Polypurine Reverse Hoogsteen (PPRH) hairpins are formed by two polypurine strands linked by a thymidine loop running in antiparallel orientations. These PPRHs interact with their specific polypyrimidine DNA sequence by Watson-Crick bonds provoking strand displacement⁽¹⁾. Previously, we demonstrated the effect of 6 different PPRHs for MYC and 5 for KRAS  targeting polypyrimidine in a specific sequence manner in reducing the cell viability, mRNA and protein levels of both targets in different cancer cell types ⁽²⁾⁽³⁾. We confirmed the specificity and affinity with each PPRH-target by EMSA analyses and melting assays. We selected two of the best PPRHs of KRAS and MYC, combined at 25nM each and transfected with DOTAP finding a decrease of up to 90% in cell viability of PC-3 cells. Then, we analysed gene expression at the level of RNA observing a decrease from 72 to 120h reaching 43 and 44% for KRAS and MYC, respectively. Nevertheless, there is an increase of up to 1.5 and 2.5 fold in KRAS and MYC mRNA expression at early time points probably to counteract the inhibitory effect of the PPRHs. Further analyses, including protein determination with specific antibodies, will be performed with these combinations in various KRAS-MYC dependant cancer cell types. Our results proved that PPRHs provoke specific oncogene gene-silencing and therefore can be used for cancer treatment at very low doses.