MRX34 is the first of a series of clinical therapeutic candidates from Mirna Therapeutics designed to mimic the activity of a human microRNA (miRNA). MRX34 is a liposome-formulated mimic of the tumor suppressor miRNA, miR-34, which is lost or expressed at reduced levels in most solid and hematologic malignancies. It functions within the p53 pathway and inhibits cancer cell growth by repressing MYC, MET, BCL2, β-catenin, and other oncogenes. The miR-34 mimic induces cell cycle arrest, senescence and apoptosis. It also interferes with the viability of cancer stem cells, creates a barrier to metastasis, and abolishes chemoresistance
To date, the anti-oncogenic function of miR-34 has been studied in numerous cancer cell types and animal models. The table below shows cancer cell types inhibited by miR-34, as well as mouse models of cancer used to demonstrate the therapeutic activity of a miR-34 mimic.
The therapeutic activity of MRX34 has been tested in a survival study (see Kaplan-Meier curve in figure below) using an orthotopic mouse model of hepatocellular carcinoma. Eight animals per study group were used. Human tumor xenografts were allowed to develop in mice for four weeks during which time tumor growth was monitored by measuring the serum levels of alpha-fetoprotein (AFP), a biomarker used to detect liver cancer. Then, MRX34 was administered over the following 6 weeks by intravenous tail vein injections. After the 6-week MRX34 therapy, mice were monitored for another 6 weeks to determine survival and the potential outgrowth of remaining tumors. As shown in the figure below (left), animals treated with phosphate-buffered saline (PBS) or a liposome containing a scrambled oligonucleotide (negative control) succumbed to tumor burden during the duration of the study. In contrast, all animals treated with MRX34 were alive and appeared healthy. The subsequent histologic and molecular analysis of these animals failed to reveal any evidence of remaining tumor cells. The survival study also included a study arm to assess the therapeutic effects of sorafenib, a small molecule inhibiting RAF and other oncogenic kinases. Sorafenib is an FDA-approved drug to treat patients with hepatocellular carcinoma.
A bio-analytical investigation of animals dosed with MRX34 shows that miR-34 mimics are maintained at high concentrations in liver cancer tissues over several days. The biodistribution profile of MRX34 also suggests that miRNA mimics can be delivered to a series of other tissues (see right panel of figure above) and cancer types. Currently, Mirna’s R&D program focuses on expanding the therapeutic utility of MRX34 and that of other miRNA mimics in oncology and in non-oncology indications. Please contact us at email@example.com to inquire about collaboration and partnering opportunities.
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Kim, N. H., Kim, H. S., Kim, N. G., Lee, I., Choi, H. S., Li, X. Y., Kang, S. E., Cha, S. Y., Ryu, J. K., Na, J. M., et al. (2011). p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal 4, ra71.
Liu, C., Kelnar, K., Liu, B., Chen, X., Calhoun-Davis, T., Li, H., Patrawala, L., Yan, H., Jeter, C., Honorio, S., et al. (2011). The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17, 211-215.