Nature: A major breakthrough! Treatment of pancreatic cancer with exosomes targeting KRAS mutant genes

- Jul 17, 2018-

An exosome is a virus-sized particle released by all cells. They naturally exist in the blood. According to a new study from the MD Anderson Cancer Center at the University of Texas, a genetic manipulation of exosomes may provide a new treatment for pancreatic cancer. The results of the study were published online June 7, 2017 in the journal Nature, entitled "Exosomes facilitating therapeutic targeting of oncogenic KRAS in pancreatic cancer". The author of the paper is Dr. Raghu Kalluri, a researcher in the Department of Cancer Biology at the MD Anderson Cancer Center at the University of Texas.


Early studies at the University of Texas MD Anderson Cancer Center have confirmed that exosomes can be used to detect pancreatic cancer, but these latest findings reveal that as a potential new therapy, genetically engineered exosomes can be used directly And specifically targeting KRAS mutant genes that are frequently associated with pancreatic cancer.


In this new study, genetically modified exosomes (called iExosome) are capable of transporting small RNA molecules that specifically target KRAS mutant genes, resulting in a remission of pancreatic cancer model mice, increasing their total Survival rate. These researchers used a targeting approach called RNA interference (RNAi): using these natural nanoparticles (ie, exosomes) to transport small interfering RNA (siRNA) or short hairpin RNA (shRNA) molecules to target KRAS mutations in pancreatic cancer cells, thereby affecting tumor burden and survival in a variety of pancreatic cancer models. They confirmed that exosomes can function as a highly efficient RNAi vector because these nano-sized vesicles (ie, exosomes) easily migrate in the body and enter target cells, including cancer cells.


KRAS, which is a molecular on/off switch, is in an "on" state when it is abruptly changed. In 80% to 95% of pancreatic ductal adenocarcinoma (PDAC), this gene is mutated, which is the most common mutation in this cancer. These researchers demonstrated that iExosome is capable of delivering siRNA and shRNA molecules that specifically target KRAS and is more efficient than their synthetic counterpart liposome. Liposomes do not have the natural complexity and advantages exhibited by exosomes.


Dr. Valerie LeBleu, assistant professor of cancer biology at the MD Anderson Cancer Center at the University of Texas, said, "Our research suggests that exosomes exhibit superior ability to deliver siRNA molecules and inhibit the growth of invasive pancreatic tumors compared to liposomes. It was confirmed that the presence of CD47 on the surface of exosomes allowed them to evade phagocytosis from circulating monocytes."


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


Dr. Sushrut Kamerkar, an intern at the Department of Cancer Biology at the MD Anderson Cancer Center at the University of Texas, said, "Fundamentally, CD47 initiates a 'Don't Eat Me' signal to suppress phagocytosis. We identified how CD47 blocks exosomes in the blood. The circulation is cleared and promotes delivery to pancreatic cancer cells."


Despite the current standard of care, the prognosis of patients with PDAC is poor, so effective new therapies are urgently needed. Genetic analysis of PDAC showed that KRAS mutations occur in the vast majority of patients and play a significant role in cancer initiation, progression and metastasis. In spite of other gene defects, the use of gene manipulation to inhibit carcinogenic KRAS genes in mice prevents tumor progression. Prior to this, it was unreachable to develop a direct and specific method for targeting KRAS.


The researchers also confirmed that a cellular process called macropocytosis promotes the uptake of exosomes by cancer cells that develop KRAS mutations. Giant cell drink participates in cells to remove nutrients and vesicles.


"Consistent with previous findings, the increased number of exosomes reaching the pancreas may provide further advantages for exosomes to enter KRAS-associated cancer cells," Kamerkar said. "Although pancreatic tumors are dense, Matrix, our results also support the efficient uptake of iExosome by cancer cells. Further research is needed to better understand whether exosomes entering cells through giant cells have other features that may enhance their anti-tumor ability. ”

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