HTL-001 peptide is effective at inhibiting the function of a family of genes responsible for the growth of Glioblastoma Multiforme (GBM)


Findings from a seven-year research project suggests that there could be a new approach to treating one of the most common and devasting forms of brain cancer in adults – Glioblastoma Multiforme (GBM).

In a peer-reviewed study published by BMC Cancer, scientists from the University of Surrey show that a short chain of amino acids (the HTL-001 peptide) is effective at targeting and inhibiting the function of a family of genes responsible for the growth of GBM – Hox genes. The study was conducted in cell and animal models.

The HTL-001 peptide used in the study has undergone safety testing and is suitable for patient trials. These trials are now being considered in GBM and other cancers.

Hardev Pandha, project lead and Professor of Medical Oncology at the University of Surrey, said:

“People who suffer from Glioblastoma Multiforme have a five percent survival rate over a five-year period – a figure that has not improved in decades. While we are still early in the process, our seven-year project offers a glimmer of hope for finding a solution to Hox gene dysregulation, which is associated with the growth of GBM and other cancers, and which has proven to be elusive as a target for so many years.”

Ironically, Hox genes are responsible for the healthy growth of brain tissue but are ordinarily silenced at birth after vigorous activity in the growing embryo. However, if they are inappropriately ‘switched on’ again, their activity can lead to the progression of cancer. Hox gene dysregulation has long been recognized in GBM.

The project was carried out in collaboration with the universities of Surrey, Leeds and Texas, and HOX Therapeutics, a University of Surrey start-up company based on the University’s Surrey Research Park.

Professor Susan Short, co-author of the study from the University of Leeds, said:

“We desperately need new treatment avenues for these aggressive brain tumors. Targeting developmental genes like the HOX genes that are abnormally switched on in the tumor cells could be a novel and effective way to stop glioblastomas growing and becoming life-threatening.”

James Culverwell, CEO of HOX Therapeutics, said:

“HOX Therapeutics is excited to be associated with this project and we hope that with our continuing support, this research will eventually lead to novel and effective treatments for both brain and other cancers where HOX gene over-expression is a clear therapeutic target.”

Glioblastoma multiforme (GBM) is the most common malignant brain cancer, characterized by high invasiveness and poor prognosis. Docetaxel (DTX) is a chemotherapeutic drug with promising anti-tumor properties. However, conventional intravenous formulations exhibit side effects of systemic biodistribution and low brain bioavailability, limiting their clinical use. The current work aimed to evaluate the effect of DTX-loaded nanostructured lipid carriers (NLC) functionalized with bevacizumab (BVZ-NLC-DTX) against GBM using in vitro and in vivo models.

The NLC was obtained by the fusion-emulsification method followed by sonication, with narrow size distribution, negative zeta potential, and low polydispersity index. NLC showed DTX entrapment efficiency above 90%. BVZ coupling efficiency was 62% and BVZ integrity after functionalization was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Calorimetry studies confirmed thermal stability and molecular dispersion of DTX in the lipid matrix.

NLC showed a sustained DTX release over 84 h. In vitro anti-tumor assays shown that BVZ-NLC-DTX selectively increased the cytotoxic of DTX in cells overexpressing VEGF (U87MG and A172), but not in peripheral blood mononuclear cells (PMBCs), promoting cell death by apoptosis.

BVZ functionalization did not impair cellular uptake. An in vivo orthotopic rat model demonstrated that free-DTX was not capable of reducing tumor growth whereas BVZ-NLC-DTX reduced up to 70% tumor volume after 15-days of treatment. Therefore, this study contributes to understanding new nanotechnology-based vehicles capable of reaching the brain more efficiently and repurposing the use of anti-cancer drugs in GBM treatment.

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More information: Einthavy Arunachalam et al, HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme, BMC Cancer (2022). DOI: 10.1186/s12885-022-09466-8


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