microRNA mimics and inhibitors to modulate genotoxic stress for cancer and aging related diseases.
OHSU # 2201
MicroRNAs (miRs) can regulate gene expression and are often critical players in controlling cellular DNA repair mechanisms. miRs can therefore provide an alternative therapeutic strategy for treatment of cancer and other diseases associated with altered miR expression and/or DNA damage repair.
Researchers at OHSU have identified a cohort of miRs that are upregulated by genotoxic stress and that act specifically to downregulate the MRN (Mre11a-Rad50 and NBS-1) complex. The MRN complex is a critical part of the cellular DNA repair machinery, which plays a key role in DNA double strand break repair, replication, and telomere maintenance. miRs targeting the MRN complex inhibited the DNA-repair machinery, induced senescence in endothelial cells, and impaired telomerase activity. Thus, OHSU researchers propose that miRs behave as a tumor suppressor by targeting the MRN complex, thereby inducing senescence, cell cycle arrest, as well as decreasing angiogenesis and tumor burden.
The OHSU researchers have also determined that miRs are enriched in the plasma post-radiation, suggesting that miR signatures in the plasma could indicate patient responsiveness to radiation or chemotherapy.
Technology at a glance:
• Targeting the MRN complex using miR mimics can be a valuable therapeutic approach that is likely to potentiate radiation and chemotherapy treatments
• Identified miRs target the DNA repair mechanism and induce cell death in proliferating cells, suggesting less toxicity than miR mimics that target apoptosis, and better synergy with DNA damaging agents
• miR inhibitors decrease senescence in cells and can potentially provide benefit in the treatment of fibrosis
• miRs can be used as a biomarker to predict response to radiation treatment
Cristina Espinosa-Diez, RaeAnna Wilson, Nathan Kanner, Rebecca Ruhl, Christina M. Hipfinger and Sudarshan Anand, Reprogramming the breast cancer microenvironment using microRNAs that target DNA repair, DOI: 10.1158/1538-7445.AM2016-1111 Published July 2016
Espinosa-Diez, C., et al., MicroRNA perturbation of the MRN complex buffers DNA damage response from VEGF signaling. bioRxiv Preprint Server, http://biorxiv.org/content/biorxiv/early/2017/04/28/132258.full.pdf, 2017.
U.S. provisional patent application filed 02/26/2016.
U.S. non-provisional patent application filed 02/24/2017
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