Neuroendocrine Differentiation and Enzalutamide Resistance in Prostate Cancer
Technical Report,01 Sep 2018,31 Aug 2019
Rutgers Cancer Institute of New Jersey Piscataway United States
Pagination or Media Count:
The goal of the present proposal is to investigate the mechanism by which TCF4 regulates neuroendocrine differentiation NED and induces enzalutamide resistance in CRPC. In treating patients with CRPC, enzalutamide, the second-generation AR antagonist, is an established standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance to enzalutamide inevitably emerges. Based on a body of preliminary data, we hypothesize that the transcription factor TCF4 is induced by AR-V7 and mediates, in part, enzalutamide resistance in CaP cells via the neuroendocrine marker, PTHrP. To test this hypothesis, two specific aims and four major tasks have been proposed. Of these objectives, major task 1 that focused on the role of AR and AR-V7 with TCF4 has been completed and published the results Lee et al, 2020. We have found that the knockdown of AR-V7 reverses neuroendocrine differentiation and TCF4 expression. In addition, AR response element has been identified. Finally, overexpression of TCF4 has demonstrated neuroendocrine differentiation in vivo. In addition, part of major task 2 has been completed in which we have confirmed the interaction between AR and AR-V7 as well as TCF4. Finally, major task 4 that examined the effect of disrupting TCF4 in vivo has been completed. We have found that such approach retards tumor growth.
- Anatomy and Physiology
- Medicine and Medical Research