miR-195 Re-Expression: A Therapeutic Strategy for Chemoresistant Ovarian Cancer
Abstract
Scientific Objective and Rationale: Around 85-90% of ovarian cancer (OvCa) patients initially respond to the therapy, but in most of the patients, the tumor reoccurs and does not respond to the therapy; these tumors are known as drug-resistant and are the main reasons for the higher mortality rate in OvCa. However, the mechanism responsible for the drug-resistant phenotype in OvCa is still evolving, and further research is urgently needed to overcome the therapeutic resistance and poor prognosis. In my previous research, I have shown that a small RNA (18-22 nucleotide long) known as micro-RNA-195 (miR-195), which does not code for any protein, is under-expressed in OvCa. Our results show that re-expressing in OvCa cells reduced their cancer-causing properties by regulating the expression of mitochondrial calcium uptake 1 (MICU1) protein. Using a mouse model of ovarian cancer, we reported that miR-195 re expression significantly reduces tumor growth, increases tumor doubling times, and enhances the overall survival of the tumor-bearing mouse. However, the role of miR-195 in the drug resistance of OvCa has not been elucidated and is the goal of the proposed research. Interestingly, by analyzing the publicly available database we found that miR-195 may target WNT7A, one of the key proteins responsible for Wnt/beta-catenin singling. WNT7A is upregulated in OvCa and is not detected in normal ovaries. The upregulation of WNT7A is responsible for the activated Wnt/beta-catenin singling, known for cancer recurrence by regulating stem-like properties in cancer cells with drug-resistant phenotype. Our preliminary data show that miR-195 negatively regulates Wnt/beta-catenin signaling pathway in OvCa cells. Based on these results, we hypothesize that the under-expression of miR-195 in OvCa is responsible for WNT7A upregulation and evolution of the drug resistance phenotype. We will use following specific aims to test the hypothesis and accomplish overall objectives: Aim 1. Investigate the role of miR-195 expression in drug-resistant OvCa. Aim 2. Evaluate the effect of miR-195 on metastasis and drug sensitivity in an OvCa model using an auroliposome-mediated miR-195 delivery system. Successful completion of the project will establish miR-195 as a regulator of drug resistance in OvCa and a potentially translatable strategy, by our recently developed highly efficient auroliposome delivery method that can deliver miRNA and siRNA with almost no side effects. PI’s Career Goals: An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemo-resistant tumor is likely a cause of poor outcomes. A thorough understanding of drug resistance mechanisms is needed, as this remains the main obstacle in treating patients with recurrent disease. Therefore, to improve outcomes in OvCa, the identification and development of new targets is a priority and motivation behind my ongoing research in OvCa. I have been working on various aspects of OvCa and non-coding RNA since Sept 2013 and have acquired a unique understanding of OvCa and microRNA biology, coupled with my doctoral research experience in drug development along with the experience of nanoliposome delivery systems gives me a unique ability to decipher the detailed role of miR-195 in drug-resistant OvCa and targeting these signaling pathway for the overall benefit of OvCa patients. The protected time afforded by the Ovarian Cancer Academy – Early-Career Investigator Award (OCA-ECIA) will not only allow me to evaluate my hypothesis, it will also provide me an opportunity for collaborative research and acquire skills and specific knowledge that will help me become established as an independent investigator. The collaborative mentorship from OCA and my mentors will provide an ideal platform to develop my career as a scientist and become an independent investigator. Applicability of the Research: OvCa is typically diagnosed at
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310772
Entities
People
- Shailendra Kumar Dhar Dwivedi
Organizations
- United States Army
- University of Oklahoma Health Sciences Center