HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme

Arunachalam, Einthavy, Rogers, William, Simpson, Guy, Moller-Levet, Carla, Bolton, Gemma, Ismael, Mohammed, Smith, Christopher, Keegen, Karl, Bagwan, Izhar, Brend, Tim, Short, Susan, Hong, Bangxing, Otani, Yoshihiro, Kaur, Balveen, Annels, Nicola, Morgan, Richard ORCID: https://orcid.org/0000-0002-8721-4479 and Pandha, Hardev (2022) HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme. BMC Cancer, 22 (1).

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Abstract

Background: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies.

Methods: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need.

Results: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines.

Conclusion: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.

Item Type: Article
Keywords: Glioblastoma Multiforme, HOX, PBX, Dysregulation
Subjects: Natural sciences > Cell and molecular biology
Related URLs:
Depositing User: Richard Morgan
Date Deposited: 18 May 2022 13:55
Last Modified: 15 Jun 2022 15:50
URI: http://repository.uwl.ac.uk/id/eprint/9093

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