*5.1.5 miR-16*

miR-16 represents another TS-miR whose decreased expression has been observed among different types of cancers, as well as in nonsmall cell lung cancer (NSCLC) [69], prostate cancer [70], or malignant pleural mesothelioma [71], making it a strong candidate for replacement therapy in future studies with potential use in clinical trials. The data presented by Takeshita et al. [72] revealed that systemic delivery of synthetic miR-16, conjugated to atelocollagen, significantly reduced bone metastases and tumor development in a prostate cancer animal model. Moreover, their *in vitro* data suggest that miR-16 suppresses prostate tumor growth by regulating the expression of genes associated with cell-cycle control and cellular proliferation such as CDK1 and CDK2. The Hao group has also revealed that miR-16-1/atelocollagen-aptamer complex used in a mice model of human prostate cancer with bone metastasis enhanced anticancer efficacy. They also demonstrated that the efficacy of this complex, including aptamers, was higher, both *in vitro* and *in vivo* models than the other atelocollagen complexes that do not include aptamers. Re-expression of miR-16 mimic in malignant pleural mesothelioma cell lines and nude mouse models has caused the inhibition of tumor growth, correlated with downregulation of target genes Bcl-2 and CCND1 [71].

### *5.1.6 miR-155*

miR-155, one of the first described oncomiRs [73], was identified as highly expressed in a wide range of tumors including chronic lymphocytic leukemia [74], lung cancer [75], breast cancer [76], acute myeloid leukemia [77], solid tumor including stomach, prostate, colon, pancreas [78], and melanoma [79].

OncomiR-155 was discovered to target RAD51, an important gene in the homologous recombination DNA repair pathway, and the clinical study of Gasparini et al. [80] for triple negative breast cancer revealed that low miR-155 expression level correlated with worse progression-free survival. Moreover, Pouliot et al. [81] reported a reduced expression of miR-155 in human epidermoid carcinoma cisplatin-resistant cell lines. Dysregulated expression of this miRNA sensitizes the cells to cisplatin-induced apoptosis by targeting WEE1 and CHK1 kinases. Based on these results, future studies are encouraged with the focus on the use of exogenous agents, such as mimics or anti-miRs to sensitize cancer cells to chemo- or radiotherapy, thus overcoming resistance to therapy.

Alexander et al. [82] found that endogenous miR-155, an important microRNA that regulates inflammation, is released from dendritic cells within exosomes and transferred to recipient dendritic cells. Administration of miR-155 containing exosomes enhances inflammatory gene expression as a response to endotoxin-induced inflammation in mice. Their findings provide strong evidence that endogenous microRNAs follow a functional transfer between immune cells and represent a regulatory mechanism for inflammatory response.

More examples of tumor-suppressor miRNA mimics, which target multiple oncogenic transcripts, were recently presented by Hosseinahli et al. [41].

### **5.2 Clinical studies involving miRNA-based therapy**

Given the results provided by *in vitro* and *in vivo* studies, several clinical trials including miRNA-based therapy in human cancers were subsequently initiated (**Table 1**).

**41**

*MiRNA-Based Therapeutics in Oncology, Realities, and Challenges*

**Clinical trials. Gov identifier**

**Company** Mirna Therapeutics. Inc

MRX34

miR-34

Mimic

Nonsmall-cell lung carcinoma, small cell lung cancer, primary liver cancer lymphoma, melanoma,

multiple myeloma, renal cell

carcinoma

EnGeneIC

miRagen

MRG-106

miR-155

Anti-miR

Cutaneous T cell lymphoma,

mycosis fungoides, chronic

lymphocytic leukemia, adult

T-cell leukemia/lymphoma

Therapeutics

**Table 1.**

*Clinical trials using miRNA therapy in human cancers (adapted after Christopher et al. [87] and Rupaimoole et al. [88]).*

MesomiR-1

miR-16

Mimic

Malignant pleural

EnGeneIC

Strong inhibition of tumor

Multicenter

NCT02369198

phase I

completed

Multicenter

NCT02580552

phase I

recruiting

delivery

growth

vehicle

LNA-modified

Reduce overexpression

and of oncomiR, leading

to decreasing aberrant cell

proliferation

antisense

inhibitor

mesothelioma, nonsmall cell

lung cancer

**Drug**

**Targeted miRNA**

**Therapy type**

**Cancer type**

**Delivery system**

LNPs

Reduction in the expression of

Multicenter

NCT01829971

phase I

terminated

oncogenes, tumor regression,

enhanced the survival, and

inhibited the growth of other

nonhepatic tumors

(Smarticles)

**Mechanism/effect**

**Trial status**

*DOI: http://dx.doi.org/10.5772/intechopen.81847*


