Genomics and Biophysical Strategies to Overcome Cisplatin Resistance in Ovarian Cancer
Abstract
The mainstay therapy for ovarian cancer is surgery followed by chemotherapy. Platinum-based anticancer drugs like cisplatin are the most commonly used chemotherapeutic agents against ovarian tumors. Almost all ovarian cancer patients receive platinum-based drugs as a treatment regimen. Although initially effective in the vast major of cases, most tumors acquire resistance to the drug and stop responding to all forms of therapies. Therefore, strategies to overcome chemoresistance will extend the survival rates of millions of ovarian cancer patients. Objective and Rationale of the Proposed Work: Although we have a good understanding of how cisplatin works by causing DNA damage in cancer cells, it is evident that better strategies through out of the box thinking are needed to overcome chemoresistance. The goal of this project is to focus on poorly understood but promising observations on the cellular behavior of cisplatin to better understand the molecular action of this drug and develop innovative strategies to overcome therapy resistance. It has been known for decades that, in addition to binding to genomic DNA where the genetic information is stored, cisplatin also interacts with another class of cellular nucleic acids known as RNAs. The significance of this interaction in the anti-cancer property of cisplatin is unknown. Based on the recent findings, we propose that the association of cisplatin to cellular RNAs plays a crucial role in its anticancer action and also in the development of therapy resistance. Critical Problems in Ovarian Cancer Addressed in the Proposed Research: As the key chemotherapeutic agents that all ovarian cancer patients depend on, it is essential to devise strategies that make the platinum drugs most effective for the patients. Even after decades of intense research on this topic, chemoresistance is still a persistent problem faced by a significant fraction of ovarian cancer patients. Therefore, new strategies have to be explored to overcome this problem. The proposed research aims to investigate the poorly understood but promising recent observations on cisplatin biology to develop innovative strategies to overcome chemoresistance. To achieve this goal, we have assembled a multi-disciplinary team composed of cell biologists, genomic experts, chemists, physicists, and ovarian cancer biologists to apply modern tools to unravel the mysteries surrounding the mechanisms of action of platinum drugs. By focusing on the role of RNAs, an unconventional target of cisplatin, this study will set new paradigms for the molecular action of cisplatin and the emergence of chemoresistance. Relevance of the Project to the Ovarian Cancer Research Program (OCRP) Mission and Vision: According to the OCRP funding opportunity announcement, innovative projects are those that introduce a new paradigm, challenge current paradigms, look at existing problems from a new perspective, or provide new insights and technologies. By focusing on the unconventional mode of action of platinum-drug targets, using novel reagents and innovative multi-disciplinary strategies, this study fulfills all the criteria for innovation. We will develop novel cisplatin-derivatives and apply them to develop new technologies to provide insights into cisplatin biology and chemoresistance. This proposal addresses two FY22 areas of emphasis: Develop Novel Therapeutic Strategies for Treatment and Prevention: This project will identify novel RNAs that cause cisplatin therapy resistance and, therefore, promises to provide novel therapeutic targets. We will test the use of targeted RNA degradation (e.g., antisense oligo therapy) to improve the efficacy of cisplatin therapy, which will be a novel strategy to overcome therapy resistance in a patient-specific manner. In the long term, RNA targeting has the potential to develop into a personalized therapeutic approach. Identify and Develop New Strategies for Screening, Early
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310265
Entities
People
- Sreejith Nair
Organizations
- Georgetown University
- United States Army