Enzon Pharmaceuticals, Inc. (Nasdaq: ENZN) today presented data from preclinical studies of three investigational messenger RNA (mRNA) antagonists. These antagonists are based on the locked nucleic acid (LNA) technology platform targets licensed from Santaris Pharma A/S. The data were presented in poster sessions at EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics, which is being held November 16-19 in Berlin, Germany.
“The robust anti-tumor activity in these preclinical studies underscores the therapeutic potential of our third-generation mRNA antagonists to inhibit key tumor targets that are generally inaccessible to antibodies and small molecules,” said Ivan Horak, MD, Enzon’s President of Research and Development and Chief Scientific Officer. “The Locked Nucleic Acid technology on which these novel compounds are based provides significant advantages over earlier RNA-targeting agents, including greater stability, affinity, and potency. We look forward to further investigating the safety and efficacy of these compounds in the clinical setting.”
LNA-Based mRNA Compound Poster Presentations
“Down-modulation of the androgen receptor with EZN-4176 inhibits the growth of prostate tumor and potentiates the inhibitory effect of MDV-3100, a novel anti-androgen,” Yixian Zhang et al. Poster No. 218
- EZN-4176 offers a new strategy for treating castration-resistant prostate cancer (CRPC), either alone or in combination with MDV-3100. MDV3100 is a novel androgen receptor antagonist currently in Phase III testing in patients with advanced prostate cancer.
- In vitro, EZN-4176 specifically inhibited the growth of prostate tumor cells that were responsive or resistant to hormone deprivation, which correlated with down-modulation of the androgen receptor (AR), as well as AR transactivation.
- In vivo, EZN-4176 demonstrated tumor inhibition comparable to MDV-3100 and bicalutamide (Casodex ®) in CWR22 tumor xenografts, which was accompanied by down-modulation of mRNA.
- Combination with anti-androgens (MDV3100 or bicalutamide) showed much-improved inhibitory effect in growth assays compared to MDV3100 alone. In vivo, The combinatorial effect with MDV3100 was synergistic.
- EZN-3892 may provide a targeted, effective method of inhibiting tumor growth through down-regulation of β-catenin, a transcriptional regulator that is critical in the development of numerous human cancers.
- In mice bearing tumors derived from human colon and lung cancers, EZN-3892 produced 71% and 76% tumor-growth inhibition, respectively.
- Administration of EZN-3892 to mice bearing polyps with sustained β-catenin activity resulted in a 50% reduction in β-catenin mRNA in polyp tissue, while non-related mRNA was unaltered.
- In vitro, EZN-3920 potently inhibited HER3 expression and tumor growth in various tumor cells lines, including a lung tumor cell line that was selected for resistance to gefitinib and an ovarian cell line that overexpresses HER2.
- In vivo, systemic administration of EZN-3920, prepared in saline, resulted in specific down-modulation of HER3 mRNA and protein expression, as well as blockade in P13K/AKT signaling pathways in the lung and ovarian cancer xenograft models.
- In established Polyomavirus middle T transgenic mammary tumors transplanted into mice, perturbation of HER2/HER3 signaling pathway with EZN-3920 resulted in tumor growth inhibition, reduced expression of HER3, and induction of apoptosis.
- EZN-3920 may provide a novel strategy to overcome resistance to HER1 and HER2 targeted therapies. Furthermore, down-regulation of HER3 may provide a novel strategy to overcome resistance to HER1 and HER2 targeted therapies.
- Down-regulation of HER3 by an LNA antisense molecule is an effective method to inhibit tumor-cell growth both in vitro and in vivo. Robust in vivo activity was observed in 2 distinct models of breast cancer and one model of lung cancer.
- Gefitinib hypersensitivity may indicate that cells are dependent on HER3 and will be inhibited by HER3 antisense molecules.
- Sustained activation of HER3 in the presence of down-regulation of phospho-EGFR may be just as important as HER3 hyperactivation in the gefitinib-resistant cells.
- Pharmacological manipulation to down-regulate HER3 by EZN-3920 could prove to be a translational approach to controlling HER3-mediated tumor growth in cancer patients.