Overcoming barriers to nucleic acid therapeutics in cancer

Nucleic acid-based drugs, e.g., siRNA, antisense and mRNA-based drugs, are a novel class of drugs that offer the prospect to revolutionize medical therapy in general and cancer therapy in particular.

However, efficient intracellular delivery of oligonucleotides to the cytosol of target cells remains a substantial obstacle to their widespread and effective use.

Here, I propose to devise novel strategies to improve tumor targeted siRNA delivery in general and in particular to malignant gliomas, with the ultimate aim to bring tumor targeted nucleic acid drugs to the clinic.

For this purpose, I will characterize the molecular mechanisms involved in siRNA-ligand-conjugate delivery and quantitatively define the key barriers to RNA-therapeutics delivery in tumors.

I hypothesize that cells, especially metabolically stressed cancer cells, continuously experience intracellular membrane damages and that these membrane damages constitute a pathway into cells for membrane impermeable siRNA drugs.

In particular, I propose that membrane destabilizing small molecule drugs might synergize with metabolically and pharmacologically stressed tumor cells to facilitate siRNA delivery.