Innovative therapy inhibits aggressive pancreatic cancer growth

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The results were led by Dr. Valerie LeBleu, Assistant Professor of Cancer Biology, and Dr. Sushrut Kamerkar, MD, MD Anderson UT Health Biomedical Graduate School and Cancer Biology Program Assistant. Published in the Natural Online Journal on June 7.

Earlier MD Anderson studies demonstrated that exosomes are a factor in the detection of pancreatic cancer, but these recent findings reveal a genetically altered exosome as a potential new approach to direct and specific targeting of mutant KRAS, which is commonly associated with pancreatic cancer. Related cancer genes.

In this study, exosomes produced by all cells and naturally present in the blood were modified to "iExosomes", which were able to deliver small RNAs to specific targeting mutant KRAS, leading to disease suppression and increased mouse models Overall survival. Researchers use a targeted approach called RNA interference (RNAi), when delivered by these natural nanoparticles or exosomes, the mutant KRAS in pancreatic cancer cells is zero, affecting tumor burden and survival in multiple pancreatic cancer models . The team has shown that exosomes can serve as an effective carrier for RNAi because these nano-sized vesicles easily cross the body into cells, including cancer cells.

When mutated, KRAS acts as a molecular on/off switch, stuck in the "on" position. It mutates in 80% to 95% of pancreatic ductal adenocarcinoma (PDAC), the most common mutation in this cancer. This study demonstrates that iExosomes is capable of providing KRAS-specific targeting genetic material called siRNA and shRNA and is more potent than their synthetic counterpart iLiposomes, which do not have the natural complexity and advantages exhibited by exosomes.

"Our research shows that exosomes have higher siRNA molecule delivery capacity and inhibit the growth of invasive pancreatic tumors compared to liposomes," LeBleu said. "We also demonstrated that the presence of CD47 on exosomes 'allows evasion of phagocytosis of circulating monocytes."

CD47 is a protein involved in many cellular processes, including cell death, growth and migration. Phagocytosis is the process by which leukocytes called macrophages digest cell debris and foreign bodies and particles. Monocytes are the largest type of white blood cells important to the immune system.

"CD47 basically activates a 'Don't Eat Me' signal to suppress phagocytosis," Kamerkar said. "We determined how CD47 helps to inhibit exosomes from clearing the circulation and enhance their delivery to pancreatic cancer cells."

Despite the current standard of care, patients with PDAC have a poor prognosis and need effective new therapies. PDAC genetic analysis shows that most patients experience KRAS mutations and play an important role in the development, progression and metastasis of cancer. Despite the presence of other genetic defects, genetic manipulation in mice to inhibit oncogenic KRAS inhibits tumor progression. Prior to this study, direct and specific goals for KRAS have been difficult to achieve.

The team also showed that cellular processes involved in cell clearance of nutrients and vesicles increased macrophages to help exons uptake in cancer cells with mutant KRAS.