Tribbles 2: A Novel Molecular Target for Therapy of Aggressive Kidney Cancer
Abstract
Most kidney cancer-related deaths occur due to advanced, aggressive kidney cancer (AKC), which is fast-growing and highly metastatic. Multi-kinase inhibitors, such as sunitinib and axitinib are commonly prescribed for AKC, though even after initial good response resistant cancer invariably develops that is incurable. Development of a good therapy for AKC is delayed because of the lack of suitable agents to effectively kill ERPC cells. Uncontrolled growth of AKC cells leads to widespread tumor metastasis causing excruciating pain and suffering. The majority of AKC patients suffer from dismal clinical outcomes, including early relapse and aggressive growth, and, unfortunately, for those in whom chemotherapy does not work, the survival time remains only a few years, highlighting a pressing need for development of novel strategies. The main reason for failure of AKC therapy is the lack of proper understanding about suitable molecular targets to selectively attack and kill AKC cells. Recently, by molecular analysis we found that both AKC cells and tumors overexpress Tribbles 2 (Trib2), a pseudokinase. Interestingly, inhibition of Trib2 by shRNA dramatically kills AKC cells. Thus, Trib2 emerges as a promising molecular target for AKC, and we hypothesize that an attractive, new, targeted therapy for AKC can be developed by suitable Trib2 inhibitors for long-lasting, disease-free patient survival. It is interesting to note that while Trib2 is highly expressed in AKC cells and tumors, it is undetectable in normal kidney tissues, 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 AKC cells. However, the mechanism of action of Trib2 in AKC cells is yet to be characterized. Based on high-level expression of Trib2, and its critical role in the survival of AKC cells, we looked for suitable Trib2 inhibitors through screening a large number of compounds and found that an FDA-approved drug, called Daclatasvir (DCV), is suitable to inhibit Trib2 function in AKC cells. DCV effectively reduces the Trib2 protein level and kills deadly AKC cells by inducing apoptosis. This finding makes a strong case for further testing of DCV against AKC using appropriate in vitro and in vivo models. The experiments outlined in this proposal are focused, (1) to understand the mechanism of action of Trib2 in AKC cells, and (2) to examine the effects of DCV in highly tumorigenic AKC cell line xenografts in mouse model. Since DCV (as Daklinza) is approved by the Food and Drug Administration for human use, its safety and efficacy are already characterized, and we believe that DCV can be repurposed as a new treatment for AKC without much delay. Therefore, this proposal is a highly significant study and bears a strong translational potential to develop a new therapy for lethal kidney cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110873
Entities
People
- Jagadananda Ghosh
Organizations
- Henry Ford Health
- United States Army