BACKGROUND: Meningiomas are the most common type of intracranial tumor, accounting for between 24 and 30 % of primary intracranial tumors. Thus far, no biomarkers exist to reliably predict the clinical outcome of meningiomas. A previous genome-wide methylation analysis revealed that HOXA9 is one of the most functionally relevant biomarkers. In this study, we have examined whether HOXA9 is a potential therapeutic target in meningiomas, using HXR9, a peptide inhibitor of the interaction between HOXA9 and its cofactor PBX. METHODS: We determined the expression level of HOXA9 in human meningiomas, meningioma cell lines, and normal brain tissue. Meningioma in culture and in subcutaneous tumors was treated with HXR9. We also examined the disruption of HOXA9/PBX dimers. RESULTS: We first confirmed that HOXA9 is highly expressed in meningiomas, but not in normal brain tissue. The HXR9 peptide blocks the binding of HOXA9 to PBX, leading to an alteration of DNA binding, and subsequent regulation of their target genes. HXR9 markedly inhibited the growth of meningioma cells and subcutaneous meningeal tumors. CONCLUSION: There is no effective chemotherapy for meningiomas at present, and targeting the HOXA9/PBX interaction may represent a novel treatment option for this disease.
BACKGROUND:Meningiomas are the most common type of intracranial tumor, accounting for between 24 and 30 % of primary intracranial tumors. Thus far, no biomarkers exist to reliably predict the clinical outcome of meningiomas. A previous genome-wide methylation analysis revealed that HOXA9 is one of the most functionally relevant biomarkers. In this study, we have examined whether HOXA9 is a potential therapeutic target in meningiomas, using HXR9, a peptide inhibitor of the interaction between HOXA9 and its cofactor PBX. METHODS: We determined the expression level of HOXA9 in humanmeningiomas, meningioma cell lines, and normal brain tissue. Meningioma in culture and in subcutaneous tumors was treated with HXR9. We also examined the disruption of HOXA9/PBX dimers. RESULTS: We first confirmed that HOXA9 is highly expressed in meningiomas, but not in normal brain tissue. The HXR9 peptide blocks the binding of HOXA9 to PBX, leading to an alteration of DNA binding, and subsequent regulation of their target genes. HXR9 markedly inhibited the growth of meningioma cells and subcutaneous meningeal tumors. CONCLUSION: There is no effective chemotherapy for meningiomas at present, and targeting the HOXA9/PBX interaction may represent a novel treatment option for this disease.
Authors: Reem Malek; Rajendra P Gajula; Russell D Williams; Belinda Nghiem; Brian W Simons; Katriana Nugent; Hailun Wang; Kekoa Taparra; Ghali Lemtiri-Chlieh; Arum R Yoon; Lawrence True; Steven S An; Theodore L DeWeese; Ashley E Ross; Edward M Schaeffer; Kenneth J Pienta; Paula J Hurley; Colm Morrissey; Phuoc T Tran Journal: Cancer Res Date: 2017-05-08 Impact factor: 12.701
Authors: Christopher Platais; Raghu Radhakrishnan; Sven Niklander Ebensperger; Richard Morgan; Daniel W Lambert; Keith D Hunter Journal: BMC Cancer Date: 2018-07-06 Impact factor: 4.430
Authors: Richard Morgan; Angie Boxall; Kevin J Harrington; Guy R Simpson; Agnieszka Michael; Hardev S Pandha Journal: BMC Urol Date: 2014-02-05 Impact factor: 2.264