Abstract 4627: The role of human endogenous retroviral proteins in the development of Merlin-deficient tumors and as potential drug targets

Abstract

Abstract Neurofibromatosis Type 2 (NF2) is a genetic disorder caused by loss of the tumour suppressor Merlin leading to the development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas. Merlin-deficient tumours may also occur sporadically including all schwannomas, 50-60% meningiomas and 29-38% ependymomas. Loss of functional Merlin have been also observed in other tumours e.g. mesothelioma, melanoma, and a portion of glioma, prostate and breast cancers. Current therapies for Merlin-deficient tumours, comprising surgery and radiosurgery are invasive and not fully effective therefore the emphasis has to be made on the development of new effective drug-based treatments. Schwannoma is the most common Merlin-deficient tumour, a hallmark for NF2 and a model for all other Merlin-deficient tumours. We have developed the human in vitro model for schwannoma to study tumour pathobiology and for drug testing. Using this model we have shown strong overexpression and activation of ErbB2/ErbB32, platelet-derived growth factor receptor (PDGFR), Insulin like growth factor receptor-I (IGF-IR) and activation of Raf/MEK/ERK, PI3K/AKT and Wnt/β-catenin signalling pathways. Following, we have successfully tested new drugs such as AZD6244, Sorafenib, BEZ235, Lapatinib, Imatinib and Nilotinib. These studies revealed that schwannomas’ pathological proliferation, survival and adhesion is regulated by highly complex networks interacting and compensating each other resulting in increased tumour pathology. We suggest that the inhibition of a single target will not be sufficient to stop tumour growth and that multi-targeted therapy would be needed. Endogenous retroviruses are viruses that have integrated themselves into germ-line chromosomes and thereby become part of the human genome sequence (8%). One group, HERVK, has been found to be overexpressed in several cancers and is currently being investigated as potential immunotherapy targets. Our preliminary data demonstrate that HERVK envelope, capsid, Rec and Np9 proteins are overexpressed in human primary schwannoma cells and tissues. Additionally, HERVK envelope and capsid proteins are released from schwannoma cells. HERVK overexpression is regulated at both the transcriptional and translational level and is partially Merlin dependent. Anti-HERVK antibodies reduced schwannoma proliferation, pERK/pAKT/ pFAK and cyclin D1 levels and increased expression of p53. Also, pre-incubation of schwannoma cells with anti-HERVK antibodies prior to treatment with AZD6244 potentiated drug's efficiency. An HIV/HERVK protease inhibitor, Ritonavir, also decreased proliferation of schwannoma cells and increased the efficiency of AZD6244, Sorafenib and BEZ235 when combined. We suggest that HERVK plays a relevant role in schwannoma and possibly other Merlin-deficient tumours’ development and is a promising therapeutic target. Citation Format: Emmanuel Maze, Shona Reeves, David Hilton, Lucy Provenzano, Robert Belshaw, Sylwia Ammoun. The role of human endogenous retroviral proteins in the development of Merlin-deficient tumors and as potential drug targets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4627.