KRAS, be silent!
Despite the increase in cancer survival, more than 90% of patients with pancreatic cancer die within five years. Most patients with pancreatic tumors (as well as half of patients with colorectal cancer) carry a mutation in the KRAS gene, which normally controls cell growth and death.
The KRAS oncogene was discovered more than 35 years ago and is considered one of the targets in cancer therapy – especially for cancer (for example, pancreas), often diagnosed late and in dire need of improved therapy to increase survival. However, researchers who continue to look for effective ways to disable the mutated form of the KRAS protein, which promotes the growth of deadly tumors, call it unapproachable.
A preclinical study conducted by the University of South Florida College of Medicine (USF Health) has shown that specially designed peptide-based nanoparticles can inhibit the growth of pancreatic cancer without toxic side effects and therapeutic resistance, often observed when testing new drugs.
Nontoxic peptide-based p5RHH nanoparticles deliver a small interfering RNA (siRNA) molecule that silences the chemical signal informing the KRAS oncogene about the synthesis of mutated KRAS proteins. The developed system of nanoparticles delivers a sufficient amount of siRNA from the bloodstream to tumor cells without destroying or removing them.
Three-dimensional reconstruction of a pancreatic cancer cell treated with siRNA nanoparticles. Confocal microscopy shows the accumulation of si-RNA (pink) within the boundaries of the cell membrane (turquoise). Lysosomes (yellow), which can destroy nanoparticles, are not affected. Source: University of Washington in St. Louis.
Compared with control cells, nanoparticle treatment of pancreatic and colon cancer cells ensures the delivery of KRAS-specific siRNA, a decrease in KRAS RNA expression and leads to the death of tumor cells. Using a mouse model of spontaneously occurring pancreatic cancer, the researchers also demonstrated that intravenously injected nanoparticles can selectively target siRNA against the KRAS oncogene to eventually slow the growth of pancreatic cancer caused by this mutation.
Pancreatic cancer is difficult to treat in part because the fibrous tissue that surrounds a solid tumor is much denser than the stroma surrounding other tumors. This protective stromal barrier can complicate nanoparticle treatment.
The p5RHH peptide nanoparticles are so small that they can penetrate into hard-to-reach areas. This guarantees the safety of treatment, since localization in specific tumor cells excludes the effect on healthy tissues.
Another advantage of the new nanoplatform carrying siRNA is that the target that needs to be silenced can easily be changed or others added to it for simultaneous treatment in the same tumor cell.
Nanoparticles have also shown the promise of treatment with siRNA in mouse models of atherosclerosis and arthritis.
Become M. S. Strand et al. Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles is published in the journal Oncotarget.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on EurekAlert: Silencing RNA nanotherapy shows promise against pancreatic cancer.