Development of a DISE-inducing, short RNA therapeutic to treat ovarian cancer

PROJECT SUMMARY Existing targeted cancer therapies have failed to produce a cure for any solid cancer. Checkpoint inhibitor immunotherapies are curative for only a small percentage of melanoma patients (<15%) and have significant side effects that reduce patients’ quality of life. Ideally, new therapeutics should either cure cancers or enable their management as chronic diseases. The goal of this Fast-Track STTR project is to continue the development of a novel, safe cancer therapy that works across cancer indications and cannot be overcome by mechanisms of resistance. NUAgo Therapeutics’ innovation is based on groundbreaking research at Northwestern University that has identified a new evolutionarily conserved RNA interference (RNAi)-based form of cell death that targets survival genes (Death Induced by Survival gene Elimination, or DISE). DISE is effective against all cancers tested to date. Importantly, the nature of the DISE mechanism means that cancer cells cannot become resistant to the therapy, and it does not affect normal tissues. The investigators have designed and validated a novel class of short interfering RNAs (termed “sRNAs” to distinguish them from traditional siRNAs) that target dozens of mRNAs encoding cell survival proteins in a microRNA (miRNA)-like fashion. Each sRNA silences many targets in multiple survival pathways, eliminating treatment resistance arising from mutations or alternative pathway selection. Importantly, naturally occurring miRNAs out-compete these sRNAs in normal cells, preventing sRNAs from binding to Argonaute proteins and loading into the RNA-induced silencing complex (RISC). However, miRNA expression is globally downregulated in cancer cells, allowing our therapeutic sRNAs to promote cancer cell death. Preliminary data show that sRNAs delivered systemically via lipid polyplexed nanoparticles (LPP) limit tumor growth in murine and rat cancer models and kill cancer cells derived from human ovarian, prostate, and liver cancer, with no observed toxicity to normal cells. This Fast-Track project focuses on the preclinical requirements to develop NUAgo Therapeutics’ first sRNA (sG5C) formulated as LPPs (“NU001”) as a therapy for ovarian cancer, where there is a high need due to rapidly emerging resistance to existing therapies. Successful completion of the aims will optimize sG5C delivery and provide necessary preclinical data to successfully achieve Investigational New Drug status. In Phase I, we will evaluate the in vivo efficacy of sG5C- LPP in platinum-resistant OC xenografts and PDX models of HGSOC. In Phase II Aim 2, we will assess the cancer selectivity and in vivo efficacy of sG5C-LPP in a murine model of ovarian cancer. Aim 3 work will develop a stable NU001 formulation that can be used in subsequent IND-enabling in vivo studies. Aim 4 work will study the absorption, distribution, metabolism, and excretion of NU001 separately administered by the intraperitoneal and intravenous routes to provide key data for an eventual IND submission.