Tribbles 2, a Novel Target for Therapy of Enzalutamide-Resistant Neuroendocrine Prostate Cancer
Abstract
Food and Drug Administration (FDA)-approved enzalutamide (Xtandi) is a popular drug that is commonly prescribed for advanced, castration-resistant prostate cancer. However, even after initial good response, enzalutamide-resistant prostate cancer (ERPC) invariably develops, which is incurable. Uncontrolled growth of ERPC cells leads to widespread tumor metastasis, causing excruciating pain and suffering, and contributes to most of the prostate cancer-related morbidity and mortality. Since, ERPC is resistant to currently available therapies, it is considered a death threat, highlighting a pressing need for development of novel strategies. Chemotherapy and PARP inhibitors are used for ERPC, but the majority of the patients suffer from dismal clinical outcomes, including early relapse and aggressive growth, and, unfortunately, for those where chemotherapy does not work, the survival time remains only few years. The main reason for failure of ERPC therapy is the lack of proper understanding about suitable molecular targets to selectively attack and kill ERPC cells. Recently, by molecular analysis, we found that both ERPC cells and tumors overexpress a gene called Tribbles 2 (Trib2), and inhibition of Trib2 by shRNA dramatically kills ERPC cells. Overexpression of Trib2 enhances prostate cancer cell growth and confers resistance to enzalutamide, and this resistance is abolished when Trib2 is inhibited. Thus, Trib2 emerges as a novel, promising molecular target for ERPC. Thus, an attractive, new, targeted therapy against ERPC can be developed by suitable Trib2 inhibitors for a long-lasting, disease-free patient survival. It is interesting to note that, while Trib2 is highly expressed in ERPC cells and tumors, it is undetectable in normal prostate glands, suggesting that the hyperactivity of Trib2 is largely associated with the cancer phenotype. Moreover, since Trib2 knockout mice are viable, it appears that Trib2 is an attractive molecular target to selectively attack and kill ERPC cells. However, the molecular mechanism of Trib2 in ERPC cells has yet to be characterized. How Trib2 confers resistance to enzalutamide in ERPC cells and what exactly happens to ERPC cells when we knockdown their Trib2 function are two important questions we need to address for better understanding of the biology of ERPC. Our preliminary data suggest that Trib2 helps prostate cancer cells to change their identity from luminal to neuroendocrine (NE) type to evade enzalutamide therapy. Based on the high level of expression of Trib2 and its critical role in the survival of ERPC cells, we looked for suitable Trib2 inhibitors through screening a large number of compounds and found that an FDA-approved anti-viral drug, called daclatasvir (DCV), is suitable to inhibit Trib2 function and kill ERPC cells. This finding makes a strong case for further testing of DCV in appropriate models for development of a new therapy for lethal ERPC. The experiments we outlined in this proposal are focused on (1) understanding the downstream mechanism of Trib2 in ERPC cells and (2) examining the effects of DCV on highly tumorigenic ERPC cell line xenografts and NE-type ERPC patient-derived xenografts (PDX) in mouse models. Since DCV (Daklinza) is FDA-approved for human use and is very well tolerated, we believe that DCV can be repurposed as an anti-cancer drug for treatment of ERPC without delay. Therefore, this proposal is a unique, highly significant study and bears a strong translational potential to develop a new, targeted therapy for ERPC. Based on the preliminary evidence, we strongly believe that successful completion of this project will provide us with experimental evidence and support to launch a clinical trial with DCV for treatment of NE type enzalutamide-resistant, lethal prostate cancer. Overarching Challenge: To develop a new, targeted therapy for the enzalutamide-resistant, NE type of aggressive and lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211010
Entities
People
- Jagadananda Ghosh
Organizations
- Henry Ford Health
- United States Army