PET Imaging of HIF-2a in Renal Cancer
Abstract
Despite extensive new therapies, most patients with metastatic renal cell carcinoma (RCC) do not reach the 5- year benchmark. Hypoxia inducible factor 2 alpha (HIF2alpha) is arguably the most important driver of clear cell RCC (ccRCC), but it was previously thought to be undruggable. This project is built upon an extraordinary journey from gene discovery to the recent approval by the U.S. Food and Drug Administration (FDA) of an HIF2alpha inhibitor, belzutifan, for patients with von Hippel-Lindau disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors. Notably, this is a unique University of Texas Southwestern Medical Center (UT Southwestern) journey that started with the discovery of the HIF2alpha gene (EPAS1), which was followed by structural studies of the protein that recognized a vulnerability and then a chemical screen that identified small molecule inhibitors. While HIF2alpha represents a core dependency, only about 50% of ccRCC patients benefit from HIF2alpha inhibitors and biomarkers to identify these patients are lacking. While circulating erythropoietin is controlled by HIF2alpha and has been used as a pharmacodynamic marker, erythropoietin downregulation by HIF2alpha inhibitors simply indicates that appropriate circulating levels of the drug have been achieved, and it does not speak to the tumor dependency on HIF2alpha. Importantly, our previous studies show that HIF2alpha-dependent tumors have higher levels of HIF2alpha expression than those that are resistant. Thus, we hypothesize that HIF2alpha levels may serve as a predictive biomarker of HIF2alpha inhibitor activity. However, measuring HIF2alpha levels in tissues is challenging. Indeed, RCC is well known for its heterogeneity. Furthermore, it has been shown that multiple biopsies are necessary to comprehensively sample a tumor. This is, however, not feasibly clinically and alternatives to evaluate potentially predictive biomarkers, such as HIF2alpha, are urgently needed. A viable approach may involve molecular imaging. Imaging approaches would also have the advantage of offering noninvasive, quantitative, and real-time measurements of HIF2alpha levels across sites of disease. We have been successful in the generation of an 18FPT2385 radiotracer that is identical to PT2385, a first-generation HIF2alpha inhibitor, and obtained an investigational new drug approval (IND156933) from the FDA and opened a clinical trial (NCT04989959). To date, we have completed seven positron emission tomography (PET) scans with 18FPT2385 in human subjects, which showed the high net influx of the radiotracer in 2/3 of HIF2alpha positive tumors demonstrating the promising potential of deriving HIF2alpha inhibitors to develop radiotracers for HIF2alpha imaging. However, the tumor uptake was limited likely due to rapid metabolism of the radiotracer (PT2385 glucuronidation occurs in humans but not in mice). While 18FPT2385 may find applications to evaluate the biliary tree, which represents an unmet medical need, in this project we propose to develop an optimized radiotracer to image HIF2alpha using a second-generation HIF2alpha inhibitor, PT2977, which was developed, precisely, to escape glucuronidation in humans. In this project, we have proposed a practical synthetic route to 18FPT2977 based on our established experience in developing 18FPT2385. To evaluate the proposed imaging of HIF2alpha, we will perform a set of experiments with 18FPT2977 in mouse models using RCC tumorgraft lines expressing high and low HIF2alpha levels to validate the anticipated correlation between PET signal readout and expression of HIF2alpha. Radiation dosimetry will be assessed by using bio-distribution along with the clearance data. Later, we will follow the same procedures as we did with 18FPT2385 to validate the production reliability and reproducibility for an FDA IND application towards the transl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310904
Entities
People
- James Brugarolas
Organizations
- United States Army
- University of Texas Southwestern Medical Center