TBK1 Serves as a Novel Therapeutic Target in Kidney Cancers with VHL Loss
Abstract
Kidney cancer is a lethal cancer that is largely resistant to drug treatment. Estimated new cases and deaths from renal (renal cell and renal pelvis) cancer in the U.S. in 2014 were 63,920 and 13,860, respectively. In kidney cancer, most patients lose the function of one critical gatekeeper, the so-called VHL. Once patients lose VHL, they will likely develop kidney cancer. Our research found that the activity of one particular kinase, TBK1, is increased when kidney cancer patients lose VHL. Also, we found that if we get rid of this TBK1, we can slow down kidney cancer cell growth. So, we think that TBK1 can be used as a good potential target for therapeutic intervention in kidney cancer. Also, it is important to point out TBK1 is specifically toxic for kidney cancer cells with the loss of VHL. Therefore, targeting TBK1 will not likely hurt normal tissues (since normal tissues have intact VHL). We propose to address some of the areas of emphasis in the DoD KCRP: (1) We will develop targeted therapies in kidney cancer by using several complementary approaches targeting TBK including genetic knockout by CRISPR-Cas9 and a highly specific TBK1 inhibitor. (2) We will examine the mechanism of therapeutic response in kidney cancer. TBK1 has never been established as a factor promoting kidney cancer before and our research will be the first one to establish TBK1 as such a factor and potential drug target. Our research will provide insight on validating TBK1 as a novel therapeutic agent to benefit most kidney cancer patients. Identification and characterization of unique pathways that are lethal to VHL-deficient kidney cancer is critical for improving kidney cancer treatment. The proposed work can also have potentially significant impact on military beneficiaries because (1) cigarette smoking, which accounts for 30% of active-duty personnel, is a significant risk factor for renal cell carcinoma, and (2) occupational exposure to heavy metals, paints, organic solvents, and other combat-related chemicals significantly increases the risk of renal cell carcinoma. Therefore, the proposed research will directly address the immediate need for understanding and treating kidney cancer and prompt Service members’ early return to active duties.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910813
Entities
People
- Qing Zhang
Organizations
- United States Army
- University of Texas Southwestern Medical Center