Evolution of Hypoxia-Inducible Factor Inhibitors for Renal Cell Carcinoma
Abstract
Renal cell carcinoma (RCC) is often a metabolically driven disease that encompasses > 10 different cancers classified by histological presentation. Each RCC subtype has unique genetic and proteomic characteristics resulting in distinct clinical presentation, prognosis, and therapeutic considerations. We propose to develop novel compounds to inhibit hypoxia inducible factor 1a (HIF1a) signaling in RCC. When cells begin growing in a low-oxygen environment (hypoxia) they turn on hypoxia inducible factor (HIF) signaling. When the HIF pathway is turned on, cells begin expressing proteins that are associated with increasing blood flow (vascularization), with increasing the utilization of glucose (glycolysis) and turning down the utilization of oxygen (oxidation phosphorylation). This pathway is turned on when proteins HIF1a or HIF2a combines with the aryl hydrocarbon receptor nuclear translocator protein (ARNT). It is this dimerization of HIF and ARNT that leads to the activation of multiple genes associated with cancer growth. In this proposal, we will develop new compounds to inhibit this dimerization We propose to design new drugs to inhibit HIF1a signaling through a process called Scanning Unnatural Protease Resistant (SUPR) peptide mRNA display. SUPR mRNA display uses evolution to identify peptides that bind tightly and selectively to protein targets such as HIF1a and HIF2a. In SUPR mRNA display, one starts with a library of trillions of peptides, which is then exposed to the target protein. Compounds in the library that bind to the target are amplified to generate a new library that again is exposed to the target protein. By repeating this process multiple times we can identify peptides that bind tightly to the target protein. These peptides can be made to be cell-permeable and have a long half-life in the bloodstream. Protein-protein interactions, such as HIF1a and ARNT, are difficult to disrupt. Because more binding interactions can occur between a cyclic peptide and a protein of interest compared to a small molecule, peptides are often better at inhibiting protein-protein interactions. Our hypothesis is that using SUPR mRNA display technology, we will be able to evolve highly selective and potent inhibitors of HIF1a that will reduce tumor growth in the hypoxia-driven clear cell RCC (ccRCC) and renal medullary carcinoma (RMC). Clear cell RCC accounts for 70% of RCC cases. Metastatic ccRCC usually initially responds to sunitinib, a first-line therapy, but over time a significant number of patients become unresponsive. Therefore, there is a pressing clinical need to develop novel therapies for the treatment of ccRCC. Approximately 90% of ccRCC tumors bear inactivating mutations in the von Hippel-Lindau (VHL) gene, which codes for the VHL protein. In normal tissue, HIF1a is produced by a cell when it experiences hypoxia (low oxygen). After normal oxygen levels return, the HIF1a protein is degraded through a protein complex involving the VHL protein. In ccRCC, mutated VHL leads to accumulation of HIF1a in the cell. Recent animal studies have demonstrated that HIF1a is essential for cancer growth and tumorigenesis in ccRCC. In addition, HIF1a was found to be expressed in tumor-associated macrophages (immune cells) in ccRCC and this expression of HIF1a was associated with higher tumor grade, increased metastasis, and lower overall survival. Renal medullary carcinoma (RMC) is a rare cancer (less than 1% of all RCC cases) but is the third most common RCC found in young patients and is resistant to all targeted therapies used in RCC. Unfortunately, an objective response is observed in only 29% of RMC patients with cytotoxic chemotherapy and the median survival is less than 12 months. Recent molecular characterization of RMC patient tissue reveals high RNA expression of HIF1a. The absence of clinical HIF1a inhibitors indicates an unmet need for a novel inhibitor that could significantly improve ove
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210435
Entities
People
- Niki Millward
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army