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Feb 15, 2014 (Vol. 34, No. 4)

MicroRNAs Leaping from Lab to Clinic

  • MicroRNAs (miRNAs) are small RNAs that regulate gene expression predominantly by inhibiting translation or promoting degradation of the target RNAs.

    Many dysregulated miRNAs are implicated in pathogenesis of various diseases. Such miRNAs have become a new hot topic in drug discovery and diagnostics. Several specific characteristics of miRNAs in combination with compelling therapeutic efficacy data have triggered the exploration of miRNAs as therapeutic entities.

    CHI’s “MicroRNA as Biomarkers and Diagnostics,” a conference scheduled to take place next month in Boston, will cover the latest developments in the use of miRNAs in the early detection and monitoring of disease progression, as well as the potential for personalized medicine based on miRNA profiles. Selected presentations from the conference will highlight the translation of miRNA bench discoveries to therapeutically useful modalities.

    Parkinson’s disease (PD) is believed to reach a relatively advanced stage by the time it is clinically diagnosed. By then, more than half of patient’s dopaminergic neurons may be lost because of neurodegeneration. Despite unification and standardization of clinical assessments, the accuracy of diagnosis is still subjective.

    “Unlike cancer, PD does not afford an opportunity for tissue biopsy. Our best hope is to find presymptomatic, sensitive, and quantifiable biomarkers in body fluids,” says Sok Kean Khoo, Ph.D., distinguished associate professor of molecular genomics at Grand Valley State University. “Such biomarkers would undoubtedly help with early disease diagnosis and potentially stop or slow down disease progression.” A number of blood and cerebrospinal fluid biomarkers have been studied, but none has yielded a biomarker possessing the ideal features.

    Dr. Khoo’s team focuses on the modulating role miRNAs may play in PD. In one investigation, the team used microarrays to perform global miRNA expression profiling on blood samples of 32 PD patients with matching controls from Mercy Health Saint Mary’s.

    The data was analyzed by integrating two statistical algorithms. One of the algorithms identified 13 miRNAs predominantly overexpressed in PD. Another algorithm identified nine miRNA pairs calculated by statistical probabilities of each miRNA in a pair being present or absent in PD. Each miRNA pair becomes an independent predictor of PD; several such pairs constitute a PD signature.

    The miRNAs were further validated using quantitative RT-PCR, narrowing it down to just three individual miRNAs and five miRNA pairs. “We were able to access a validation sample set from Umea University Hospital in Sweden,” recalls Dr. Khoo. “This set contained 30 patients with treated or untreated PD, but also has samples from patients with multiple system atrophy and progressive supranuclear palsy, as well as healthy controls. Initially one miRNA was undetectable, but with a nonbias amplification method, we are now able to replicate all our findings.”

    Encouraged by these results, Dr. Khoo together with the Michael J. Fox Foundation will use the miR panel to follow the PD progression. The miRNA signatures may help researchers understand the differences between PD fast and slow progressors. At the same time, Dr. Khoo continues to dive deeper into the biology of the miRNA biomarkers. “We have yet to understand the biological functions of some of the strongest PD predictors in our signature set,” remarks Dr. Khoo.

  • Opportunities in Colorectal Cancer

    Click Image To Enlarge +
    Researchers at Stony Brook University School of Medicine are evaluating miR-129 as a mediator of intrinsic apoptosis in cancer cells. Besides functioning as a tumor suppressor in colorectal cancer and a sensitizer to 5-FU-based chemotherapy, miR-129 acts as a master regulator to suppress the protein expression of three critical targets —BCL2, TS, and E2F3. Downregulation of anti-apoptotic protein BCL2 activates the intrinsic apoptosis pathway by cleaving caspase-9 and caspase-3. Downregulation of TS and E2F3 inhibits cell proliferation by impacting the cell cycle.

    One of the reasons for failure to treat advanced colorectal cancer is due to development of resistance to standard fluoropyrimidine-based chemotherapy,” says Jingfang Ju, Ph.D., co-director of the translational research laboratory at Stony Brook University School of Medicine. “Our long-term goal is to understand the contribution of miRNAs to development of resistance and to improve patient care.”

    About eight years ago, Dr. Ju’s lab demonstrated high stability of miRNAs in formalin-fixed paraffin-embedded (FFPE) tissues, triggering an explosion of miRNA-based biomarker discovery projects that burst through hospital repositories of archival FFPE tissues. At present, Dr. Ju pursues both prognostic and therapeutic explorations of miRNA’s role in colorectal cancer.

    A significant percentage of stage II colorectal cancer patients can be cured by surgery alone without adjuvant therapy. Toxicity of chemotherapy, combined with the almost inevitable onset of resistance, is only detrimental for those patients who could be cured by surgery alone.

    His team compared expression profiles of miRNAs from paired samples of colon tumors and normal specimens and pointed to a potential role of miRNA-215 (miR-215) in controlling cell cycle and proliferation through a complicated regulatory cascade mechanism. A recent study confirmed that miR-215 is clinically relevant as a prognostic biomarker in stage II and III colorectal cancer. Patients with low miR-215 expression had a more chemosensitive phenotype, and responded well to fluoropurimidine treatment with survival benefit.

    Stony Brook University licensed the patent covering miR-215 cancer diagnostics to Progen LifeSciences. The company is currently preparing for prospective large cohort independent validation studies in support of the commercialization of personalized miRNA-based diagnostics.

    Dr. Ju emphasized that in case of colorectal cancer, tissue specimens from affected areas are readily available as a result of routine colonoscopies or needle biopsies. Diagnostics based on tissue samples directly correlates the biomarker and the affected tissues.

    “Our therapeutic direction focuses on miR-129 as a mediator of intrinsic apoptosis in cancer cells,” explains Dr. Ju. Downregulation of miR-129 allows cancer cells to escape DNA damage-induced apoptosis, which is the primary mechanism of action of fluoropurimidine. Conversely, exogenously added synthetic miR-129 restored chemosensitivity of colorectal cancer cells and acted synergistically with the chemotherapy agent.

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