Author ORCID Identifier
https://orcid.org/0000-0001-6900-3267
Date of Graduation
5-2018
Document Type
Thesis (MS)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Anil K. Sood, MD
Committee Member
Swathi Arur, PhD
Committee Member
Russell R. Broaddus, MD/PhD
Committee Member
Jeffrey N. Myers, MD/PhD
Committee Member
Jason Roszik, PhD/MBA
Abstract
Re-purposing of targeted therapies for additional tumor types is a promising avenue for expanding treatment options for cancer patients, however accurately predicting what re-purposed targeted therapy will be effective remains challenging. To address this need, we developed a Therapy Predicting Tool (TPT) that accurately predicts the beneficial therapeutic effect of clinically relevant targeted therapies and the downstream pathways they may impact in the cancer of interest. Using ovarian cancer as a model to biologically validate our tool, we determined that Bromodomain and Extra-Terminal motif inhibitors (BETis), which target proteins such as BRD4, held the greatest promise to produce therapeutic effects and impact relevant oncogenic gene targets, such as Notch3, in this disease. In our pre-clinical models, we demonstrated that BETis produce therapeutic effects and prolong survival. Furthermore, we discovered that BRD4 directly regulates Notch3 transcription and its downstream targets in ovarian cancer. Our findings provide a basis for further exploration and application of our tool to identify and re-purpose targeted therapies for specific tumor types.
Keywords
ovarian cancer, targeted therapies, BRD4, Notch3, Bromodomain and extraterminal domain inhibitors