Loss of VHL Activates SFMBT1-SPHK1 Oncogenic Signaling in Kidney Cancer
Abstract
Estimated new cases and deaths from kidney (renal cell and renal pelvis) cancer in the Unites States for 2020 are 73,750 and 14,830, respectively. Kidney cancer incidence has been increasing steadily for the past several decades, although the reasons for this are unclear. Loss of expression of the Von Hippel-Lindau (VHL) protein is one of the major underlying causes of kidney cancer. Loss of VHL leads to the stabilization of several important oncogenic proteins and this effect is important in cancer initiation and progression. Therefore, it is critical to identify the proteins that are affected by VHL loss and that lead to kidney cancer development, which will help in the design of strategies to target these drivers of kidney cancer. In recent published work, I identified such a protein, SFMBT1, that I found is normally degraded by VHL, is stabilized in VHL-deficient renal cancer, and that promotes kidney tumorigenesis. In this proposal, I aim to investigate how SFMBT1 promotes kidney cancer and I explore therapeutic strategies to inhibit SFMBT1-associated oncogenic signaling in order to suppress kidney tumor growth. Since most kidney cancer patients exhibit VHL loss-of-function/expression and our research focuses on the oncogenic events initiated by VHL loss, our proposal will benefit the majority of kidney cancer patients. Importantly, I showed that SFMBT1 stabilization and expression leads to the upregulation of the gene encoding a protein known as SPHK1. For SFMBT1 or SPHK1 inhibition, I showed that this does not harm normal kidney epithelial cells while displaying specific toxicity toward kidney cancer cells that have VHL loss. Therefore, I hypothesize that blocking this signaling axis will greatly benefit the majority of kidney cancer patients without causing toxicities. An SPHK1 specific inhibitor (PF-543) is readily available, thus, I believe that this research will be highly applicable for preclinical renal cancer studies in the short-term and potential clinical studies thereafter. My goal is to establish my own independent lab within the next three years with a focus on kidney cancer research. I will obtain critical training in grant writing, scientific communication skills, and educational programs during my postdoctoral years. I will be co-mentored by two outstanding scientists: Dr. Albert Baldwin at UNC-Chapel Hill, who received an NCI R35 outstanding investigator award, and Dr. Qing Zhang at UT Southwestern, who has extensive experience in kidney cancer exemplified by impactful publications in Science, Molecular Cell, Cancer Discovery, Nature Communications, and Proceedings of the National Academy of Sciences. Importantly, Dr. Baldwin and Dr. Zhang have collaborated extensively on the majority of this published work. I will meet with each of them informally at least weekly, and then have a formal monthly meeting with both co-mentors. I will also be advised by collaborator Dr. William Kim at UNC, a kidney cancer researcher and clinician, who will provide me with renal cancer PDX models and expertise on clinical insight and PDX-related studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110430
Entities
People
- Xijuan Liu
Organizations
- United States Army
- University of North Carolina at Chapel Hill