Pancreatic ductal adenocarcinoma (PDAC) stands as a formidable opponent in the cancer arena, known for its stealthy progression and devastating impact. It ranks among the top causes of cancer-related deaths globally and, by the next decade, is expected to rise to a leading cause. The lethality of PDAC lies in its aggressive nature, the deep-seated anatomical location of the pancreas, its frequent diagnosis at advanced stages, and its notorious reputation for shrugging off limited conventional treatments. This dire situation underscores an urgent call to action for the scientific community to decode the molecular mysteries driving PDAC’s relentless advance, paving the way for innovative and effective therapeutic interventions.
PDAC, known for its aggressive nature and challenging treatment landscape, may soon face a new contender in the battle against cancer progression. Prof. Upender Manne and his colleagues at the University of Alabama at Birmingham, in collaboration with researchers from Washington University in St. Louis and the University of Texas Rio Grande Valley, have published a groundbreaking study in the peer-reviewed journal Neoplasia. The results illuminate a novel therapeutic target, TRIP13. This protein, overexpressed in PDAC tumors, plays a significant role in tumor growth, metastasis, and chemotherapy resistance.
The innovative approach of the research focused on genetic knockdown of TRIP13 and its pharmacological inhibition using a small molecule inhibitor, DCZ0415. Prof. Manne and his colleagues meticulously documented the substantial impact of TRIP13 suppression on PDAC cell proliferation, invasion, migration, and metastasis. Key signaling pathways associated with cancer progression were disrupted, marking a significant step forward in PDAC treatment strategies.
The foundation of this remarkable study rested on a diverse and robust methodological framework. Initially, the research team sought to understand the oncogenic role of TRIP13 in PDAC. They discovered that TRIP13 acts as a promoter of PDAC growth and metastasis. Notably, targeting TRIP13 with the inhibitor DCZ0415, either alone and alongside standard treatments, effectively halts the progression of PDACs characterized by high TRIP13 expression.
To explore this role across a spectrum of PDAC cell behaviors, the team employed a variety of human PDAC cell lines, showcasing a range of genetic backgrounds. “We procured Human PDAC cell lines that exhibited various mutational statuses. These cell lines were instrumental in our comprehensive analysis,” explained Prof. Manne.
A key aspect of the research was assessing the migratory potential of PDAC cells through wound healing assays. This method not only illuminated the impact of TRIP13 inhibition on cell migration but also provided a tangible measure of the inhibitor’s efficacy. “For shRNA studies, TRIP13-silenced and control cells, as well as those treated with DCZ0415, underwent wound healing assays to determine the effect on migration. This approach allowed us to visually and quantitatively assess the impact of TRIP13 targeting on PDAC cell dynamics,” Prof. Manne elaborated on the methodological nuances.
The implications of these findings are profound, provide a rationale to conduct a biomarker-driven clinical trial, and offer hope for improved therapeutic strategies against PDAC. By targeting TRIP13, the study not only paves the way for potentially more effective treatments but also contributes significantly to our understanding of the molecular underpinnings of this lethal disease. In summary, the innovative research by Prof. Manne and his team marks a significant advancement in the fight against PDAC. Through meticulous methodology and a focus on TRIP13’s role in PDAC progression, this study opens new avenues for therapeutic intervention, bringing hope to patients facing this challenging diagnosis.
JOURNAL REFERENCE
Farrukh Afaq, Sumit Agarwal, Prachi Bajpai, et al., “Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma,” Neoplasia, 2024.
DOI: https://doi.org/10.1016/j.neo.2023.100951.
ABOUT THE AUTHOR
Upender Manne, MS., PhD. Dr. Manne is a professor of Pathology, Surgery, and Epidemiology at the University of Alabama at Birmingham (UAB). He is also the Director of the Translational Anatomic Pathology Section, the Co-Director of the UAB Tissue Biorepository, a Senior Scientist of the O’Neal Comprehensive Cancer Center, a Senior Scientist of the Nutrition and Obesity Research Center, and a Senior Scientist of the Minority Health & Health Equity Research Center of the Heersink School of Medicine of UAB. For about three decades, Prof. Manne has served as Principal Investigator on investigator-initiated R, P, and U series grants of the National Institutes of Health/National Cancer Institute (NCI) of the United States. He has published extensively in the field of cancer molecular biomarker discovery and validation and cancer health disparities of several human malignancies. He has developed several preclinical cancer (patient-derived xenograft and organoid) models for experimental drug testing. Additional aspects of Prof. Manne’s academic career is to train students, physicians, and scientists to conduct cancer research and to have productive academic careers.
