Paraganglioma: HIF-2a as a new biomarker and treatment target

Paragangliomas and pheochromocytomas (PPGLs) are mainly slow growing neuroendocrine tumors, however there is no treatment or cure for patients with metastatic disease. A fraction of PPGLs is driven by mutations in the EPAS1 gene (encoding HIF-2a), and these tumors present with poor outcome. PPGLs arise from cells of the transient embryonic structure neural crest. However, there is a lack of embryonic models for PPGL initiation studies, and the paucity of understanding the functional mechanisms of how HIF-2a cause aggressiveness and metastasis refrains us from identification of early diagnostic and prognostic markers, and novel therapeutic targets. To overcome these limitations, we use chick embryos as a proxy for a functional embryonic environment. We are creating PPGL cells expressing structural versions of HIF-2a and establish chick embryo models with and without expression of mutated HIF-2a to study its functional role in progenitor cell fate, migration, tumor initiation, disease aggressiveness and metastasis. We are also testing a novel antagonist of HIF-2a, with the potential to inhibit the tumor-promoting function of the protein. Basic and pre-clinical research of tumor initiation and progression lay the foundation for novel clinical interventions and improved patient outcome