The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
Describes NUAgo’s underlying technology, toxic 6-mer sequences, are functionally active in ovarian cancer cells and patient samples treated with platinum (Pt)-base chemotherapy agents, first-line in ovarian cancer. Finding that an increase in RISC-bound (active) miRNAs carrying toxic 6mer seeds and a decrease in miRNAs with nontoxic seeds. Pt-resistant cells did not exhibit this Pt induced toxicity shift but retained sensitivity to death mediated by siRNAs carrying toxic 6mer seeds. Analysis of active miRNAs in OC patient samples revealed that miRNA 6mer seed toxicity ratios were predictive of treatment outcomes. Offering a potential diagnostic in identifying Pt-resistance in patients. These results argue that 6mer seed toxicity can be exploited to treat patients with Pt-resistant OC
6mer seed toxicity in tumor suppressive miRNAs
Identifies the rules for the "kill code“ and the basis of NUAgo’s Class-1 technology through a screen of all possible combinations of 6mer seeds sequences (4096 sRNAs) with G-rich seeds targeting C-rich seed matches in the 3' UTR of a set of survival genes. These survival genes contain C-rich sequences near the beginning of their 3' UTR. miR-34-5p family of miRNAs effect is through this mechanism. Additionally, the Peter Lab describes that the kill code is evolutionally conserved and at least 800-million-year-old. Finally, this paper describes first evidence that chemotherapeutic drugs engage the 6mer seed toxicity mechanism and that cells devoid of most miRNAs (e.g., Drosha or Dicer ko cells) are hypersensitive to anything that acts through this kill mechanism.
Induction of DISE in ovarian cancer cells in vivo
sRNAs coupled nanoparticles treat xenografted ovarian cancer cells in mice. Tumors slowed down in growth and did not become resistant to treatment, and treatment did not cause toxicity in the treated mice.
Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism
Describes sRNAs killing cells through RNA inhibition by silencing genes that are essential for cell survival, determines that a 6-nucleotide sequence is sufficient to have full toxic activity and that cells devoid of microRNA are hypersensitive to cell death upon treatment, concluding that this is due to the protective activity of miRNAs blocking access to the RISC in normal tissues