Simultaneous Targeting of Androgen Receptor Signaling and MNK-Activated eIF4E Translation Initiation for Suppressing Growth and Progression of Prostate Cancer
Abstract
Prostate cancer commonly affects 1 out of every 7 men in their lifetime. Prostate cancer is also the most frequently diagnosed cancer in males and the second most leading cause of cancer-related death in the United States. Prostate cancers initially depend on androgens, a steroid hormone produced by the testis for their growth and survival. Hence, androgen deprivation either by surgical or chemical means serves as the frontline therapy for treating prostate cancer patients. Although most patients respond to this treatment method initially, the disease often re-emerges as "castration-resistant prostate cancer (CRPC)" as the cancer starts developing despite castrate levels of androgen. CRPC is considered deadly as the cancer usually spreads beyond the prostate to other nonadjacent vital organs (clinically referred to as metastasis). The outcome for men with metastatic prostate cancer is quite poor. Despite numerous trials evaluating various new molecular targets and single/multi-agent chemotherapeutic regimes for CRPC and advanced metastatic prostate cancer, only modest improvements in mortality have been reported. Identifying novel targets in prostate cancer for achieving maximum therapeutic benefit is still a challenge. The proposed research in this application is to test the hypothesis that concurrent target of androgen receptor (AR) signaling and eIF4E protein synthesis machinery will provide efficacious, greatest, and long-term therapeutic benefit for men with prostate cancer, particularly the castration-resistant type. The reason for targeting AR and eIF4E protein synthesis machinery in advanced prostate cancer stems from the fact that CRPC usually occurs due to reactivation of AR signaling irrespective of androgen stimulation. In addition, overactivation of a particular type of protein synthesis machinery referred to as eIF4E, which is responsible for producing proteins that promote cancer development and progression, is also observed in majority of prostate cancer patients. Recent findings have confirmed that simultaneous targeting of both these pathways could be an effective approach for treating and improving well-being in men with prostate cancer, particularly castration-resistant and metastatic prostate cancer. Preliminary screening of various compounds synthesized in our laboratory have shown that Novel Retinamides (NRs) strongly block the expression and activity of various proteins associated with AR and eIF4E signaling in prostate cancer cells. Interestingly, some of the retinoic acid metabolism blocking agents (RAMBAs) Retinamides that we analyzed inhibited growth of prostate cancer cells at very low concentrations and more effectively than the drugs Casodex, MDV3100, and Abiraterone acetate that are currently used for treating prostate cancer. This proposal actually aims to establish the proof-of-principle by which NRs inhibit both these crucial targets (AR and eIF4E) in prostate cancer cells, net effect of the blockade of AR and eIF4E on prostate cancer growth and progression, and also analyze their (RAMBA retinamide) effect in inhibiting prostate cancer growth in a well-established mouse model of prostate cancer. Successful completion of the project will establish whether targeting both AR and eIF4E simultaneously is a vital therapeutic approach for treating prostate cancer. Moreover, we will also be able to identify potent novel retinamides that can target both AR and eIF4E and have the therapeutic potential for managing prostate cancers, particularly CRPC for which effective treatment strategies are of dire need. Efficacious accomplishment of this project will also allow potential agents to be tested for further clinical evaluation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510586
Entities
People
- Vidya Ramamurthy
Organizations
- United States Army
- University of Maryland, Baltimore