Determining the Role of Novel CRNDE-Derived lncRNA in Kidney Cancer
Abstract
Scientific Objective and Rationale: Renal cell carcinoma (RCC) is the most common type of kidney cancer and the most lethal malignant urological tumor, with a predicted 320,000 new cases and ~140,000 deaths attributable to the disease worldwide in 2020. Importantly, rates of disease progression and mortality remain high due to undruggable protein-targets and cancer cell drug resistance. Therefore, there is an unmet need to identify and characterize new drug targets in order to improve RCC patient outcomes. A growing body of evidence has implicated long noncoding RNAs (lncRNAs), a class of non-protein-coding genes, in the initiation and progression of cancer, but our understanding of how lncRNAs contribute to RCC pathogenesis is limited. To better understand how specific lncRNAs promote RCC progression, I utilized a powerful, cutting-edge technique called CRISPR interference to identify new lncRNAs required for RCC cell growth and survival. This revealed a lncRNA gene called CRNDE as an essential lncRNA for RCC cell survival. Moreover, I found that absence of CRNDE in RCC cells impaired ribosome biogenesis, an important cellular process for protein production, cell proliferation, and survival. In this proposed study, I aim to investigate the function of CRNDE in promoting RCC cell growth and characterizing potential novel therapeutic targets involved in CRNDE-mediated RCC survival. At present, there are no data available regarding lncRNA function broadly, and CRNDE specifically, in RCC ribosome biogenesis and survival. Ultimate Applicability: Since RCC rarely causes signs or symptoms in its early stages, and there are no routine tests used to screen for kidney cancer in the absence of symptoms, the overall prognosis is still poor, specifically for patients who present with late-stage disease. Surgical tumor resection is the preferred first-line treatment option for RCC. However, this is not an option for some patients and can be a costly burden to patients with risk of recurrence. For non-surgical candidates, first-line therapy options often consist of targeted therapies that attempt to inhibit key driver mutations of protein-encoding genes in signaling pathways known to be involved in RCC growth and survival such as mTOR. Although targeted therapies against mTORC1 signaling pathways in kidney cancer have been extensively studied and used over the past decade, treatment responses are varied, and most high-grade kidney cancer patients eventually progress. In this proposal, I will test coordinated targeting of CRNDE with antisense oligonucleotides and existing mTORC1 inhibitors to improve on the current clinical use of mTORC1 inhibitors alone, providing additional therapeutic strategies for both first line treatment and treatment to combat acquired resistance. Successful completion of this aim will be timely and beneficial to patients suffering from kidney cancer since this study will utilize existing mTORC1 inhibitors and antisense oligonucleotides, which have been proven as emerging classes of therapeutics for diverse diseases. PI’s Career Goals: My long-term goal is to become an independent kidney cancer researcher who studies important regulatory RNAs with roles in oncogenic pathways driving tumorigenesis. To achieve this goal, I have assembled a prestigious team of mentors led by Dr. Joshua T. Mendell, a world-renowned expert in noncoding RNAs and cancer biology, as well as an outstanding group of collaborators with expertise in the study of kidney cancer and translational cancer research. Dr. Mendell will provide valuable training in the design, execution, and communication of scientific experiments aimed at identifying and characterizing novel functional lncRNAs in kidney cancer. To gain advanced knowledge and expertise in designing translational research and preclinical analysis of lncRNAs in kidney cancer, I will collaborate with Dr. Tu Dan, a radiation oncologist and member of Dr. Mendell s
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110815
Entities
People
- Jong-sun Lee
Organizations
- United States Army
- University of Texas Southwestern Medical Center