Targeting GPNMB in Renal Tumors in Tuberous Sclerosis Complex and Translocation Renal Cell Carcinoma
Abstract
The current work will address the following KCRP Focus Area: Define the biology of rare kidney cancers and develop treatments to improve outcomes and reduce death. The MiT/TFE proteins (such as TFE3 and TFEB) are known oncogenes involved in so-called translocation renal cell carcinomas (tRCC) and in normal cells their activity is thought to be suppressed by mTORC1 signaling. Surprisingly, we recently found that increased mTORC1 activity (as seen in tuberous sclerosis complex TSC) also drives MiT/TFE activity in renal cells and tumors. The mechanisms of tumor formation by MiT/TFE proteins are not well understood, and despite considerable advances in our understanding of the basic biology of MiT/TFE function, we have not successfully leveraged this knowledge for detection or treatment of renal tumors driven by TFE3 and TFEB. GPNMB is a known oncogenic factor and transcriptional target downstream of TFE3 and TFEB, which is highly upregulated when these proteins are active. Accordingly, GPNMB expression is increased in many MiT/TFE-driven tumors like tRCC, as well as mTORC1-driven tumors. GPNMB may be a sensitive biomarker for these tumors when it is secreted, however, its role in tumorigenesis has not been investigated. Here, we will comprehensively examine whether GPNMB upregulation promotes tumor formation in tRCC and mTORC1-related renal tumors and test whether it may be a novel therapeutic target or biomarker in this disease. Importantly, GPNMB is a transmembrane protein and has been targeted by a fully human anti-GPNMB antibody that has been tested in clinical trials where it was conjugated to a cellular toxin. Radiotherapy with alpha-particle emitters (aRPT), is emerging as a superior form of targeted therapy with increased biological effectiveness, minimal damage to normal cells, and decreased susceptibility to normal mechanisms of tumor cell resistance, but its therapeutic potential has been untested in tRCC and renal tumors associated with mTORC1 activation. Thus, we will also develop and characterize an alpha-emitting radionuclide (225Ac), coupled with a highly selective, clinically tested anti-GPNMB antibody, and evaluate its therapeutic efficacy in reducing tumor growth in tRCC or renal tumors driven by mTORC1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210377
Entities
People
- Kaushal Asrani
Organizations
- Johns Hopkins University
- United States Army