On August 25, 2020 Sirnaomics, Inc. , a leading biopharmaceutical company in discovery and development of RNAi therapeutics for treatment of cancer and fibrotic diseases, reported that it has published data from a preclinical discovery effort using a novel siRNA-gemcitabine conjugate construct to enhance therapeutic efficacy of the active pharmaceutical ingredient potentially for treatment of multiple types of cancer (Press release, Sirnaomics, AUG 25, 2020, View Source [SID1234564022]). The findings appeared in a manuscript entitled "A novel siRNA–gemcitabine construct as a potential therapeutic for treatment of pancreatic cancer" in the journal Nucleic Acid Research, Cancer. 2020, Vol. 2, No. 3 1.
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SiRNAs are Short Interfering RNA oligos that induce silencing effect of specific targeted genes. Gemcitabine is a nucleotide-based small molecule chemo drug that has been used in the treatment of cancers such as pancreatic cancer, bladder cancer, NSCLC, ovarian cancer, breast cancer, cholangiocarcinoma and others. Gemcitabine replaces the nucleic acid cytidine during DNA replication and can inhibit tumor growth since new nucleosides cannot be attached to this nucleoside mimic, resulting in apoptosis of the cells. While Gemcitabine is the "gold standard" therapeutic for treatment of pancreatic cancer currently, the benefit of gemcitabine treatment in patients with stage IV pancreatic cancer is marginal.
Targeted therapies have been actively sought to potentiate the efficacy of gemcitabine in killing tumor cells and therefore allow a reduction of the dose required for therapeutic efficacy. The publication describes the ability to attach gemcitabine moieties directly to a siRNA and examines the efficacy and potency improvements associated with inserting gemcitabine at various locations throughout the siRNA sequence. By modifying an siRNA against targets that augment the activity of gemcitabine (CHK1 or RAD17), Sirnaomics believes that it has demonstrated synergism in reducing cell viability across a number of pancreatic tumor cells upon transfection of the siRNAs into the cells. This synergism resulted in a product that can kill pancreatic tumor cells at a 5-100 fold lower dose than gemcitabine alone.
In the optimal construct, the gemcitabine is attached to the Sense strand of the siRNA. When administered to tumor cells, the antisense strand is separated from the sense strand as it binds to the RISC complex. The antisense strand induces silencing of the targeted gene while the sense strand is degraded in the cytoplasm – releasing the gemcitabine moieties to augment the activity from the reduction in gene expression. This siRNA-Chemo-Oligo Nucleotide (SICON) construct provides a novel therapeutic modality for advancing RNAi Cancer Therapeutics.
David Evans, PhD, Chief Scientific Officer of Sirnaomics and the senior author of the publication, stated, "Sirnaomics can deliver this SICON construct into tumor cells and tumor microenvironment, using our proprietary polypeptide nanoparticle formulation (PNP) that protects the siRNA in the plasma and minimizes toxicity of gemcitabine outside tumor tissue. The SICON construct is a single agent that provides a dual mechanism of action – making it easier for regulatory approval than using 2 separate agents. The construct will also alleviate the requirement to infuse free gemcitabine into patients at a high dose required to get delivery to the tumor tissue. Silencing the right gene target associated with gemcitabine drug resistance and tumorigenicity can further enhance the potency of our RNAi cancer drug candidates."
Patrick Lu, PhD, President and CEO of Sirnaomics, added, "This publication illustrates the Company’s continuing effort to enhance our RNAi cancer therapeutic platform, in addition to advancing our delivery technologies, large scale CMC process and clinical studies to treat various types of cancer. With advancements of our local and systemic delivery formulations, plus this unique SICON drug modality, we envision expanding the potential of RNAi cancer therapeutics."