacological inhibitor of RNA Pol I, which is known to degrade RPA194 protein. Our results demonstrated that BMH-21 can selectively induce apoptosis in various PanCa cells but not in HPNE cells. We also found that the cytotoxic effect of BMH-21 was dependent on the expression pattern of RPA-194 and p53 status. We further examined the therapeutic efficacy of BMH-21 in orthotopic xenograft mouse models by using two different PanCa cells, AsPC1 which contains non-functional p53 and MIA PaCa-2 which contains functional mutant p53. We observed that BMH-21 significantly inhibited the growth of tumors derived from both cancer cell lines. Interestingly, BMH-21-mediated inhibition of tumor growth was more significant in tumors derived from MIA PaCa-2 cells compared to AsPC1 cells. Further examination revealed that the inhibition of tumor growth was correlated with RPA194 degradation followed by inhibition of cell proliferation. Overall, our results strongly suggest that BMH-21 is a promising non-toxic agent for the treatment of advanced PanCa and its therapeutic potential depends on RPA194 expression and p53 status in PanCa cells.
Academic/Professional Position
Faculty
Mentor/PI Department
Immunology and Microbiology
Recommended Citation
Ahmad, Mudassier; Alvi, Sahir Sultan; Ahsan, Haider; Perez, Carlos; Bangash, Muhammad; Massey, Andrew; Anning, Emmanuel; Bangash, Aun A.; Sebastian, Manu; Tripathi, Manish; Joon Kim, Dae; Chauhan, Subhash C.; and Hafeez, Bilal B., "Clinical significance of targeting ribosome biogenesis in pancreatic cancer therapy" (2024). Research Symposium. 35.
https://scholarworks.utrgv.edu/somrs/2024/talks/35
Included in
Clinical significance of targeting ribosome biogenesis in pancreatic cancer therapy
Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine (GEM), a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis (RiBi), which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting RiBi process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A (RPA194) overexpression and how its targeting along with p53 status impacts RNA polymerase I inhibitor therapy against PanCa. The expression level of RPA194 was significantly elevated in pancreatic tumor tissues when compared with adjacent normal pancreatic tissues. BMH-21 is a potent pharmacological inhibitor of RNA Pol I, which is known to degrade RPA194 protein. Our results demonstrated that BMH-21 can selectively induce apoptosis in various PanCa cells but not in HPNE cells. We also found that the cytotoxic effect of BMH-21 was dependent on the expression pattern of RPA-194 and p53 status. We further examined the therapeutic efficacy of BMH-21 in orthotopic xenograft mouse models by using two different PanCa cells, AsPC1 which contains non-functional p53 and MIA PaCa-2 which contains functional mutant p53. We observed that BMH-21 significantly inhibited the growth of tumors derived from both cancer cell lines. Interestingly, BMH-21-mediated inhibition of tumor growth was more significant in tumors derived from MIA PaCa-2 cells compared to AsPC1 cells. Further examination revealed that the inhibition of tumor growth was correlated with RPA194 degradation followed by inhibition of cell proliferation. Overall, our results strongly suggest that BMH-21 is a promising non-toxic agent for the treatment of advanced PanCa and its therapeutic potential depends on RPA194 expression and p53 status in PanCa cells.