Targeting TFE3 Fusion Proteins in Translocation Renal Cell Carcinoma (tRCC) by PROTAC-Mediated Targeted Protein Degradation
Abstract
Translocation renal cell carcinoma (tRCC) is the most common type of renal cell carcinoma in young individuals, accounting for roughly 30% of pediatric and adolescent cases. tRCC is one of the most aggressive kidney tumors, and patients diagnosed with tRCC have poor prognosis. When tRCC becomes metastatic, it is largely incurable. tRCC is caused by the Microphthalmia (MiT) family of genes, which includes TFE3, TFEB and MiTF, that become abnormally activated as a result of a translocation. Translocation (from the Latin trans (across) + location (place)) emphasizes how MiT genes are activated - through a change in their genome location, which causes them to be produced in large quantities. However, how they dictate tRCC tumorigenesis and cancer progression is unclear. This limited understanding of tRCC biology combined with the rarity of the disease has contributed to the lack in effective therapies. Various technologies have been recently developed to effectively disrupt the expression of the disease causing gene of interest including small interfering RNAs (siRNAs), anti-sense RNA, gene editing, and PROteolysis-TArgeting Chimeras (PROTAC). This study proposes to test an emerging novel therapeutic approach termed PROTAC for its efficacy in tRCC. PROTAC are hetero-bifunctional synthetic compounds, considered as magic bullets that are designed to specifically bind and target the disease-causing proteins of interest (POI) for destruction. PROTACs recruits the host protein degradation machinery to mark POI for its subsequent elimination. We propose to design and synthesize a TFE3 targeting PROTAC and test its potential in targeting tRCC. We anticipate that TFE3 degradation should halt target gene expression, and significantly reduce tRCC cell viability. We will evaluate the treatment potential of the TFE3-PROTAC using tRCC primary cells expressing the most common TFE translocation (ASPSCR1-TFE3) as well as in a tRCC preclinical model, patient-derived xenograft (PDX), that we have generated by implanting kidney tumors from tRCC patients (after obtaining consent) into immunocompromised mouse kidneys. If successful, these experiments will lead to an innovative therapeutic approach to treat the most common form of tRCC. If clinically validated, the approach could be lifesaving for young tRCC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210092
Entities
People
- Gopinath Prakasam
Organizations
- United States Army
- University of Texas Southwestern Medical Center