Exosomes facilitate targeted therapy in pancreatic cancer

Exosomes can be used as vehicles to deliver therapeutic siRNAs, which specifically target the mutant form of KRAS, to the pancreas inhibiting the action of this oncogene. About 70% of patients with pancreatic cancer harbour mutations in the gene KRAS. Exosomes carrying siRNA contain at their surface the CD47 protein, the "don't eat me" signal that allows the exosomes to bypass the clearance by the immune system. In this way, exosomes carrying the siRNA arrive to the pancreas leading to a considerable inhibition of tumor growth and metastatic dissemination in mouse models of pancreatic cancer.

Authors and Affiliations: 

Sushrut Kamerkar¹, Valerie S. LeBleu¹, Hikaru Sugimoto¹, Sujuan Yang¹, Carolina F. Ruivo², Sónia A. Melo^1,2, Jack J. Lee³ and Raghu Kalluri^1
1 Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77005 

² Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal (i3S), 4200 Porto, Portugal; Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP), 4200 Porto, Portugal 
³ Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77005 

Abstract:
The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic KrasG12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes."

Journal: Nature

Link: http://www.nature.com/nature/journal/v546/n7659/full/nature22341.html?foxtrotcallback=true