A groundbreaking RNA therapy has emerged as a powerful weapon against one of the most challenging cancer genes, offering new hope in the fight against this deadly disease. This innovative approach, developed by researchers from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine), has successfully targeted the Kirsten rat sarcoma viral oncogene homolog (KRAS), a gene that has long been considered a formidable challenge in cancer research.
KRAS acts as a molecular switch, controlling cell growth and division. In healthy cells, this switch functions normally, turning on and off as required. However, in cancers like pancreatic, lung, and colorectal, KRAS mutations lock the switch in the 'on' position, leading to uncontrolled cell growth and the evasion of immune defenses. With over 90% of pancreatic cancers driven by KRAS mutations, finding an effective treatment has been a top priority.
But here's where it gets controversial: the KRAS protein's tight binding to its signaling molecules and lack of easy-to-target binding sites have made it notoriously difficult to treat. Traditionally, this gene has been considered 'undruggable,' making it one of the most critical and complex targets in cancer research.
The research team, in collaboration with experts from NUS Institute for Health Innovation and Technology (iHealthtech), Nanyang Technological University (NTU), Agency for Science, Technology and Research (A*STAR), and international partners, has developed a combination therapy using antisense oligonucleotides (ASOs) to silence mutant KRAS genes. They also utilized an immunomodulatory RNA (immRNA) to activate the Retinoic acid-Inducible Gene I (RIG-I) immune pathway, which acts as an alarm system in our cells, detecting viruses and alerting our immune system.
In the first study, published in Theranostics, the researchers demonstrated that this dual treatment effectively killed KRAS-mutant cancer cells, including those from lung, colorectal, and pancreatic cancers. By blocking oncogenic KRAS activity and triggering an antiviral-like immune response, the treatment transformed 'cold' tumors, which typically evade immune attack, into 'hot' tumors that the immune system could recognize and target. This led to reduced tumor burden and extended survival in laboratory studies, without harming healthy cells.
Building on this success, the second study, published in the Journal of Controlled Release on Science Direct, advanced the therapy to the preclinical stage for pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC) with peritoneal metastasis. PDAC is an extremely deadly form of cancer with a 5-year survival rate of just 10%. However, the treatment significantly suppressed tumor growth, limited abdominal spread, and prolonged survival in laboratory studies. Importantly, safety testing showed no observable toxicity, suggesting a promising future for clinical evaluation.
Associate Professor Minh Le, from the Department of Pharmacology and Institute for Digital Medicine (WisDM), NUS Medicine, explained, "KRAS mutations hijack cancer cells and suppress immune responses, enabling metastasis. Our EV platform precisely targets mutants, sparing healthy tissue, and synergizes KRAS knockdown with RIG-I activation, unleashing interferons, immunogenic cell death, and T-cell memory, ultimately halting tumor growth and extending survival without toxicity."
Associate Professor Glenn Bonney, a Senior Consultant in the Division of Hepatobiliary & Pancreatic Surgery at the National University Hospital (NUH), who contributed patient-derived organoids for the studies, added, "This dual nucleic acid delivery via biocompatible vesicles overcomes KRAS resistance barriers, offering a safe and scalable approach to treat peritoneal metastasis, a critical unmet need in PDAC."
Professor Dahai Luo from NTU's Lee Kong Chian School of Medicine and co-author of the papers, emphasized, "By engineering EVs for targeted delivery, we've transformed natural cell messengers into precision weapons, with broad potential for other KRAS-addicted cancers like colorectal and lung."
Adjunct Professor Jonathan Loh Yuin-Han, Deputy Executive Director (Research) at the Institute of Molecular and Cell Biology (IMCB), A*STAR, and co-author of one publication, said, "This innovative combination of KRAS-targeting ASOs and RIG-I agonists delivered via extracellular vesicles reprograms the tumor microenvironment, opening up new possibilities for treating KRAS-driven cancers and bringing us closer to effective, personalized immunotherapies that could revolutionize cancer treatment."
The research highlights the immense potential of extracellular vesicles as safe and versatile carriers for nucleic acid-based therapies. Beyond pancreatic cancer, this platform could be adapted to other KRAS-driven malignancies and combined with existing immunotherapies to enhance treatment outcomes.
And this is the part most people miss: the potential for this therapy to transform the way we treat cancer is immense. With further research and development, we could be on the cusp of a new era in cancer treatment, offering hope to those affected by this devastating disease.
