Molecular Characterization and Therapeutic Targeting of TFE3 Fusion Kidney Cancers
Abstract
Background: Over the last decade, the most common type of kidney cancer, clear cell renal cell carcinoma (RCC), has evolved from a chemotherapy-resistant disease with very limited treatment options to a model cancer due to the clinical success of molecularly targeted therapies. This therapeutic transformation largely stems from an improved understanding of kidney cancer biology and pathogenesis. In contrast, rare kidney cancers have a serious basic research and clinical treatment disparity. There is no standard of care for rare kidney cancer patients due to the low incidence and the lack of research on the diseases. Among rare kidney cancers, TFE3 fusion kidney cancers occur rarely in adults (1% to 2%), but account for ~50% of kidney cancer in young individuals under 35 years old. These tumors are common in children, representing 20% to 50% of all pediatric kidney cancer cases. TFE3 fusion kidney cancers are caused by fusions between various genes and the TFE3 gene located on the short arm of chromosome X. Hence, TFE3 fusion kidney cancers are also called Xp11.2 translocation renal cell carcinomas. These are aggressive cancers without standard pharmacological treatment, leaving these patients and their families without options. To study the molecular basis of TFE3 fusion kidney cancers for the development of future therapeutics, we have established cell lines from human TFE3 fusion kidney tumors and implanted human tumors in mice to establish preclinical experimental models. With these patient-derived resources, we plan to apply state-of-the-art technology to interrogate the molecular origin of TFE3 fusion kidney cancers and identify new therapeutic targets for the treatment of these tumors. Furthermore, we plan to generate a novel mouse model of TFE3 fusion kidney cancer to determine whether and how this genetic alteration induces kidney tumors in mice. We will use this mouse model to test the therapeutic effects of immunotherapy in combination with targeted therapy. Areas of Emphasis: Rare Kidney Cancers; Chromatin and Gene Regulation; Targeted Therapies; Immunotherapies; Metabolism Innovation: We have established invaluable experimental models of TFE3 fusion kidney cancers for the study of mechanisms and treatment of TFE3 fusion kidney cancers. An innovative approach involving advanced sequencing and genome-mapping techniques will be performed to establish the molecular networks of TFE3 fusions with the goal of identifying new therapeutic targets. To this end, our preliminary studies have uncovered several therapeutic targets, paving the way for new potential clinical trials. Furthermore, a novel mouse model of TFE3 fusion kidney cancer will be generated to help elucidate the molecular mechanisms by which TFE3 fusion promotes kidney cancer initiation and facilitate the discovery and assessment of novel therapeutics including immunotherapy. Impact: This proposal is mechanism-driven but can be easily translated into clinics. Our investigation of the molecular mechanisms by which TFE3 fusion proteins promote tumor initiation and maintenance will advance the knowledge regarding the biological function of TFE3 fusion proteins and will have significant impact now and in the future. In the short term, our preclinical studies testing various therapy combinations that target TFE3 fusion-regulated pathways can be translated into clinical trials and benefit patients immediately. In the long term, our creation of TFE3 fusion mouse kidney cancer model will offer a physiological preclinical for future therapeutic interventions including immunotherapy, thus accelerating new drug development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910706
Entities
People
- Emily Cheng
Organizations
- Sloan-Kettering Institute
- United States Army