EDVs Combat Drug Resistant Tumors using siRNAs
Multi-drug resistance is the biggest threat to long-term survival of cancer patients. Despite treatment, some tumor cells survive chemotherapy and become resistant to the drugs, causing follow-up treatments to fail. These drug-resistant tumors become untreatable and continue to flourish, ultimately killing the patient. Multi-drug resistance proteins expressed by tumor cells are a major source of resistance to conventional chemotherapeutic drugs. Small interfering RNAs (siRNAs) can silence these messenger RNAs that make multi-drug resistance proteins and EnGeneIC has discovered that EDVs can effectively load up to 10,000 copies of siRNA and deliver them directly to cancer cells. This process silences the respective messenger RNAs and makes the tumor cells sensitive to chemotherapeutic drugs which are subsequently delivered via the EDVs to eradicate the formerly drug resistant tumor. EnGeneIC has demonstrated in mouse studies carrying human drug resistant tumors and the data has been published in our Nature Biotechnology scientific publication.
Mice bearing tumors derived from a highly aggressive human uterine cancer cell line (MES-SA/Dx5) that markedly overexpresses MDR1, were treated with 1 x 109 EDVs per dose (arrowheads indicate days on which mice were treated, as indicated on the x- axis). EDVs were targeted to the epidermal growth factor receptor (EGFR) on the cancer cells (EGFREDV) and loaded with either the chemotherapeutic drug doxorubicin (EGFREDVDox), a short hairpin RNA targeting MDR1 (EGFREDVshMDR1), or a short hairpin nonsense control (EGFREDVshNonsense). Error bars indicate ± s.e.m, with 6 mice per treatment group.
siRNA delivery to directly combat tumors
There are a number of validated siRNAs that can directly trigger the death of different cancer cells. Via the EDVs, we have done a number of xenograft studies in mice where we have shown potent anti-tumor efficacy via the delivery of specific siRNAs. By way of example;
Mice bearing tumors derived from a colorectal cancer cell line (HCT116), were treated with 1 x 109 EDVs per dose (arrowheads indicate days on which mice were treated, as indicated on the x- axis). EDVs were targeted to the epidermal growth factor receptor (EGFR) on the cancer cells (EGFREDV) and loaded with either small interfering RNA (siRNA) targeting KSP-2 (EGFREDVsiRNA-KSP-2), siRNA targeting Plk-1 (EGFREDVsiRNA-PLK-1), siRNA targeting CDK-1 (EGFREDVsiRNA-CDK-1), or a siRNA nonsense control (EGFREDVsiRNA-Nonsense). Error bars indicate ± s.e.m, with 8 mice per treatment group.
Human trials – siRNA delivery to treat end-stage Adreno-cortical cancer patients (Tailored EDV Trial)
In our tailored EDV trial, EGFR-targeted, siRNA-packaged EDVs have been used to treat end-stage Adreno-cortical cancer patients. This safety, Phase I trial is at an early stage but no adverse events have been noted due to the siRNA.