Endogenous retroviral proteins as potential drug targets for merlin-deficient tumours
type: CreativeWork
description: Merlin is a tumour suppressor, and its loss is the major cause of a hereditary disease Neurofibromatosis type 2 (NF2) characterised by the development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas. Current surgical treatments and radiotherapy for this group of tumours are not fully effective and there is an urgent need for new therapeutic options. Human endogenous retroviruses (HERVs) are retroviruses that have been incorporated into the human genome during evolution, now comprising 5% of it. The majority of HERVs are defective except for a few groups, including type K (HERV-K) which kept full-intact open reading frames. HERV-K (HML-2) is transcriptionally active in many cancer tissues and tumour cell lines, and several studies have highlighted its role in cancer. Preliminary data showed overall HERV-K upregulation in Merlin-deficient schwannoma, and thus this project aims to investigate the role of HERV-K (HML-2) in Merlin-deficient schwannoma and meningioma development and to investigate the potential of HERV-K as a novel therapeutic target as well as testing anti-retroviral drugs’ efficacy for the treatment of these tumours. I have demonstrated that HERV-K (HML-2) Env overexpression (Env o/e) in primary Schwann cells resulted in increased proliferation and elevated expression of the transcription factor cJun. Env o/e also increased pERK1/2 activity and upregulated S phase cyclin A2. I have also revealed that HERV-K Env overexpression is regulated by TEAD-mediated transcription both in Merlin-deficient schwannoma and grade I meningioma. Furthermore, I have successfully tested the FDA approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir which could be potentially repurposed for the treatment of Merlin-deficient schwannoma and grade I meningioma. Ritonavir and Lopinavir effectively decreased the proliferation of Merlin-deficient primary schwannoma cells at concentrations much lower than have already…
abstract: Merlin is a tumour suppressor, and its loss is the major cause of a hereditary disease Neurofibromatosis type 2 (NF2) characterised by the development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas. Current surgical treatments and radiotherapy for this group of tumours are not fully effective and there is an urgent need for new therapeutic options. Human endogenous retroviruses (HERVs) are retroviruses that have been incorporated into the human genome during evolution, now comprising 5% of it. The majority of HERVs are defective except for a few groups, including type K (HERV-K) which kept full-intact open reading frames. HERV-K (HML-2) is transcriptionally active in many cancer tissues and tumour cell lines, and several studies have highlighted its role in cancer. Preliminary data showed overall HERV-K upregulation in Merlin-deficient schwannoma, and thus this project aims to investigate the role of HERV-K (HML-2) in Merlin-deficient schwannoma and meningioma development and to investigate the potential of HERV-K as a novel therapeutic target as well as testing anti-retroviral drugs’ efficacy for the treatment of these tumours. I have demonstrated that HERV-K (HML-2) Env overexpression (Env o/e) in primary Schwann cells resulted in increased proliferation and elevated expression of the transcription factor cJun. Env o/e also increased pERK1/2 activity and upregulated S phase cyclin A2. I have also revealed that HERV-K Env overexpression is regulated by TEAD-mediated transcription both in Merlin-deficient schwannoma and grade I meningioma. Furthermore, I have successfully tested the FDA approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir which could be potentially repurposed for the treatment of Merlin-deficient schwannoma and grade I meningioma. Ritonavir and Lopinavir effectively decreased the proliferation of Merlin-deficient primary schwannoma cells at concentrations much lower than have already…
author: Agit, Bora
language: eng
keywords: Cancer, Retrovirus, Neurofibromatosis, Schwannoma, Meningioma, Merlin
date published: 2022-01-01T08:00:00Z
date modified: 2026-07-24T03:50:32Z
provider: University of Plymouth
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Plymouth