Date of Award

5-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

Committee Chair

Andrea L. Kasinski

Committee Member 1

Stephen F. Konieczny

Committee Member 2

Donna Fekete

Committee Member 3

David thompson

Abstract

New alternative therapies to treat cancer have emerged such as the use of small molecules that target key oncogenic drivers. For instance, clinically relevant tumor suppressive microRNAs (miRNAs) that target key oncogenic drivers have been identified as potential therapeutics to treat cancer. MiRNAs are small non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. It has been shown that aberrant miRNA expression, through misexpression of miRNA target genes, can have profound cellular effects leading to a variety of diseases, including cancer. While altered miRNA expression contributes to a cancerous state, restoration of miRNA expression has therapeutic benefits. For example, ectopic expression of miRNA-34a (mir-34a), a tumor suppressor miRNA that is a direct transcriptional target of p53 and thus is reduced in p53 mutant tumors, has clear effects on cell proliferation and survival in murine models of cancer. It is expected that miRNA replacement therapies will have profound effects in the clinic; however, miRNA therapeutics are still in their infancy and there are critical challenges that need to be addressed for the advancement of miRNA-based therapies. Firstly, one of the biggest challenges for miRNA advancement into the clinic is efficient delivery of miRNA mimics due to problems such as delivery-associated toxicity, poor transfection, systemic clearance, poorly understood biodistribution, degradation in circulation, immune response, and endosomal sequestration. Secondly, strategies to enhance the therapeutic efficacy of a miRNAs, such as through combinatorial miRNA therapeutics, have yet to be explored meticulously.

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