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

被引：11

作者：

Arunachalam, Einthavy ^{[1
]}

Rogers, William ^{[1
]}

Simpson, Guy R. ^{[1
]}

Moller-Levet, Carla ^{[1
]}

Bolton, Gemma ^{[1
,2
]}

Ismael, Mohammed ^{[1
,2
]}

Smith, Christopher ^{[1
]}

Keegen, Karl ^{[2
]}

Bagwan, Izhar ^{[3
]}

Brend, Tim ^{[4
]}

Short, Susan C. ^{[4
]}

Hong, Bangxing ^{[5
]}

Otani, Yoshihiro ^{[5
]}

Kaur, Balveen ^{[5
]}

Annels, Nicola ^{[1
]}

Morgan, Richard ^{[6
]}

Pandha, Hardev ^{[1
]}

机构：

[1] Univ Surrey, Fac Hlth & Med Sci, Dept Clin & Expt Med, Targeted Canc Therapy, Guildford GU2 7WG, Surrey, England

[2] HOX Therapeut Ltd, Surrey Technol Ctr, Unit 2440 Occam Rd, Guildford GU2 7YG, Surrey, England

[3] Royal Surrey Cty Hosp, Dept Pathol, Egerton Rd, Guildford GU2 7XX, Surrey, England

[4] Univ Leeds, Fac Med & Hlth, Leeds Inst Med Res St Jamess, Leeds LS9 7TF, W Yorkshire, England

[5] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Neurosurg, 7000 Fannin St, Houston, TX 77030 USA

[6] Univ West London, Sch Biomed Sci, St Marys Rd, London W5 5RF, England

来源：

BMC CANCER | 2022年 / 22卷 / 01期

关键词：

Glioblastoma multiforme; HOX; PBX; Dysregulation; CANCER; CELLS; TUMORS; EXPRESSION; RESISTANCE; PROTEINS;

D O I：

10.1186/s12885-022-09466-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：13

共 46 条

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