MicroRNA theragnostics for the clinical management of multiple myeloma

Abstract

Theragnostics represent cutting-edge, multi-disciplinary strategies that combine diagnostics with therapeutics in order to generate personalized therapies that improve patient outcome. In oncology, the approach is aimed at more accurate diagnosis of cancer, optimization of patient selection to identify those most likely to benefit from a specific therapy and to generate effective therapeutics that enhance patient survival. MicroRNAs (miRNAs) are master regulators of the human genome that orchestrate myriad cellular pathways to control growth during physiologic and pathologic conditions. Compelling evidence shows that miRNA deregulation promotes events linked to tumor initiation, metastasis and drug resistance as seen in multiple myeloma (MM), an invariably fatal hematologic malignancy. miRNAs are readily detected in body fluids, for example, serum, plasma, urine, as well as circulating tumor cells to demonstrate their potential as readily accessible, non-invasive diagnostic and prognostic biomarkers and potential therapeutics. Specific miRNAs are aberrantly expressed early in myelomagenesis and may more readily detect high-risk disease than current methods. Although only recently discovered miRNAs have rapidly advanced from preclinical studies to evaluation in human clinical trials. The development of miRNA theragnostics should provide widely applicable tools for the targeted delivery of personalized medicines to improve the outcome of patients with MM.

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

“…A number of epigenetic modifications have been so far linked to cancer, including posttranslational modification of histones, DNA methylation, and the most recently discovered noncoding RNAs, which are currently considered key determinants in human cancer pathogenesis (2). In the last few years, a wealth of studies has shown deep dysregulation of miRNAs in human cancers, including multiple myeloma (3). Importantly, replacement of downregulated tumor suppressor (TS) miRNAs (4,5) or inhibition of oncogenic miRNAs (6)(7)(8) have demonstrated therapeutic value in multiple myeloma preclinical settings.…”

“…HDACs, key enzymes regulating the acetylation status of both histone-and non-histone proteins, are classified into 4 classes: class I (HDAC1, 2,3,8), class IIa (HDAC4, 5, 7, 9) and class IIb (HDAC6,10), class-III (SIRT1-7), and class-IV (HDAC11; ref. 12).…”

Genomic heterogeneity in multiple myeloma

“…MicroRNA studies (Table 1) MicroRNAs (miRNAs) constitute an important class of small RNAs, and understanding their functions has become a major area of research to develop potential targeted therapies [34].…”

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

“…28 Literature advocates the deregulation of several miRNAs including miR-15, 16, 17, 20, 135, 30, 150, 160 and so on, which are regarded as hallmarks of tumor progression, clinical staging, prognosis, and drug responses in MM. [29][30][31][32][33][34] Basic mechanisms of miRNAs include positive or negative regulation of critical oncogenes or tumor suppressors, epigenetic modifications etc. that predominantly determines cell survival and malignant transformation.…”