A genetically engineered microRNA-34a prodrug demonstrates anti-tumor activity in a canine model of osteosarcoma

Abstract

Osteosarcoma (OSA) represents the most common primary bone tumor in humans and pet dogs. Little progress has been made with regard to viable treatment options in the past three decades and patients presenting with metastatic disease continue to have a poor prognosis. Recent mouse studies have suggested that microRNA-34a (miR-34a) may have anti-tumor activities in human OSA models. Due to the conservation of microRNA across species, we hypothesized that a bioengineered miR-34a prodrug (tRNA/miR-34a) would have similar effects in canine OSA, providing a valuable preclinical model for development of this therapeutic modality. Using a panel of canine OSA cell lines, we found that tRNA/miR-34a reduced viability, clonogenic growth, and migration and invasion while increasing tumor cell apoptosis. Furthermore, canine OSA cells successfully process the tRNA/miR-34a into mature miR-34a which reduces expression of target proteins such as platelet derived growth factor receptor alpha (PDGFRα), Notch1 and vascular endothelial growth factor (VEGF). Additionally, our subcutaneous OSA xenograft model demonstrated in vivo tumor growth delay, increased necrosis and apoptosis by tRNA/miR-34a, and decreased cellular proliferation ability. Taken together, these data support that this novel microRNA-based therapy may possess clinical utility in a spontaneously-occurring large animal model of OSA, which can then serve to inform the clinical development of this therapy for human OSA patients.

Current trends in drug metabolism and pharmacokinetics

“…With such novel bioengineered miRNA agents produced cost effectively and on a large scale, extensive functional studies have been conducted and the results showed rather a modest change in the PK of major CYP probe drugs in mouse models 134 . Further studies have demonstrated the utility of miRNAs as therapeutics or sensitizing agents for the treatment of human diseases in various animal models 133 , 135, 136, 137, 138, 139.…”

MiRNAs in Canine and Human Osteosarcoma: A Highlight Review on Comparative Biomolecular Aspects

“…Stable overexpression of miR-34a in canine OS cell lines also reduced the expression of angiogenic factors such as VEGFA (Vascular Endothelial Growth Factor) with a concomitant consequent decrease in cell invasion and migration [ 47 ]. Furthermore, lower expression of mi-34a in tumor and plasma has also been associated with poor prognosis and chemo resistance, and, recently, a new bioengineered tRNA/miR-34a prodrug demonstrated important antitumor activity in a canine model of OS [ 4 ].…”

“…The comparison of the expression of microRNAs among neoplastic and normal cells has further established their role in the oncogenesis of many tumors by means of interaction and promotion mechanisms on target genes [ 3 ]. Moreover, the miRNAs alterations often correlate with a more aggressive tumor biological behavior, making these molecules potential prognostic and therapeutic targets [ 4 ].…”

Novel approaches for efficient in vivo fermentation production of noncoding RNAs

“…BERAs carry no or minimal posttranscriptional modifications, are biologically active in regulating target gene expression and cellular processes, and are well tolerated in animal models (Alegre et al 2018;Chen et al 2015;Ho et al 2018;Jian et al 2017;Jilek et al 2017;Jilek et al 2019;Li et al 2015;Li et al 2018;Tu et al 2019;Umeh-Garcia et al 2019;Xu et al 2019;Zhang et al 2018;Zhao et al 2016;Zhao et al 2015), resembling cellular RNAi mechanisms (Fig. 3).…”