Role of PRAME in Epigenetic Reprogramming and Chromosomal Instability
Principal Investigator: Stefan Kurtenbach, PhD
University of Miami
Mentor: J. William Harbour, MD
Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UM has a propensity to undergo early micrometastasis prior to treatment of the primary tumor, with later emergence of overt metastatic disease. Unfortunately, there has been no dramatic improvement in survival over the past half century. PRAME (Preferentially Expressed Antigen In Melanoma) is a gene that is usually only found in testis, is also found highly expressed in a variety of tumors. We have recently reported that PRAME does correlate with metastatic risk in UM, which is also true for many other cancer types including cutaneous melanoma. Besides the broad interest in PRAME, how PRAME promotes tumor progression and metastasis is not yet understood. In this proposal, we present preliminary data showing that PRAME is not only a biomarker for poor outcome, but plays a role in the formation of metastasis itself. We further show that PRAME expression may cause a defect in proper genomic DNA maintenance, which could be exploited for treatment with PARP inhibitors. Indeed, we present preliminary data for PARP inhibitors that is very promising, where UM cells expressing PRAME are more susceptible to PARP treatment. This proposal will cover two aims, where we intend to (1) generate a comprehensive map of where PRAME binds in the genome to regulate expression of genes involved in genomic instability and tumor progression, and (2) test PARP inhibitors for their suitability as a treatment option in our mouse metastasis model. For Aim 1, we will make use of a unique set of cell lines we have generated allowing for the inducible expression and knockdown of PRAME, including normal human uveal melanocytes, presenting a unique resource. Further, will use a variety of state-of-the-art next generation sequencing techniques to decipher the mechanism by which PRAME modulates gene expression. For Aim 2, we will utilize a mouse metastasis model we have established that allows for imaging of tumor growth and metastatic spread in live animals.
Together, the results of this proposal will draw a detailed picture of how PRAME re-shapes the epigenetic landscape around genes important for tumor development, as well as exploit PRAME’s function in chromosomal maintenance for treatment using a mouse model, which could have a strong translational impact in the clinical setting.