Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

George Calin, MD, PhD

Committee Member

Pratip Bhattacharya, PhD

Committee Member

Giulio Draetta, MD, PhD

Committee Member

Cristina Ivan, PhD

Committee Member

Shuxing Zhang, PhD

Abstract

As cancer research continues to move towards more personalized methods, targeted inhibitors of oncogenic drivers of cancer are found to be an innovative and promising therapeutic approach. Previously thought to be undruggable regions of the genome, RNA has become an area of increasing interest in cancer due to the identification of more targetable regions and their relationship to tumor growth and progression. This work reports on the development of IACS-13743, a novel small molecule found to directly bind and inhibit microRNA-10b. Oncogenic miR-10b has been found to be overexpressed in several malignant cancer types, making it an attractive biomarker for targeted inhibitor therapy. IACS-13743 is found to impede tumor progression and proliferation in brain cancer, gastric cancer and pancreatic cancer in vitro. This effect is also shown in a cerebral organoid model. Using a multidisciplinary approach, this study identifies a relationship between oncogenic miR-10b and the dysregulation of the PI3K/AKT pathway in cancer, along with putting forth a compound that can mitigate these effects. These findings provide a fundamental step in moving forward a targeted therapeutic for a known oncogenic RNA driver and unique biomarker in multiple malignant cancer types.

Keywords

RNA therapeutics, drug discovery, small molecules, cerebral organoids

Available for download on Saturday, May 07, 2022

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