For Dr. Ourania Andrisani, Distinguished Professor of Basic Medical Sciences, understanding the complexities of liver cancer has been a defining passion throughout her career. Her work marks a critical step toward developing more effective treatments for this devastating disease.
“My passion for this research stems from a deep desire to understand the intricate workings of nature, particularly the mechanisms that govern health and disease,” Dr. Andrisani said as she explained what drives her persistent pursuit of research breakthroughs.
Dr. Andrisani’s focus is on Hepatocellular Carcinoma (HCC), a form of liver cancer characterized by tumor growth in the liver. According to Johns Hopkins Medicine, liver cancer is one of the deadliest cancers in adults, claiming over 12,000 lives annually in the U.S.
In 2024, Dr. Andrisani’s team achieved a significant milestone by studying RNA helicase DDX5, an enzyme crucial for suppressing three major pathways involved in liver cancer. Their research revealed that when DDX5 is absent—such as during treatment with the liver cancer drug sorafenib—these pathways become activated, leading to treatment failure. This problem is especially prevalent in patients with Metabolic Associated Fatty Liver Disease (MAFLD), often linked to obesity and type II diabetes, where these DDX5-repressed pathways are activated.
Sorafenib, a kinase inhibitor used when immunotherapy is contra-indicated or fails, works by blocking abnormal proteins that signal cancer cells to multiply, thereby inhibiting their spread. However, the development of resistance to sorafenib remains a significant challenge, reducing its effectiveness against tumors. Dr. Andrisani and her team conducted experiments to determine why sorafenib fails to eliminate cancer cells, aiming to address this critical barrier in liver cancer treatment.
Their findings, published in August 2024 in the Nature journal Cell Death and Disease, are detailed in the study titled “DDX5 deficiency drives non-canonical NF-kB activation and NRF2 expression, influencing sorafenib response and hepatocellular carcinoma progression.” The study was funded by the NIH and supported in part by the Purdue Institute for Cancer Research (PICR), with collaboration from several Purdue faculty members, including Dr. Yoon Yeo, the Lillian Barboul Thomas Professor of Industrial and Molecular Pharmaceutics and Biomedical Engineering; Dr. Majid Kazemian, associate professor of biochemistry and computer science; Drs. Nadia Lanman and Bennett Elzey, research associate professors in the College of Veterinary Medicine’s Comparative Pathobiology Department; and Dr. Zhili Li, postdoctoral fellow in the college’s Basic Medical Sciences Department, and the first author of this study.
Dr. Andrisani explained that her team’s research identified three key pathways driving the resistance of liver cancer cells to sorafenib. This discovery not only revealed how these pathways are interconnected but also opens the door to innovative treatment strategies targeting all three pathways simultaneously. This represents a significant shift from traditional approaches that focus on suppressing individual pathways using chemical drug inhibitors.
“Our findings identify the complex interplay of key biological pathways in cancer biology. They highlight how deregulation of interconnected pathways drives disease progression and underscores the adaptability of cancer cells for continued growth,” Dr. Andrisani explained. “By proposing novel siRNA-based approaches to target multiple cancer-driving pathways, we offer a more comprehensive therapeutic strategy.”
Looking ahead, Dr. Andrisani said, “The plan is to develop tiny particles called lipid nanoparticles to deliver treatments directly to the liver. These nanoparticles will carry RNA molecules designed to block all three pathways at once. This approach has the potential to improve liver cancer treatment and prevent progression from severe liver disease, like MAFLD, to cancer.”
Dr. Andrisani notes that while the study marks significant progress in liver cancer research by identifying DDX5 as a critical factor in both development and treatment of liver cancer, key questions remain unanswered. “We still do not understand why DDX5 expression decreases with sorafenib treatment or during the progression from severe liver disease to liver cancer. Additionally, the mechanisms by which DDX5 suppresses expression of related genes across different chromosomes remain unclear.”
Despite these still unanswered questions, this research offers promising new avenues for liver cancer treatment. “This breakthrough demonstrates the power of basic science to inspire innovative solutions to fight aggressive cancers. While this is an exciting step forward, significant work remains to translate these findings into practical clinical applications.”
