ERG Involvement in Treatment Resistance of Metastatic Castration-Resistant Prostate Cancers
Abstract
Scientific Objective and Rationale: Prostate cancer is the second most common cancer among men. The evolution of the disease leads to advanced cases for which there is currently no efficient treatment. Patients with metastatic castration-resistant prostate cancer (mCRPC), one of the most advanced subtypes, are oriented towards a taxane-based treatment, which is not specific to prostate cancer but targets all highly proliferative cells. Although taxanes have proved to extend survival in some patients, mCRPC patients ultimately fail due to the development of drug resistance. These mechanisms of resistance are still poorly understood; nevertheless, we have already identified some actors that drive the resistance. ERG is a transcription factor that is overexpressed in more than 50% of prostate cancer, resulting of a gene rearrangement. We have previously described that ERG is able to directly interact with a major component of the cell cytoskeleton, tubulin, impairing the activity of the treatment. ERG destabilizes the tubulin polymers while taxane stabilizes them. The objective of my project is to elucidate the mechanism of resistance driven by ERG to counteract it by developing adapted treatments. Applicability of the Research: Despite the fact that the actors of the mechanism can be present from the first stages of the disease, my project focuses on mechanism of resistance that is described in mCRPC, which mainly represent the 25,000 prostate cancer deaths per year in the US. The direct clinical application will be to develop a new treatment, and knowing that there is no efficient treatment in this context, the benefits for the patients are clearly higher than the risks. I will test drugs that have already been approved by the Food and Drug Administration and are currently used to treat other cancers. The projected time to achieve the data needed as a rationale for a new biomarker-based clinical trial could be extremely short (2-3 years) compared to the development of a new drug. My Career Goals: With a solid background in molecular biology and a strong interest in translational research, I would like to establish my own laboratory working on gene regulation leading to prostate cancer development, evolution, and mechanisms of resistance. My postdoctoral position in Dr. David Rickman?s laboratory at Weill Cornell Medicine is a great opportunity for me to acquire a strong prostate cancer background and the expertise in analyzing the response to drug treatment. In addition, I will greatly benefit from the co-mentorship of Dr. Giannakakou as she provides synergistic expertise in drug resistance and microtubule biology. Contribution for Prostate Cancer Research: This project will contribute in advancing the field of prostate cancer research by providing knowledge on the mechanisms that drive a resistance to the treatments currently used for patients with mCRPC. These mechanisms, which are poorly understood to date, need to be highlighted and carefully described to isolate new therapeutic targets and adapt the strategy of treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710162
Entities
People
- Adeline Berger
Organizations
- United States Army
- Weill Cornell Medicine